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CHEMBL1255352 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Polyclonal population structure of Streptococcus pneumoniae isolates in Spain carrying mef and mef plus erm(B). | 18362188 | 10.1128/aac.01487-07 | nan | de la Pedrosa EG, Morosini MI, van der Linden M, Ruiz-Garbajosa P, Galán JC, Baquero F, Reinert RR, Cantón R. | 2008 | 52 | 6 | 1964 | 1969 | PUBLICATION | The population structure (serotypes, pulsed-field gel electrophoresis [PFGE] types, and multilocus sequencing types) of 45 mef-positive Streptococcus pneumoniae isolates [carrying mef alone (n = 17) or with the erm(B) gene n = 28)] were studied. They were selected from among all erythromycin-resistant isolates (n = 244) obtained from a collection of 712 isolates recovered from different Spanish geographic locations in the prevaccination period from 1999 to 2003. The overall rates of resistance (according to the criteria of the CLSI) among the 45 mef-positive isolates were as follows: penicillin G, 82.2%; cefotaxime, 22.2%; clindamycin, 62.2%; and tetracycline, 68.8% [mainly in isolates carrying erm(B) plus mef(E); P < 0.001]. No levofloxacin or telithromycin resistance was found. Macrolide resistance phenotypes (as determined by the disk diffusion approximation test) were 37.7% for macrolide resistance [with all but one due to mef(E)] and 62.2% for constitutive macrolide-lincosamide-streptogramin B resistance [cMLS(B); with all due to mef(E) plus erm(B)]. Serotypes 14 (22.2%), 6B (17.7%), 19A (13.3%), and 19F (11.1%) were predominant. Twenty-five different DNA patterns (PFGE types) were observed. Our mef-positive isolates were grouped (by eBURST analysis) into four clonal complexes (n = 18) and 19 singleton clones (n = 27). With the exception of clone Spain(9V)-3, all clonal complexes (clonal complexes 6B, Spain(6B)-2, and Sweden(15A)-25) and 73.6% of singleton clones carried both the erm(B) and the mef(E) genes. The international multiresistant clones Spain(23F)-1 and Poland(6B)-20 were represented as singleton clones. A high proportion of mef-positive S. pneumoniae isolates presented the erm(B) gene, with all isolates expressing the cMLS(B) phenotype. A polyclonal population structure was demonstrated within our Spanish mef-positive S. pneumoniae isolates, with few clonal complexes overrepresented within this collection. | 7 | 1 | 64 | CHEMBL_10 | 2011-05-26 |
CHEMBL1240374 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Selection of mutations to detect multidrug-resistant Mycobacterium tuberculosis strains in Shanghai, China. | 20008778 | 10.1128/aac.00964-09 | nan | Luo T, Zhao M, Li X, Xu P, Gui X, Pickerill S, DeRiemer K, Mei J, Gao Q. | 2010 | 54 | 3 | 1075 | 1081 | PUBLICATION | Novel tools are urgently needed for the rapid, reliable detection of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. To develop such tools, we need information about the frequency and distribution of the mycobacterial mutations and genotypes that are associated with phenotypic drug resistance. In a population-based study, we sequenced specific genes of M. tuberculosis that were associated with resistance to rifampin and isoniazid in 242 phenotypically MDR isolates and 50 phenotypically pan-susceptible isolates from tuberculosis (TB) cases in Shanghai, China. We estimated the sensitivity and specificity of the mutations, using the results of conventional, culture-based phenotypic drug susceptibility testing as the standard. We detected mutations within the 81-bp core region of rpoB in 96.3% of phenotypically MDR isolates. Mutations in two structural genes (katG and inhA) and two regulatory regions (the promoter of mabA-inhA and the intergenic region of oxyR-ahpC) were found in 89.3% of the MDR isolates. In total, 88.0% (213/242 strains) of the phenotypic MDR strains were confirmed by mutations in the sequenced regions. Mutations in embB306 were also considered a marker for MDR and significantly increased the sensitivity of the approach. Based on our findings, an approach that prospectively screens for mutations in 11 sites of the M. tuberculosis genome (rpoB531, rpoB526, rpoB516, rpoB533, and rpoB513, katG315, inhA-15, ahpC-10, ahpC-6, and ahpC-12, and embB306) could detect 86.8% of MDR strains in Shanghai. This study lays the foundation for the development of a rapid, reliable molecular genetic test to detect MDR strains of M. tuberculosis in China. | 2 | 1 | 30 | CHEMBL_10 | 2011-05-26 |
CHEMBL1145954 | Journal of medicinal chemistry. | 1 | Scientific Literature | Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selection pressure of the biological target. | 12540234 | 10.1021/jm025589m | nan | Hochgürtel M, Biesinger R, Kroth H, Piecha D, Hofmann MW, Krause S, Schaaf O, Nicolau C, Eliseev AV. | 2003 | 46 | 3 | 356 | 358 | PUBLICATION | New and potent inhibitors of neuraminidase, a key enzyme in the influenza virus activity, have been discovered in dynamic combinatorial libraries based on ketones and amines as building blocks. Selective synthesis of a number of inhibitors among multiple theoretically possible combinations of building blocks is driven by the presence of the target enzyme. | 6 | 1 | 6 | CHEMBL_1 | 2009-09-03 |
CHEMBL1130732 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Homologated aza analogs of arabinose as antimycobacterial agents. | 9871661 | 10.1016/s0960-894x(98)00017-1 | nan | Maddry JA, Bansal N, Bermudez LE, Comber RN, Orme IM, Suling WJ, Wilson LN, Reynolds RC. | 1998 | 8 | 3 | 237 | 242 | PUBLICATION | A series of hydrolytically-stable aza analogs of arabinofuranose was prepared and evaluated against Mycobacterium tuberculosis and M. avium. The compounds were designed to mimic the putative arabinose donor involved in biogenesis of the essential cell wall polysaccharide, arabinogalactan. Though most compounds displayed little activity in cell culture, one compound showed significant activity in infected macrophage models. | 17 | 2 | 72 | CHEMBL_1 | 2009-09-03 |
CHEMBL3102779 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma. | 24326277 | 10.1016/j.bmc.2013.11.003 | nan | Paige M, Kosturko G, Bulut G, Miessau M, Rahim S, Toretsky JA, Brown ML, Üren A. | 2014 | 22 | 1 | 478 | 487 | PUBLICATION | Respiratory failure due to pulmonary metastasis is the major cause of death for patients with osteosarcoma. However, the molecular basis for metastasis of osteosarcoma is poorly understood. Recently, ezrin, a member of the ERM family of proteins, has been associated with osteosarcoma metastasis to the lungs. The small molecule NSC 668394 was identified to bind to ezrin, inhibit in vitro and in vivo cell migration, invasion, and metastatic colony survival. Reported herein are the design and synthesis of analogues of NSC 668394, and subsequent functional ezrin inhibition studies. The binding affinity was characterized by surface plasmon resonance technique. Cell migration and invasion activity was determined by electrical cell impedance methodology. Optimization of a series of heterocyclic-dione analogues led to the discovery of compounds 21k and 21m as potential novel antimetastatic agents. | 18 | 6 | 68 | CHEMBL_19 | 2014-07-03 |
CHEMBL3352621 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Pentapeptide boronic acid inhibitors of Mycobacterium tuberculosis MycP1 protease. | 24915878 | 10.1016/j.bmcl.2014.05.056 | nan | Frasinyuk MS, Kwiatkowski S, Wagner JM, Evans TJ, Reed RW, Korotkov KV, Watt DS. | 2014 | 24 | 15 | 3546 | 3548 | PUBLICATION | Mycosin protease-1 (MycP1) cleaves ESX secretion-associated protein B (EspB) that is a virulence factor of Mycobacterium tuberculosis, and accommodates an octapeptide, AVKAASLG, as a short peptide substrate. Because peptidoboronic acids are known inhibitors of serine proteases, the synthesis and binding of a boronic acid analog of the pentapeptide cleavage product, AVKAA, was studied using MycP1 variants from Mycobacterium thermoresistible (MycP1mth), Mycobacterium smegmatis (MycP1msm) and M. tuberculosis (MycP1mtu). We synthesized the boropentapeptide, HAlaValLysAlaAlaB(OH)2 (1) and the analogous pinanediol PD-protected HAlaValLysAlaAlaBO2(PD) (2) using an Fmoc/Boc peptide strategy. The pinanediol boropentapeptide 2 displayed IC50 values 121.6±25.3 μM for MycP1mth, 93.2±37.3 μM for MycP1msm and 37.9±5.2 μM for MycP1mtu. Such relatively strong binding creates a chance for crystalizing the complex with 2 and finding the structure of the unknown MycP1 catalytic site that would potentially facilitate the development of new anti-tuberculosis drugs. | 2 | 1 | 6 | CHEMBL_21 | 2016-02-01 |
CHEMBL3272150 | Journal of medicinal chemistry. | 1 | Scientific Literature | Studies on antianaphylactic agents. 5. Synthesis of 3-(1H-tetrazol-5-yl)chromones, a new series of antiallergic substances. | 13214 | 10.1021/jm00211a030 | nan | Nohara A, Kuriki H, Saijo T, Sugihara H, Kanno M, Sanno Y. | 1977 | 20 | 1 | 141 | 145 | PUBLICATION | A number of 3-(1H-tetrazol-5-yl)chromones were synthesized and found to have antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test. These compounds are active when administered orally in rats and of possible value for the treatment of asthma. | 32 | 2 | 40 | CHEMBL_20 | 2015-01-14 |
CHEMBL3397035 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Spectral and biological evaluation of a synthetic antimicrobial peptide derived from 1-aminocyclohexane carboxylic acid. | 25684423 | 10.1016/j.bmc.2015.01.027 | nan | Abercrombie JJ, Leung KP, Chai H, Hicks RP. | 2015 | 23 | 6 | 1341 | 1347 | PUBLICATION | Ac-GF(A6c)G(A6c)K(A6c)G(A6c)F(A6c)G(A6c)GK(A6c)KKKK-amide (A6c=1-aminocyclohexane carboxylic acid) is a synthetic antimicrobial peptide (AMP) that exhibits in vitro inhibitory activity against drug resistant strains of Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter aerogenes, and Enterococcus faecium at concentrations ranging from 10.9 to 43μM. Spectroscopic investigations were conducted to determine how this AMP interacts with simple membrane model systems in order to provide insight into possible mechanisms of action. CD and 2D-(1)H NMR experiments indicated this AMP on binding to SDS and DPC micelles adopts conformations with varying percentages of helical and random coil conformers. CD investigations in the presence of three phospholipid SUVs consisting of POPC, 4:1 POPC/POPG, and 60% POPE/21%POPG/19%POPC revealed: (1) The interactions occurring with POPC SUVs have minimal effect on the conformational diversity of the AMP yielding conformations similar to those observed in buffer. (2) The interactions with 4:1 POPC/POPG, and 60% POPE/21%POPG/19%POPC SUVs exhibited a greater influence on the percentage of different conformers contributing to the CD spectra. (3) The presence of a high of percentage of helical conformers was not observed in the presence of SUVs as was the case with micelles. This data indicates that the diversity of surface bound conformations adopted by this AMP are very different from the diversity of conformations adopted by this AMP on insertion into the lipid bilayer. CD spectra of this AMP in the presence of SUVs consisting of LPS isolated from P. aeruginosa, K. pneumoniae and Escherichia coli exhibited characteristics associated with various helical conformations. | 1 | 9 | 14 | CHEMBL_21 | 2016-02-01 |
CHEMBL3045565 | European journal of medicinal chemistry. | 1 | Scientific Literature | Microwave synthesis, characterization and bio-efficacy evaluation of novel chalcone based 6-carbethoxy-2-cyclohexen-1-one and 2H-indazol-3-ol derivatives. | 23229055 | 10.1016/j.ejmech.2012.10.038 | nan | Shakil NA, Singh MK, Sathiyendiran M, Kumar J, Padaria JC. | 2013 | 59 | nan | 120 | 131 | PUBLICATION | Novel chalcone based 6-carbethoxy-2-cyclohexen-1-one and 2H-indazol-3-ol derivatives were synthesized and characterized by using spectral techniques like IR, (1)H NMR, (13)C NMR, COSY, DEPT, and GC-MS. All these compounds were screened for anti-fungal, anti-bacterial and anti-oxidant activity. Cyclohexenone derivatives, in general, showed better anti-fungal and anti-bacterial activity than parent chalcones. Whereas, all the Indazole derivatives showed very good anti-oxidant activity and some were also found to be active as anti-bacterial agent. Among the screened compounds, 15 was found to be most active as anti-fungal agent (against Rhizoctonia solani, LC(50) = 2.36 μg mL(-1)), 15b was found to be most active anti-bacterial agent (against Klebsiella pneumonia, MIC = 24.68 μg mL(-1)) and 14b emerged as most active anti-oxidant (IC(50) = 19.81 μg mL(-1)). | 53 | 10 | 695 | CHEMBL_19 | 2014-07-03 |
CHEMBL1275489 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | The KQ element, a complex genetic region conferring transferable resistance to carbapenems, aminoglycosides, and fluoroquinolones in Klebsiella pneumoniae. | 18573935 | 10.1128/aac.00493-08 | nan | Rice LB, Carias LL, Hutton RA, Rudin SD, Endimiani A, Bonomo RA. | 2008 | 52 | 9 | 3427 | 3429 | PUBLICATION | The bla(KPC-3) and qnrB19 determinants of transferable Klebsiella pneumoniae plasmid pLRM24 reside within a complex region consisting of a Tn1331 backbone into which a Tn4401-like element and qnrB19 mobilized by an adjacent ISEcp1 insertion sequence have been inserted. This novel element represents a coalescence of genes conferring multidrug resistance in K. pneumoniae. | 1 | 1 | 1 | CHEMBL_10 | 2011-05-26 |
CHEMBL3352347 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | ΔF508-CFTR correctors: synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles. | 25452003 | 10.1016/j.bmcl.2014.09.067 | nan | Ye L, Hu B, El-Badri F, Hudson BM, Phuan PW, Verkman AS, Tantillo DJ, Kurth MJ. | 2014 | 24 | 24 | 5840 | 5844 | PUBLICATION | The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry. | 7 | 1 | 14 | CHEMBL_21 | 2016-02-01 |
CHEMBL1221167 | Nature chemical biology. | 1 | Scientific Literature | Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis. | 16407990 | 10.1038/nchembio706 | nan | Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LE. | 2005 | 1 | 1 | 29 | 32 | PUBLICATION | Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health and potential use as agents of bioterrorism. Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity. Several lines of evidence suggest that siderophores have a critical role in bacterial iron acquisition inside the human host, where the free iron concentration is well below that required for bacterial growth and virulence. Thus, siderophore biosynthesis is an attractive target in the development of new antibiotics to treat tuberculosis and plague. In particular, such drugs, alone or as part of combination therapies, could provide a valuable new line of defense against intractable multiple-drug-resistant infections. Here, we report the design, synthesis and biological evaluation of a mechanism-based inhibitor of domain salicylation enzymes required for siderophore biosynthesis in M. tuberculosis and Y. pestis. This new antibiotic inhibits siderophore biosynthesis and growth of M. tuberculosis and Y. pestis under iron-limiting conditions. | 3 | 5 | 14 | CHEMBL_9 | 2011-01-20 |
CHEMBL1130757 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthetic arabinofuranosyl oligosaccharides as mycobacterial arabinosyltransferase substrates. | 9871594 | 10.1016/s0960-894x(98)00049-3 | nan | Ayers JD, Lowary TL, Morehouse CB, Besra GS. | 1998 | 8 | 5 | 437 | 442 | PUBLICATION | A series of arabinofuranosyl oligosaccharides found as constituent parts of the polysaccharide portion of the cell wall of Mycobacterium tuberculosis have been chemically synthesized. Screening of these oligosaccharides as substrates for arabinosyltransferases present in mycobacterial membrane preparations suggests that modified oligosaccharide analogs as small as disaccharides may be inhibitors of glycan biosynthesis. Such inhibitors would be of potential utility as lead compounds in the identification of new drugs for the treatment of mycobacterial infections. | 6 | 1 | 23 | CHEMBL_1 | 2009-09-03 |
CHEMBL3352813 | Journal of natural products. | 1 | Scientific Literature | Prostaglandin Derivatives: Nonaromatic Phosphodiesterase-4 Inhibitors from the Soft Coral Sarcophyton ehrenbergi. | 25075977 | 10.1021/np500394d | nan | Cheng ZB, Deng YL, Fan CQ, Han QH, Lin SL, Tang GH, Luo HB, Yin S. | 2014 | 77 | 8 | 1928 | 1936 | PUBLICATION | Ten new prostaglandin derivatives (PGs), sarcoehrendins A-J (1-10), together with five known analogues (11-15) were isolated from the soft coral Sarcophyton ehrenbergi. Compounds 4-8 represented the first examples of PGs featuring an 18-ketone group. The structures including the absolute configurations were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates and six synthetic analogues (3a, 3b, 4a, and 11a-11c) were screened for inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 2, 10, 11a, 11b, and 13-15 exhibited inhibition with IC50 values less than 10 μM, and compound 15 (IC50 = 1.4 μM) showed comparable activity to the positive control rolipram (IC50 = 0.60 μM). The active natural PGs (2, 10, and 13-15) represent the first examples of PDE4 inhibitors without an aromatic moiety, and a preliminary structure-activity relationship is also proposed. | 22 | 1 | 33 | CHEMBL_21 | 2016-02-01 |
CHEMBL1146640 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | A new 2-carbamoyl pteridine that inhibits mycobacterial FtsZ. | 15149666 | 10.1016/j.bmcl.2004.04.012 | nan | Reynolds RC, Srivastava S, Ross LJ, Suling WJ, White EL. | 2004 | 14 | 12 | 3161 | 3164 | PUBLICATION | The preparation of a new 2-carbamoyl pteridine, its activity data against FtsZ from M. tuberculosis (Mtb), and in vitro antibacterial data against Mtb strain H37Ra are presented. | 2 | 2 | 8 | CHEMBL_1 | 2009-09-03 |
CHEMBL3297728 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antituberculosis activity of novel 5-styryl-4-(hetero)aryl-pyrimidines via combination of the Pd-catalyzed Suzuki cross-coupling and S(N)(H) reactions. | 24856062 | 10.1016/j.bmcl.2014.05.006 | nan | Kravchenko MA, Verbitskiy EV, Medvinskiy ID, Rusinov GL, Charushin VN. | 2014 | 24 | 14 | 3118 | 3120 | PUBLICATION | Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SN(H)) reactions proved to be a convenient method for the synthesis of 5-styryl-4-(hetero)aryl substituted pyrimidines from commercially available 5-bromopyrimidine. All intermediate 5-bromo-4-(hetero)aryl substituted pyrimidines and also the targeted 5-styryl-4-(hetero)arylpyrimidines were found to be active in micromolar concentrations in vitro against Mycobacterium tuberculosis H37Rv, avium, terrae, and multi-drug-resistant strain isolated from tuberculosis patients in Ural region (Russia). It has been found that some of these compounds possess a low toxicity and have a bacteriostatic effect, comparable and even higher with that of first-line antituberculosis drugs. | 17 | 4 | 84 | CHEMBL_20 | 2015-01-14 |
CHEMBL3244318 | Journal of medicinal chemistry. | 1 | Scientific Literature | Prostaglandins and congeners. 14. Synthesis and bronchodilator activity of dl-16,16-trimethyleneprostaglandins. | 894672 | 10.1021/jm00218a010 | nan | Skotnicki JS, Schaub RE, Weiss MJ. | 1977 | 20 | 8 | 1042 | 1047 | PUBLICATION | The interesting bronchodilator activity of novel dl-16,16-trimethyleneprostaglandin congeners and their preparation via the conjugate addition of the appropriate vinyl lithiocuprate reagent to several cyclopentenones are described. Also discussed is the preparation of the key intermediate vinyl iodine 7. | 33 | 2 | 97 | CHEMBL_20 | 2015-01-14 |
CHEMBL1153717 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. | 19889539 | 10.1016/j.bmcl.2009.10.090 | nan | Rawls KA, Lang PT, Takeuchi J, Imamura S, Baguley TD, Grundner C, Alber T, Ellman JA. | 2009 | 19 | 24 | 6851 | 6854 | PUBLICATION | The development of low muM inhibitors of the Mycobacterium tuberculosis phosphatase PtpA is reported. The most potent of these inhibitors (K(i)=1.4+/-0.3 microM) was found to be selective when tested against a panel of human tyrosine and dual-specificity phosphatases (11-fold vs the highly homologous HCPtpA, and >70-fold vs all others tested). Modeling the inhibitor-PtpA complexes explained the structure-activity relationships observed in vitro and revealed further possibilities for compound development. | 43 | 9 | 57 | CHEMBL_6 | 2010-08-27 |
CHEMBL1629559 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Real-time PCR detection of gyrA and parC mutations in Streptococcus pneumoniae. | 18725440 | 10.1128/aac.00082-08 | nan | Page S, Vernel-Pauillac F, O'Connor O, Bremont S, Charavay F, Courvalin P, Goarant C, Le Hello S. | 2008 | 52 | 11 | 4155 | 4158 | PUBLICATION | Fluoroquinolone resistance in Streptococcus pneumoniae mainly involves stepwise mutations predominantly in the parC and gyrA genes. We have developed a single-run real-time PCR assay for detection of the four most common mutations in the quinolone resistance-determining regions of these genes. This assay provides a useful tool for both clinical and epidemiological use. | 7 | 1 | 247 | CHEMBL_11 | 2011-08-01 |
CHEMBL1136204 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Thymidine and thymidine-5'-O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase. | 12941330 | 10.1016/s0960-894x(03)00643-7 | nan | Vanheusden V, Van Rompaey P, Munier-Lehmann H, Pochet S, Herdewijn P, Van Calenbergh S. | 2003 | 13 | 18 | 3045 | 3048 | PUBLICATION | The affinity of a series of 2', 3'- and 5-modified thymidine analogues for Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) was evaluated. The affinities of several non-phosphorylated analogues are in the same order of magnitude as those of their phosphorylated congeners. In view of drug delivery problems associated with phosphorylated compounds, these 'free' nucleosides seem more promising leads in the search of TMPKmt inhibitors as novel anti-tuberculosis agents. | 36 | 1 | 43 | CHEMBL_1 | 2009-09-03 |
CHEMBL1255347 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Multiclonal outbreak of Klebsiella pneumoniae producing extended-spectrum beta-lactamase CTX-M-2 and novel variant CTX-M-59 in a neonatal intensive care unit in Brazil. | 18347108 | 10.1128/aac.01440-07 | nan | de Oliveira Garcia D, Doi Y, Szabo D, Adams-Haduch JM, Vaz TM, Leite D, Padoveze MC, Freire MP, Silveira FP, Paterson DL. | 2008 | 52 | 5 | 1790 | 1793 | PUBLICATION | An outbreak of cephalosporin-resistant Klebsiella pneumoniae occurred in a neonatal intensive care unit in São Paulo, Brazil. Of the 10 pulsotypes identified during the outbreak and follow-up periods, nine produced CTX-M-2 or its new variant CTX-M-59 and one produced SHV-5. bla(CTX-M-2/59) genes were located on closely related plasmids that were transferable. | 7 | 2 | 184 | CHEMBL_10 | 2011-05-26 |
CHEMBL1212759 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Antifungal activity of colistin against mucorales species in vitro and in a murine model of Rhizopus oryzae pulmonary infection. | 19858263 | 10.1128/aac.00956-09 | nan | Ben-Ami R, Lewis RE, Tarrand J, Leventakos K, Kontoyiannis DP. | 2010 | 54 | 1 | 484 | 490 | PUBLICATION | In immunosuppressed hosts, mucormycosis is a life-threatening infection with few treatment options. We studied the activity of colistin (polymyxin E) against Mucorales species in vitro and in a murine model of pulmonary Rhizopus oryzae infection. Colistin exhibited fungicidal activity in vitro against Mucorales spores and mycelia. At the colistin MIC, initial R. oryzae hyphal damage was followed by rapid regrowth; however, regrowth was prevented by combining colistin with a subinhibitory concentration of amphotericin B. Using electron microscopy and FM4-64 staining, we demonstrated that colistin disrupts R. oryzae cytoplasmic and vacuolar membranes, resulting in the leakage of intracellular contents. The prophylactic intranasal treatment of immunosuppressed mice with colistimethate significantly reduced the mortality rate and pulmonary fungal burden resulting from inhalational challenge with R. oryzae spores, whereas intraperitoneal colistimethate treatment had no effect. We conclude that colistin has modest in vitro and in vivo fungicidal activity against Mucorales spp. Further studies are warranted to assess the use of this drug in the prevention and treatment of mucormycosis. | 3 | 5 | 104 | CHEMBL_9 | 2011-01-20 |
CHEMBL1154641 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Carbonic anhydrase inhibitors. Characterization and inhibition studies of the most active beta-carbonic anhydrase from Mycobacterium tuberculosis, Rv3588c. | 19846301 | 10.1016/j.bmcl.2009.10.009 | nan | Carta F, Maresca A, Covarrubias AS, Mowbray SL, Jones TA, Supuran CT. | 2009 | 19 | 23 | 6649 | 6654 | PUBLICATION | The Rv3588c gene product of Mycobacterium tuberculosis, a beta-carbonic anhydrase (CA, EC 4.2.1.1) denominated here mtCA 2, shows the highest catalytic activity for CO(2) hydration (k(cat) of 9.8 x 10(5)s(-1), and k(cat)/K(m) of 9.3 x 10(7)M(-1)s(-1)) among the three beta-CAs encoded in the genome of this pathogen. A series of sulfonamides/sulfamates was assayed for their interaction with mtCA 2, and some diazenylbenzenesulfonamides were synthesized from sulfanilamide/metanilamide by diazotization followed by coupling with amines or phenols. Several low nanomolar mtCA 2 inhibitors have been detected among which acetazolamide, ethoxzolamide and some 4-diazenylbenzenesulfonamides (K(I)s of 9-59 nM). As the Rv3588c gene was shown to be essential to the growth of M. tuberculosis, inhibition of this enzyme may be relevant for the design of antituberculosis drugs possessing a novel mechanism of action. | 37 | 3 | 81 | CHEMBL_4 | 2010-05-18 |
CHEMBL1148365 | Journal of medicinal chemistry. | 1 | Scientific Literature | Rational design of new antituberculosis agents: receptor-independent four-dimensional quantitative structure-activity relationship analysis of a set of isoniazid derivatives. | 15239654 | 10.1021/jm049913k | nan | Pasqualoto KF, Ferreira EI, Santos-Filho OA, Hopfinger AJ. | 2004 | 47 | 15 | 3755 | 3764 | PUBLICATION | A 4D-QSAR analysis was carried out for a set of 37 hydrazides whose minimum inhibitory concentrations against M. tuberculosis var. bovis were evaluated. These ligands are thought to act like isoniazid in mycolic acid biosynthesis. Results indicate that nonpolar groups in the acyl moiety of ligands markedly decrease biological activity. Molecular modifications of the ligand NAD moiety, including nonpolar groups and hydrogen bond donor and acceptor groups, seemingly improve ligand interactions with amino acid residues of the InhA active site. | 37 | 1 | 37 | CHEMBL_1 | 2009-09-03 |
CHEMBL1122389 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and substituent effects on antibacterial activity, alkaline hydrolysis rates, and infrared absorption frequencies of some cephem analogues related to latamoxef (moxalactam). | 6631914 | 10.1021/jm00365a006 | nan | Narisada M, Yoshida T, Ohtani M, Ezumi K, Takasuka M. | 1983 | 26 | 11 | 1577 | 1582 | PUBLICATION | Relationships between intrinsic antibacterial activity and beta-lactam reactivity of 7 beta-[(4-hydroxyphenyl)acetyl]amino- and 7 beta-[(4-hydroxyphenyl)malonyl]amino derivatives of 1-oxa- and 1-thiacephems, with or without the 7 alpha-methoxy group (1-8), were investigated in order to clarify the enhanced antibacterial activity of latamoxef disodium (1). Substituent effects of a carbon atom at the 1- and 7 alpha-positions were also investigated by using racemic 1-carbacephem 9 and 7 alpha-methyl-1-oxacephem 10. Syntheses of 2-8 and 10 are also described. Acid chlorides derived from the O-benzyloxycarbonyl derivative of (4-hydroxyphenyl)acetic acid and the p-methoxybenzyl derivative of (4-hydroxyphenyl)malonic acid smoothly effected the introduction of these side chains. Conjugate addition of lithium dimethylcuprate to the quinoid system in 16 proceeded stereospecifically, furnishing the 7 alpha-methyl group for the synthesis of 10. Values of log (1/C) averaged for the sensitive Gram-negative strains (Escherichia coli NIHJ JC-2 and Klebsiella pneumoniae SRL-1) were taken as an estimation of the intrinsic antibacterial activity. The chemical reactivity of the beta-lactam ring was estimated either by pseudo-first-order rate constants (k) of alkaline hydrolysis measured at pH 9.20 and 35.0 degrees C or by infrared stretching frequencies of the beta-lactam carbonyl measured in dimethyl sulfoxide. Substitution of an oxygen atom at the 1-position increases both the hydrolysis rates and the antibacterial activity by a factor of approximately 6.3, while substitution of a 7 alpha-methoxy group increases the antibacterial activity by a factor of approximately 3.2 without significant change in the hydrolysis rates. The effect of the 7 alpha-methoxy group on the transition state in alkaline hydrolysis is discussed. Substitutions at the 1-position with a methylene group and, especially, at the 7 alpha-position with a methyl group greatly diminished the antibacterial activity, whereas the hydrolysis rate remained high with the substitution of a methylene group. Substitution of an oxygen atom for the sulfur atom at the 1-position of 1-thiacephems increased the beta-lactam carbonyl frequencies by approximately 6 cm-1, whereas introduction of a 7 alpha-methoxy group in 1-thia- and 1-oxacephems reduced the frequencies by approximately 5 cm-1. | 10 | 3 | 54 | CHEMBL_1 | 2009-09-03 |
CHEMBL1821613 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and evaluation of 5-substituted 2'-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. | 21657202 | 10.1021/jm2004688 | nan | Kögler M, Vanderhoydonck B, De Jonghe S, Rozenski J, Van Belle K, Herman J, Louat T, Parchina A, Sibley C, Lescrinier E, Herdewijn P. | 2011 | 54 | 13 | 4847 | 4862 | PUBLICATION | A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor. | 14 | 2 | 56 | CHEMBL_13 | 2012-02-21 |
CHEMBL1287747 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Highly active antimycobacterial derivatives of benzoxazine. | 21044844 | 10.1016/j.bmc.2010.10.017 | nan | Petrlíková E, Waisser K, Divišová H, Husáková P, Vrabcová P, Kuneš J, Kolář K, Stolaříková J. | 2010 | 18 | 23 | 8178 | 8187 | PUBLICATION | New 3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. The antimycobacterial activity increased with the replacement of the carbonyl group by the thiocarbonyl group in the starting 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-diones. The most active derivatives were more active than isonicotinhydrazide (INH). Free-Wilson analysis was also carried out and the activity contribution was examined. | 58 | 3 | 464 | CHEMBL_10 | 2011-05-26 |
CHEMBL1275448 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis. | 18458127 | 10.1128/aac.00298-08 | nan | Danilchanka O, Mailaender C, Niederweis M. | 2008 | 52 | 7 | 2503 | 2511 | PUBLICATION | The impermeability of the outer membrane in combination with drug efflux are major determinants of the natural drug resistance of mycobacteria. beta-Lactams are the most widely used antibiotics for treatment of bacterial infections. However, it is unknown how beta-lactams enter Mycobacterium tuberculosis and whether efflux pumps exist that can export these drugs out of the cell. To identify the molecular mechanisms of M. tuberculosis resistance to beta-lactams, a library of 7,500 transposon mutants was generated in the model organism Mycobacterium bovis BCG. Thirty-three unique insertion sites were determined that conferred medium or high-level (> or =2,000 microg/ml) resistance to ampicillin. Three mutants in sulfolipid synthesis or transport were highly resistant to ampicillin, indicating an indirect effect of the lipid composition on the outer membrane permeability of M. bovis BCG to ampicillin. Mutants with insertions in genes encoding surface molecules such as PPE proteins or lipoarabinomannan were also completely resistant to ampicillin, thus suggesting a lack of transport across the outer membrane. Insertion of the transposon in front of bcg0231 increased transcription of the gene and concomitantly the resistance of M. bovis BCG to ampicillin, streptomycin, and chloramphenicol by 32- to 64-fold. Resistance to vancomycin and tetracycline was increased four- to eightfold. Bcg0231 and Rv0194 are almost identical ATP-binding cassette transporters. Expression of rv0194 significantly reduced accumulation of ethidium bromide and conferred multidrug resistance to Mycobacterium smegmatis. Both effects were abrogated in the presence of the efflux pump inhibitor reserpine. These results demonstrate that Rv0194 is a novel multidrug efflux pump of M. tuberculosis. | 7 | 3 | 66 | CHEMBL_10 | 2011-05-26 |
CHEMBL1153576 | European journal of medicinal chemistry. | 1 | Scientific Literature | Novel ureas and thioureas of 15-membered azalides with antibacterial activity against key respiratory pathogens. | 19303171 | 10.1016/j.ejmech.2009.02.001 | nan | Bukvić Krajacić M, Novak P, Dumić M, Cindrić M, Paljetak HC, Kujundzić N. | 2009 | 44 | 9 | 3459 | 3470 | PUBLICATION | The new ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-gamma-aminopropyl) (4), 9a-(N'-thiocarbamoyl-gamma-aminopropyl) (6), 9a-[N'-(beta-cyanoethyl)-N'-(carbamoyl-gamma-aminopropyl)] (8) and 9a-[N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-gamma-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against a panel of erythromycin susceptible and erythromycin-resistant gram-positive and gram-negative bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against erythromycin sensitive gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae. In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae. | 25 | 8 | 277 | CHEMBL_3 | 2010-04-16 |
CHEMBL1629685 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Macrolide and clindamycin resistance in Streptococcus milleri group isolates from the airways of cystic fibrosis patients. | 20404127 | 10.1128/aac.01845-09 | nan | Grinwis ME, Sibley CD, Parkins MD, Eshaghurshan CS, Rabin HR, Surette MG. | 2010 | 54 | 7 | 2823 | 2829 | PUBLICATION | Organisms belonging to the Streptococcus milleri group (SMG) are known for their role in pyogenic infections but have recently been implicated as etiological agents of pulmonary exacerbation in adult patients with cystic fibrosis (CF). The prolonged exposure of CF patients to antibiotics prompted us to investigate the susceptibility profiles of 118 SMG isolates from the airways of CF patients to 12 antibiotics compared to 43 SMG isolates from patients with invasive infections. We found that approximately 60% of all isolates failed to grow using the standard medium for disc diffusion, Mueller-Hinton blood agar (MHBA), so we explored the usefulness of brain heart infusion (BHI) agar for susceptibility testing. Zone-of-inhibition comparisons between BHI and MHBA showed strong correlations for six antibiotics, and interpretations were similar for both medium types. For ceftriaxone and cefepime, both groups of isolates were highly susceptible. Tetracycline resistance levels were comparable between the two groups (22% in CF isolates and 17.4% in invasive isolates). However, more than half of the CF isolates were not susceptible to azithromycin, erythromycin, and clindamycin, compared to 11%, 13%, and 6.5% of invasive isolates, respectively. There were 5-fold and 8-fold increased risks of azithromycin and clindamycin resistance, respectively, for the isolates from the airways of CF patients relative to the invasive isolates. Macrolide resistance was strongly linked to chronic azithromycin therapy in CF patients. This study shows that BHI agar is a suitable alternative for antimicrobial susceptibility testing for the SMG and that SMG isolates from the airways of CF patients are more resistant to macrolides and clindamycin than strains isolated from patients with invasive infections. | 6 | 3 | 72 | CHEMBL_11 | 2011-08-01 |
CHEMBL1134471 | Journal of medicinal chemistry. | 1 | Scientific Literature | Antimycobacterial activity of substituted isosteres of pyridine- and pyrazinecarboxylic acids. 2. | 11334565 | 10.1021/jm000350w | nan | Gezginci MH, Martin AR, Franzblau SG. | 2001 | 44 | 10 | 1560 | 1563 | PUBLICATION | Pyridines and pyrazines substituted with 1,2,4-oxadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, and 1,3,4-oxathiazoline-2-ones were synthesized and tested against Mycobacterium tuberculosis. The two former ring systems were documented in the literature to act as carboxylic acid isosteres. The latter series was synthesized as possible synthetic intermediates to 1,2,4-thiadiazole-3-ones and was included in this study due to their interesting activity. Pivaloyloxymethyl derivatives of the isosteres were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. The derivatized isosteres were expected to be biotransformed by esterases to the active species after penetration of the mycobacterial cell wall. Biological properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the compounds exhibited activities ranging from 0.5 to 16 times the potency of pyrazinamide. | 18 | 1 | 36 | CHEMBL_1 | 2009-09-03 |
CHEMBL1671721 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Chemical validation of phosphodiesterase C as a chemotherapeutic target in Trypanosoma cruzi, the etiological agent of Chagas' disease. | 20625148 | 10.1128/aac.00313-10 | nan | King-Keller S, Li M, Smith A, Zheng S, Kaur G, Yang X, Wang B, Docampo R. | 2010 | 54 | 9 | 3738 | 3745 | PUBLICATION | Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases. | 53 | 5 | 204 | CHEMBL_11 | 2011-08-01 |
CHEMBL1129477 | Journal of medicinal chemistry. | 1 | Scientific Literature | Structure-activity relationships of the quinolone antibacterials against mycobacteria: effect of structural changes at N-1 and C-7. | 8576916 | 10.1021/jm9507082 | nan | Renau TE, Sanchez JP, Gage JW, Dever JA, Shapiro MA, Gracheck SJ, Domagala JM. | 1996 | 39 | 3 | 729 | 735 | PUBLICATION | The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl > or = cyclopropyl > 2,4-difluorophenyl > ethyl approximately cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria. | 52 | 7 | 364 | CHEMBL_1 | 2009-09-03 |
CHEMBL1255361 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Differential antibiotic susceptibility of Mycobacterium abscessus variants in biofilms and macrophages compared to that of planktonic bacteria. | 18378709 | 10.1128/aac.00986-07 | nan | Greendyke R, Byrd TF. | 2008 | 52 | 6 | 2019 | 2026 | PUBLICATION | Mycobacterium abscessus causes refractory pulmonary infections requiring surgery for cure. It exists as a smooth biofilm-forming phenotype which is noninvasive and a rough, non-biofilm-forming phenotype which can invade macrophages and cause persistent pulmonary infection in mice. We have postulated that the dissociation of the smooth phenotype to the rough phenotype may lead to invasive lung disease following initial colonization of the airways. Amikacin, cefoxitin, and clarithromycin are standard therapies for this infection. We determined the MICs of these antibiotics against this pathogen in biofilms and macrophages, the niches that it likely occupies in the human host. Our results demonstrate that even though the MICs indicate sensitivity to these antibiotics, the minimal bactericidal concentrations for amikacin and clarithromycin were substantially higher and were out of the range of the concentrations achievable in serum. Cefoxitin demonstrated only bacteriostatic activity. In addition, although amikacin had modest activity against M. abscessus in biofilms, clarithromycin demonstrated only minimal activity at the highest concentrations tested. Our results indicate that M. abscessus in mature biofilms is in a stationary-phase state and that clarithromycin is relatively inactive against stationary-phase M. abscessus. In human macrophages, all three antibiotics were only bacteriostatic for M. abscessus variants at 10 times their MICs. These results suggest why treatment failure with antibiotics alone is common in the clinical setting of M. abscessus pulmonary infection. Determination of the efficacies of new antibiotics should include an assessment of their activities against the smooth and rough M. abscessus morphotypes in biofilms and macrophages. | 3 | 2 | 23 | CHEMBL_10 | 2011-05-26 |
CHEMBL1155164 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Sequencing and comparative genomic analysis of pK29, a 269-kilobase conjugative plasmid encoding CMY-8 and CTX-M-3 beta-lactamases in Klebsiella pneumoniae. | 17526756 | 10.1128/aac.00167-07 | nan | Chen YT, Lauderdale TL, Liao TL, Shiau YR, Shu HY, Wu KM, Yan JJ, Su IJ, Tsai SF. | 2007 | 51 | 8 | 3004 | 3007 | PUBLICATION | A 269-kilobase conjugative plasmid, pK29, from a Klebsiella pneumoniae strain was sequenced. The plasmid harbors multiple antimicrobial resistance genes, including those encoding CMY-8 AmpC-type and CTX-M-3 extended-spectrum beta-lactamases in the common backbone of IncHI2 plasmids. Mechanisms for dissemination of the resistance genes are highlighted in comparative genomic analyses. | 12 | 2 | 42 | CHEMBL_2 | 2009-11-30 |
CHEMBL1153545 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro infection model characterizing the effect of efflux pump inhibition on prevention of resistance to levofloxacin and ciprofloxacin in Streptococcus pneumoniae. | 17846144 | 10.1128/aac.00391-07 | nan | Louie A, Brown DL, Liu W, Kulawy RW, Deziel MR, Drusano GL. | 2007 | 51 | 11 | 3988 | 4000 | PUBLICATION | The prevalence of fluoroquinolone-resistant Streptococcus pneumoniae is slowly rising as a consequence of the increased use of fluoroquinolone antibiotics to treat community-acquired pneumonia. We tested the hypothesis that increased efflux pump (EP) expression by S. pneumoniae may facilitate the emergence of fluoroquinolone resistance. By using an in vitro pharmacodynamic infection system, a wild-type S. pneumoniae strain (Spn-058) and an isogenic strain with EP overexpression (Spn-RC2) were treated for 10 days with ciprofloxacin or levofloxacin in the presence or absence of the EP inhibitor reserpine to evaluate the effect of EP inhibition on the emergence of resistance. Cultures of Spn-058 and Spn-RC2 were exposed to concentration-time profiles simulating those in humans treated with a regimen of ciprofloxacin at 750 mg orally once every 12 h and with regimens of levofloxacin at 500 and 750 mg orally once daily (QD; with or without continuous infusions of 20 microg of reserpine/ml). The MICs of ciprofloxacin and levofloxacin for Spn-058 were both 1 microg/ml when susceptibility testing was conducted with each antibiotic alone and with each antibiotic in the presence of reserpine. For Spn-RC2, the MIC of levofloxacin alone and with reserpine was also 1 mug/ml; the MICs of ciprofloxacin were 2 and 1 microg/ml, respectively, when determined with ciprofloxacin alone and in combination with reserpine. Reserpine, alone, had no effect on the growth of Spn-058 and Spn-RC2. For Spn-058, simulated regimens of ciprofloxacin at 750 mg every 12 h or levofloxacin at 500 mg QD were associated with the emergence of fluoroquinolone resistance. However, the use of ciprofloxacin at 750 mg every 12 h and levofloxacin at 500 mg QD in combination with reserpine rapidly killed Spn-058 and prevented the emergence of resistance. For Spn-RC2, levofloxacin at 500 mg QD was associated with the emergence of resistance, but again, the resistance was prevented when this levofloxacin regimen was combined with reserpine. Ciprofloxacin at 750 mg every 12 h also rapidly selected for ciprofloxacin-resistant mutants of Spn-RC2. However, the addition of reserpine to ciprofloxacin therapy only delayed the emergence of resistance. Levofloxacin at 750 mg QD, with and without reserpine, effectively eradicated Spn-058 and Spn-RC2 without selecting for fluoroquinolone resistance. Ethidium bromide uptake and efflux studies demonstrated that, at the baseline, Spn-RC2 had greater EP expression than Spn-058. These studies also showed that ciprofloxacin was a better inducer of EP expression than levofloxacin in both Spn-058 and Spn-RC2. However, in these isolates, the increase in EP expression by short-term exposure to ciprofloxacin and levofloxacin was transient. Mutants of Spn-058 and Spn-RC2 that emerged under suboptimal antibiotic regimens had a stable increase in EP expression. Levofloxacin at 500 mg QD in combination with reserpine, an EP inhibitor, or at 750 mg QD alone killed wild-type S. pneumoniae and strains that overexpressed reserpine-inhibitable EPs and was highly effective in preventing the emergence of fluoroquinolone resistance in S. pneumoniae during therapy. Ciprofloxacin at 750 mg every 12 h, as monotherapy, was ineffective for the treatment of Spn-058 and Spn-RC2. Ciprofloxacin in combination with reserpine prevented the emergence of resistance in Spn-058 but not in Spn-RC2, the EP-overexpressing strain. | 3 | 5 | 56 | CHEMBL_3 | 2010-04-16 |
CHEMBL1275504 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Detection of macrolide resistance in Mycoplasma pneumoniae by real-time PCR and high-resolution melt analysis. | 18644962 | 10.1128/aac.00582-08 | nan | Wolff BJ, Thacker WL, Schwartz SB, Winchell JM. | 2008 | 52 | 10 | 3542 | 3549 | PUBLICATION | Mycoplasma pneumoniae is a significant cause of community-acquired pneumonia, which is often empirically treated with macrolides or azalides such as erythromycin or azithromycin. Recent studies have discovered the existence of macrolide-resistant strains within the population that have been mapped to mutations within the domain V region of the 23S rRNA gene. Currently, identification of these resistant strains relies on time-consuming and labor-intensive procedures such as restriction fragment length polymorphism, MIC studies, and sequence analysis. The current study reports two distinct real-time PCR assays that can detect the A2063G or A2064G base mutation (A2058G or A2059G by Escherichia coli numbering) conferring macrolide resistance. By subjecting the amplicon of the targeted domain V region of the 23S rRNA gene to a high-resolution melt curve analysis, macrolide-resistant strains can quickly be separated from susceptible strains. Utilizing this method, we screened 100 clinical isolates and found 5 strains to possess mutations conferring resistance. These findings were concordant with both sequencing and MIC data. This procedure was also used successfully to identify both susceptible and resistant genotypes in 23 patient specimens. These patient specimens tested positive for the presence of M. pneumoniae by a separate real-time PCR assay, although the bacteria could not be isolated by culture. This is the first report of a real-time PCR assay capable of detecting the dominant mutations that confer macrolide resistance on M. pneumoniae, and these assays may have utility in detecting resistant strains of other infectious agents. These assays may also allow for clinicians to select appropriate treatment options more rapidly and may provide a convenient method to conduct surveillance for genetic mutations conferring antibiotic resistance. | 3 | 1 | 27 | CHEMBL_10 | 2011-05-26 |
CHEMBL1629585 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Nationwide survey of CTX-M-type extended-spectrum beta-lactamases among Klebsiella pneumoniae isolates in Slovenian hospitals. | 19001116 | 10.1128/aac.00746-08 | nan | Mesko Meglic K, Koren S, Palepou MF, Karisik E, Livermore DM, Pike R, Andlovic A, Jeverica S, Krizan-Hergouth V, Müller-Premru M, Seme K, Slovenian ESBL Study Group, Woodford N. | 2009 | 53 | 1 | 287 | 291 | PUBLICATION | Among 177 extended-spectrum beta-lactamase-producing Klebsiella pneumoniae isolates collected from 11 Slovenian hospitals in 2005 and 2006, 60 (34%), from eight hospitals, harbored genes for CTX-M enzymes, with bla(CTX-M-15) detected by sequencing. These 60 isolates comprised 11 pulsed-field gel electrophoresis-defined strains, with several clusters of closely related isolates. Plasmids encoding CTX-M-15 enzyme were highly transmissible. | 12 | 2 | 249 | CHEMBL_11 | 2011-08-01 |
CHEMBL1212808 | Nature chemical biology. | 1 | Scientific Literature | The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. | 20081827 | 10.1038/nchembio.293 | nan | Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C, Gaillard P, Rückle T, Schwarz MK, Shokat KM, Shaw JP, Williams RL. | 2010 | 6 | 2 | 117 | 124 | PUBLICATION | Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies. | 13 | 4 | 52 | CHEMBL_9 | 2011-01-20 |
CHEMBL1136232 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Novel inhibitors of an emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose synthesis. | 12951098 | 10.1016/s0960-894x(03)00673-5 | nan | Babaoglu K, Page MA, Jones VC, McNeil MR, Dong C, Naismith JH, Lee RE. | 2003 | 13 | 19 | 3227 | 3230 | PUBLICATION | The emergence of multi-drug resistant tuberculosis, coupled with the increasing overlap of the AIDS and tuberculosis pandemics has brought tuberculosis to the forefront as a major worldwide health concern. In an attempt to find new inhibitors of the enzymes in the essential rhamnose biosynthetic pathway, a virtual library of 2,3,5 trisubstituted-4-thiazolidinones was created. These compounds were then docked into the active site cavity of 6'hydroxyl; dTDP-6-deoxy-D-xylo-4-hexulose 3,5-epimerase (RmlC) from Mycobacterium tuberculosis. The resulting docked conformations were consensus scored and the top 5% were slated for synthesis. Thus far, 94 compounds have been successfully synthesized and initially tested. Of those, 30 (32%) have > or =50% inhibitory activity (at 20 microM) in the coupled rhamnose synthetic assay with seven of the 30 also having modest activity against whole-cell M. tuberculosis. | 11 | 2 | 26 | CHEMBL_1 | 2009-09-03 |
CHEMBL1212756 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. | 19858254 | 10.1128/aac.00715-09 | nan | Padilla E, Llobet E, Doménech-Sánchez A, Martínez-Martínez L, Bengoechea JA, Albertí S. | 2010 | 54 | 1 | 177 | 183 | PUBLICATION | Respiratory infections caused by Klebsiella pneumoniae are characterized by high rates of mortality and morbidity. Management of these infections is often difficult, due to the high frequency of strains that are resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. In the present study, we investigated the role of the K. pneumoniae AcrRAB operon in antimicrobial resistance and virulence by using isogenic knockouts deficient in the AcrB component and the AcrR repressor, both derived from the virulent strain 52145R. We demonstrated that the AcrB knockout was more susceptible, not only to quinolones, but also to other antimicrobial agents, including beta-lactams, than the wild-type strain and the AcrR knockout. We further showed that the AcrB knockout was more susceptible to antimicrobial agents present in human bronchoalveolar lavage fluid and to human antimicrobial peptides than the wild-type strain and the AcrR knockout. Finally, the AcrB knockout exhibited a reduced capacity to cause pneumonia in a murine model, in contrast to the wild-type strain. The results of this study suggest that, in addition to contributing to the multidrug resistance phenotype, the AcrAB efflux pump may represent a novel virulence factor required for K. pneumoniae to resist innate immune defense mechanisms of the lung, thus facilitating the onset of pneumonia. | 15 | 1 | 43 | CHEMBL_9 | 2011-01-20 |
CHEMBL1649490 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | First detection of plasmid-encoded blaOXY beta-lactamase. | 19380592 | 10.1128/aac.01473-08 | nan | González-López JJ, Coelho A, Larrosa MN, Lavilla S, Bartolomé R, Prats G. | 2009 | 53 | 7 | 3143 | 3146 | PUBLICATION | Three Klebsiella oxytoca isolates and one Klebsiella pneumoniae isolate from three children admitted to the Hematology Unit of Hospital Vall d'Hebron (Barcelona, Spain) exhibited a susceptibility pattern suggesting OXY beta-lactamase hyperproduction. All the isolates contained a 95-kb plasmid that harbored bla(OXY-1), which was transferred by electrotransformation but could not be self-transferred by conjugation. A qnrS1 gene was also harbored in the bla(OXY-1)-carrying plasmid. This is the first report of a plasmid-encoded OXY beta-lactamase. | 9 | 3 | 90 | CHEMBL_11 | 2011-08-01 |
CHEMBL1275460 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Molecular characterization and epidemiology of extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates causing health care-associated infection in Thailand, where the CTX-M family is endemic. | 18505851 | 10.1128/aac.00171-08 | nan | Kiratisin P, Apisarnthanarak A, Laesripa C, Saifon P. | 2008 | 52 | 8 | 2818 | 2824 | PUBLICATION | Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae have rapidly spread worldwide and pose a serious threat for health care-associated (HA) infection. We conducted molecular detection and characterization of ESBL-related bla genes, including bla(TEM), bla(SHV), bla(CTX-M), bla(VEB), bla(OXA), bla(PER), and bla(GES), among 362 isolates of ESBL-producing E. coli (n = 235) and ESBL-producing K. pneumoniae (n = 127) collected from patients who met the definition of HA infection at two major university hospitals in Thailand from December 2004 to May 2005. The prevalence of ESBL-producing E. coli and ESBL-producing K. pneumoniae, patient demographics and the susceptibilities of these bacteria to various antimicrobial agents were described. A total of 87.3% of isolates carried several bla genes. The prevalence of bla(CTX-M) was strikingly high: 99.6% for ESBL-producing E. coli (CTX-M-14, -15, -27, -40, and -55) and 99.2% for ESBL-producing K. pneumoniae (CTX-M-3, -14, -15, -27, and -55). ISEcp1 was found in the upstream region of bla(CTX-M) in most isolates. Up to 77.0% and 71.7% of ESBL-producing E. coli and ESBL-producing K. pneumoniae, respectively, carried bla(TEM); all of them encoded TEM-1. ESBL-producing K. pneumoniae carried bla(SHV) at 87.4% (SHV-1, -2a, -11, -12, -27, -71, and -75) but only at 3.8% for ESBL-producing E. coli (SHV-11 and -12). bla genes encoding VEB-1 and OXA-10 were found in both ESBL-producing E. coli (8.5% and 8.1%, respectively) and ESBL-producing K. pneumoniae (10.2% and 11.8%, respectively). None of the isolates were positive for bla(PER) and bla(GES). Pulsed-field gel electrophoresis analysis demonstrated that there was no major clonal relationship among these ESBL producers. This is the first study to report CTX-M-3, CTX-M-27, CTX-M-40, SHV-27, SHV-71, and SHV-75 in Thailand and to show that CTX-M ESBL is highly endemic in the country. | 10 | 2 | 112 | CHEMBL_10 | 2011-05-26 |
CHEMBL1255356 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB. | 18362193 | 10.1128/aac.01644-07 | nan | Garvey MI, Piddock LJ. | 2008 | 52 | 5 | 1677 | 1685 | PUBLICATION | One way to combat multidrug-resistant microorganisms is the use of efflux pump inhibitors (EPIs). Spontaneous mutants resistant to the EPI reserpine selected from Streptococcus pneumoniae NCTC 7465 and R6 at a frequency suggestive of a single mutational event were also multidrug resistant. No mutations in pmrA (which encodes the efflux protein PmrA) were detected, and the expression of pmrA was unaltered in all mutants. In the reserpine-resistant multidrug-resistant mutants, the overexpression of both patA and patB, which encode ABC transporters, was associated with accumulation of low concentrations of antibiotics and dyes. The addition of sodium orthovanadate, an inhibitor of ABC efflux pumps, or the insertional inactivation of either gene restored wild-type antibiotic susceptibility and wild-type levels of accumulation. Only when patA was insertionally inactivated were both multidrug resistance and reserpine resistance lost. Strains in which patA was insertionally inactivated grew significantly more slowly than the wild type. These data indicate that the overexpression of both patA and patB confers multidrug resistance in S. pneumoniae but that only patA is involved in reserpine resistance. The selection of reserpine-resistant multidrug-resistant pneumococci has implications for analogous systems in other bacteria or in cancer. | 1 | 2 | 26 | CHEMBL_10 | 2011-05-26 |
CHEMBL1133646 | Journal of medicinal chemistry. | 1 | Scientific Literature | BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. | 11000002 | 10.1021/jm0002679 | nan | Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA. | 2000 | 43 | 19 | 3482 | 3486 | PUBLICATION | nan | 7 | 3 | 15 | CHEMBL_1 | 2009-09-03 |
CHEMBL1147641 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase. | 15006410 | 10.1016/j.bmcl.2003.09.102 | nan | Watson KG, Cameron R, Fenton RJ, Gower D, Hamilton S, Jin B, Krippner GY, Luttick A, McConnell D, MacDonald SJ, Mason AM, Nguyen V, Tucker SP, Wu WY. | 2004 | 14 | 6 | 1589 | 1592 | PUBLICATION | A set of trimeric and tetrameric derivatives 6-11 of the influenza virus neuraminidase inhibitor zanamivir 1 have been synthesized by coupling a common monomeric zanamivir derivative 3 onto various multimeric carboxylic acid core groups. These discrete multimeric compounds are all significantly more antiviral than zanamivir and also show outstanding long-lasting protective activity when tested in mouse influenza infectivity experiments. | 8 | 3 | 36 | CHEMBL_1 | 2009-09-03 |
CHEMBL1154500 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis. | 18762421 | 10.1016/j.bmcl.2008.07.130 | nan | Lu X, Zhang H, Tonge PJ, Tan DS. | 2008 | 18 | 22 | 5963 | 5966 | PUBLICATION | Menaquinone (vitamin K(2)) is an essential component of the electron transfer chain in many pathogens, including Mycobacterium tuberculosis and Staphylococcus aureus, and menaquinone biosynthesis is a potential target for antibiotic drug discovery. We report herein a series of mechanism-based inhibitors of MenE, an acyl-CoA synthetase that catalyzes adenylation and thioesterification of o-succinylbenzoic acid (OSB) during menaquinone biosynthesis. The most potent compound inhibits MenE with an IC(50) value of 5.7microM. | 6 | 2 | 18 | CHEMBL_2 | 2009-11-30 |
CHEMBL1629641 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | An important site in PBP2x of penicillin-resistant clinical isolates of Streptococcus pneumoniae: mutational analysis of Thr338. | 19075056 | 10.1128/aac.01107-08 | nan | Zerfass I, Hakenbeck R, Denapaite D. | 2009 | 53 | 3 | 1107 | 1115 | PUBLICATION | Penicillin-binding protein 2x (PBP2x) of Streptococcus pneumoniae represents a primary resistance determinant for beta-lactams, and low-affinity PBP2x variants can easily be selected with cefotaxime. Penicillin-resistant clinical isolates of S. pneumoniae frequently contain in their mosaic PBP2x the mutation T338A adjacent to the active site S337, and T338P as well as T338G substitutions are also known. Site-directed mutagenesis has now documented that a single point mutation at position T338 confers selectable levels of beta-lactam resistance preferentially to oxacillin. Despite the moderate impact on beta-lactam susceptibility, the function of the PBP2x mutants appears to be impaired, as can be documented in the absence of a functional CiaRH regulatory system, resulting in growth defects and morphological changes. The combination of low-affinity PBP2x and PBP1a encoded by mosaic genes is known to result in high cefotaxime resistance. In contrast, introduction of a mosaic pbp1a into the PBP2x(T338G) mutant did not lead to increased resistance. However, the mosaic PBP1a gene apparently complemented the PBP2x(T338G) defect, since Cia mutant derivatives grew normally. The data support the view that PBP2x and PBP1a interact with each other on some level and that alterations of both PBPs in resistant clinical isolates have evolved to ensure cooperation between both proteins. | 4 | 1 | 72 | CHEMBL_11 | 2011-08-01 |
CHEMBL1275459 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Alteration of GyrA amino acid required for ciprofloxacin resistance in Klebsiella pneumoniae isolates in China. | 18505849 | 10.1128/aac.00151-08 | nan | Fu Y, Guo L, Xu Y, Zhang W, Gu J, Xu J, Chen X, Zhao Y, Ma J, Liu X, Zhang F. | 2008 | 52 | 8 | 2980 | 2983 | PUBLICATION | Resistance to ciprofloxacin was detected in 111 (48.1%) isolates of Klebsiella pneumoniae from China. GyrA alterations were identified in the ciprofloxacin-resistant and ciprofloxacin-susceptible isolates. The results, including previously published data, indicate that the single substitution Ser83-->Ile and three types of double mutations at Ser83 and Asp87 were required for ciprofloxacin resistance (P < 0.05). | 2 | 1 | 74 | CHEMBL_10 | 2011-05-26 |
CHEMBL1151904 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Computer-aided rational molecular design of argifin-derivatives with increased inhibitory activity against chitinase B from Serratia marcescens. | 19395258 | 10.1016/j.bmcl.2009.04.013 | nan | Gouda H, Sunazuka T, Iguchi K, Sugawara A, Hirose T, Noguchi Y, Saito Y, Yanai Y, Yamamoto T, Watanabe T, Shiomi K, Omura S, Hirono S. | 2009 | 19 | 10 | 2630 | 2633 | PUBLICATION | Argifin, a novel pentapeptide chitinase inhibitor isolated from Gliocladium fungal culture, is a promising candidate for the development of new fungicides, insecticides, and anti-asthma medications. In this study, we undertook rational molecular design of argifin-derivatives and tested them against chitinase B from Serratia marcescens (SmChiB). The work involved molecular dynamics simulation with explicit water molecules, the molecular docking calculation, and free-energy analysis using the molecular mechanics Poisson-Boltzmann surface area method. The custom-designed derivatives were synthesized via effective solid phase synthesis, developed recently in our laboratory, and their inhibitory activities were measured against SmChiB. Finally, we identified and obtained a derivative which exhibited 28-fold more inhibition than argifin itself, a compound in which the d-Ala(5) of argifin was replaced with d-Leu and the 4-benzylpiperdine was attached to l-Asp(4). | 8 | 1 | 8 | CHEMBL_3 | 2010-04-16 |
CHEMBL1255359 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Mechanisms of macrolide resistance among Streptococcus pneumoniae isolates from Russia. | 18378707 | 10.1128/aac.01270-07 | nan | Reinert RR, Filimonova OY, Al-Lahham A, Grudinina SA, Ilina EN, Weigel LM, Sidorenko SV. | 2008 | 52 | 6 | 2260 | 2262 | PUBLICATION | Among 76 macrolide-nonsusceptible Streptococcus pneumoniae isolates collected between 2003 and 2005 from Central Russia, the resistance mechanisms detected in the isolates included erm(B) alone (50%), mef alone [mef(E), mef(I), or a different mef subclass; 19.7%], or both erm(B) and mef(E) (30.3%). Isolates with dual resistance genes [erm(B) and mef(E)] belonged to clonal complex CC81 or CC271. | 2 | 1 | 14 | CHEMBL_10 | 2011-05-26 |
CHEMBL1240419 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antibacterial activity of 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin A: a novel class of acylides. | 20554083 | 10.1016/j.ejmech.2010.05.009 | nan | Wu Z, Lu Y, Luo M, He X, Xiao Y, Yang J, Pan Y, Qiu G, Guo H, Hu H, Zhou D, Hu X. | 2010 | 45 | 9 | 3636 | 3644 | PUBLICATION | A novel series of acylides, 3-O-carbamoyl derivatives of 6,11-di-O-methylerythromycin A, were synthesized and evaluated for their antibacterial activity. These compounds have significant antibacterial activity against gram-positive pathogens, including erythromycin-resistant but methicillin-susceptible Staphylococcus aureus, erythromycin-resistant and methicillin-resistant S. aureus, erythromycin-resistant Streptococcus pneumoniae, and gram-negative pathogens, such as Haemophilus influenzae. Among the derivatives tested, compounds 4p, 4r, 4w, 4x and 4z were found to have potent activity against most susceptible and resistant bacteria. Compound 4p exhibited excellent antibacterial activity in comparison to the others. | 29 | 3 | 203 | CHEMBL_10 | 2011-05-26 |
CHEMBL1255248 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Fitness of Streptococcus pneumoniae fluoroquinolone-resistant strains with topoisomerase IV recombinant genes. | 18160515 | 10.1128/aac.00731-07 | nan | Balsalobre L, de la Campa AG. | 2008 | 52 | 3 | 822 | 830 | PUBLICATION | The low prevalence of ciprofloxacin-resistant (Cp r) Streptococcus pneumoniae isolates carrying recombinant topoisomerase IV genes could be attributed to a fitness cost imposed by the horizontal transfer, which often implies the acquisition of larger-than-normal parE-parC intergenic regions. A study of the transcription of these genes and of the fitness cost for 24 isogenic Cp r strains was performed. Six first-level transformants were obtained either with PCR products containing the parC quinolone resistance-determining regions (QRDRs) of S. pneumoniae Cp r mutants with point mutations or with a PCR product that includes parE-QRDR-ant-parC-QRDR from a Cp r Streptococcus mitis isolate. The latter yielded two strains, T6 and T11, carrying parC-QRDR and parE-QRDR-ant-parC-QRDR, respectively. These first-level transformants were used as recipients in further transformations with the gyrA-QRDR PCR products to obtain 18 second-level transformants. In addition, strain Tr7 (which contains the GyrA E85K change) was used. Reverse transcription-PCR experiments showed that parE and parC were cotranscribed in R6, T6, and T11; and a single promoter located upstream of parE was identified in R6 by primer extension. The fitness of the transformants was estimated by pairwise competition with R6 in both one-cycle and two-cycle experiments. In the one-cycle experiments, most strains carrying the GyrA E85K change showed a fitness cost; the exception was recombinant T14. In the two-cycle experiments, a fitness cost was observed in most first-level transformants carrying the ParC changes S79F, S79Y, and D83Y and the GyrA E85K change; the exceptions were recombinants T6 and T11. The results suggest that there is no impediment due to a fitness cost for the spread of recombinant Cp r S. pneumoniae isolates, since some recombinants (T6, T11, and T14) exhibited an ability to compensate for the cost. | 2 | 1 | 50 | CHEMBL_10 | 2011-05-26 |
CHEMBL1275259 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro antituberculosis activities of ACH-702, a novel isothiazoloquinolone, against quinolone-susceptible and quinolone-resistant isolates. | 20516287 | 10.1128/aac.00287-10 | nan | Pucci MJ, Ackerman M, Thanassi JA, Shoen CM, Cynamon MH. | 2010 | 54 | 8 | 3478 | 3480 | PUBLICATION | ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of <or=1 microg/ml, comparable to that of the fluoroquinolone moxifloxacin for quinolone-susceptible isolates but superior to that for quinolone-resistant isolates. Biochemical assays involving M. tuberculosis gyrase enzymes indicated that ACH-702 had significantly improved inhibitory activity compared with fluoroquinolones. | 7 | 2 | 98 | CHEMBL_10 | 2011-05-26 |
CHEMBL1275539 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro activity of ceftaroline against Streptococcus pneumoniae isolates exhibiting resistance to penicillin, amoxicillin, and cefotaxime. | 18725443 | 10.1128/aac.00712-08 | nan | Fenoll A, Aguilar L, Robledo O, Giménez MJ, Granizo JJ, Biek D, Tarragó D. | 2008 | 52 | 11 | 4209 | 4210 | PUBLICATION | nan | 10 | 1 | 218 | CHEMBL_10 | 2011-05-26 |
CHEMBL1155509 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | 3-Indolyl sultams as selective CRTh2 antagonists. | 20457519 | 10.1016/j.bmcl.2010.04.046 | nan | Tumey LN, Robarge MJ, Gleason E, Song J, Murphy SM, Ekema G, Doucette C, Hanniford D, Palmer M, Pawlowski G, Danzig J, Loftus M, Hunady K, Sherf B, Mays RW, Stricker-Krongrad A, Brunden KR, Bennani YL, Harrington JJ. | 2010 | 20 | 11 | 3287 | 3290 | PUBLICATION | CRTh2 (DP(2)) is a prostaglandin D(2) receptor implicated in the recruitment of eosinophils and basophils within the asthmatic lung. Here we report the discovery of a novel series of 3-indolyl sultam antagonists with low nM affinity for CRTh2. These compounds proved to be selective over the other primary prostaglandin D(2) receptor (DP1) as well as the thromboxane A(2) receptor (TP). | 26 | 3 | 35 | CHEMBL_6 | 2010-08-27 |
CHEMBL1133902 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Biflavonoids as novel antituberculosis agents. | 11514148 | 10.1016/s0960-894x(01)00382-1 | nan | Lin YM, Flavin MT, Cassidy CS, Mar A, Chen FC. | 2001 | 11 | 16 | 2101 | 2104 | PUBLICATION | A series of naturally occurring and synthetic biflavonoids was evaluated for inhibitory activity against Mycobacterium tuberculosis H37Rv (Mtb). Compounds 6, 24, and 25 demonstrated 96, 95, and 87% inhibition, respectively, at a screening concentration of 12.5 microg/mL. The type of linkage and the presence of methoxy- and nitro-substituents in biflavonoids may contribute to the observed inhibitory activity. The results of this study represent the discovery of biflavonoids as a potential new class of antituberculosis agent. | 29 | 1 | 32 | CHEMBL_1 | 2009-09-03 |
CHEMBL3525921 | Drug metabolism and disposition : the biological fate of chemicals. | 1 | Scientific Literature | Metabolic pathways of inhaled glucocorticoids by the CYP3A enzymes. | 23143891 | 10.1124/dmd.112.046318 | nan | Moore CD, Roberts JK, Orton CR, Murai T, Fidler TP, Reilly CA, Ward RM, Yost GS. | 2013 | 41 | 2 | 379 | 389 | PUBLICATION | Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6β-hydroxylation and Δ(6)-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Δ(6)-flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis. | 17 | 3 | 55 | CHEMBL_21 | 2016-02-01 |
CHEMBL3097988 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and characterization of new N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)amide/sulfonamide derivatives as possible antimicrobial and antitubercular agents. | 24361479 | 10.1016/j.ejmech.2013.11.002 | nan | Ranjith PK, Pakkath R, Haridas KR, Kumari SN. | 2014 | 71 | nan | 354 | 365 | PUBLICATION | In this paper we report the SAR studies of a series of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)amide and N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)sulfonamide derivatives 6(a-o) and 7(a-o), were synthesized in good yields and characterized by (1)H NMR, (13)C NMR and mass spectral analyses. The preparation of the key intermediate highlights an optimized palladium catalyzed (Pd₂(dba)₃/RuPhos) Buchwald cross-coupling of intermediate 2 and 3. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, (Gram-positive), Escherichia coli and Klebsiella pneumoniae (Gram-negative), antifungal activity against Candida albicans, Aspergillus flavus and Rhizopus sp. and antitubercular activity against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis, Mycobacterium fortuitum and MDR-TB strains. The synthesized compounds displayed interesting antimicrobial activity. The compounds 7d, 7f, 7h and 7n displayed significant activity against Mycobacterium tuberculosis H37Rv strain. | 34 | 9 | 360 | CHEMBL_19 | 2014-07-03 |
CHEMBL1649324 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro activity of tebipenem, a new oral carbapenem antibiotic, against beta-lactamase-nonproducing, ampicillin-resistant Haemophilus influenzae. | 20585130 | 10.1128/aac.00054-10 | nan | Kishii K, Chiba N, Morozumi M, Ono A, Ida T, Ubukata K. | 2010 | 54 | 9 | 3970 | 3973 | PUBLICATION | In vitro activity of tebipenem, a new oral carbapenem antibiotic, against clinical Haemophilus influenzae isolates was compared with those of 8 reference agents. Isolates were classified into 6 resistance classes after PCR identification of beta-lactamase genes and ftsI gene mutations. For all isolates, the minimal concentration at which 90% of isolates were inhibited was lower for tebipenem than for the reference oral antibiotics, except for cefditoren. Tebipenem also showed excellent bactericidal activity against beta-lactamase-nonproducing, ampicillin-resistant isolates. | 9 | 1 | 118 | CHEMBL_11 | 2011-08-01 |
CHEMBL1795340 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition. | 21641210 | 10.1016/j.bmcl.2011.05.021 | nan | Yang Y, Gao P, Liu Y, Ji X, Gan M, Guan Y, Hao X, Li Z, Xiao C. | 2011 | 21 | 13 | 3943 | 3946 | PUBLICATION | Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by determining the molecular mechanism of ActD inhibition followed by structure-based virtual screening. The molecular interaction of inhibition was determined by circular dichroism and tryptophan fluorescence quenching. The structure-based search and virtual screening were performed using the Molecular Operating Environment (MOE) program and SYBYL 7.5, respectively. Two inhibitors were identified with an IC(50) for pantothenate synthetase that was at least ten times better than that of ActD. | 8 | 2 | 30 | CHEMBL_13 | 2012-02-21 |
CHEMBL3351273 | Journal of natural products. | 1 | Scientific Literature | NRPS substrate promiscuity leads to more potent antitubercular sansanmycin analogues. | 24964393 | 10.1021/np5001494 | nan | Xie Y, Cai Q, Ren H, Wang L, Xu H, Hong B, Wu L, Chen R. | 2014 | 77 | 7 | 1744 | 1748 | PUBLICATION | Sansanmycins, members of the uridyl peptide antibiotics, are assembled by nonribosomal peptide synthetases (NRPSs), the substrate promiscuity of which results in the diversity of products. Further exploration of the NRPSs' substrate promiscuity by reinvestigating sansanmycin producer strain led to the isolation and structural elucidation of eight new uridyl peptides, sansanmycins H-O (1-8). Among them, sansanmycin L, containing a 6-OH-bicyclic residue and Phe3 first found at the position AA3, exhibited activity against M. tuberculosis H37Rv with an MIC value of 2 μg/mL, 8-fold more potent than that of the major compound, sansanmycin A (MIC = 16 μg/mL). | 12 | 2 | 23 | CHEMBL_21 | 2016-02-01 |
CHEMBL1255372 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Presence of plasmid-mediated quinolone resistance in Klebsiella pneumoniae isolates possessing blaKPC in the United States. | 18426899 | 10.1128/aac.00158-08 | nan | Endimiani A, Carias LL, Hujer AM, Bethel CR, Hujer KM, Perez F, Hutton RA, Fox WR, Hall GS, Jacobs MR, Paterson DL, Rice LB, Jenkins SG, Tenover FC, Bonomo RA. | 2008 | 52 | 7 | 2680 | 2682 | PUBLICATION | The presence of plasmid-mediated quinolone resistance genes [i.e., qnrA, qnrB, qnrS, aac(6')-Ib-cr, and qepA] was evaluated among 42 bla(KPC)-containing Klebsiella pneumoniae isolates collected in the eastern United States. One isolate carried the bla(KPC-3) and qnrB19 genes on the same conjugative plasmid, whereas another carried the bla(KPC-3) and qnrA1 genes on separate plasmids. | 18 | 2 | 108 | CHEMBL_10 | 2011-05-26 |
CHEMBL1649428 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | An ABC transporter of Streptococcus pneumoniae involved in susceptibility to vancoresmycin and bacitracin. | 19273682 | 10.1128/aac.01485-08 | nan | Becker P, Hakenbeck R, Henrich B. | 2009 | 53 | 5 | 2034 | 2041 | PUBLICATION | Vancoresmycin is a novel tetramic acid antibiotic, probably interfering with functions of the cytoplasmic membrane. To investigate its mode of action, mutants of Streptococcus pneumoniae exhibiting reduced susceptibility to vancoresmycin were isolated at a low frequency. Four of them were further examined and showed similar pleiotropic phenotypes, including reduced growth rate, early autolysis, and chain formation. In one mutant, the level of transcripts from a single locus encoding the potential ABC transporter Spr0812-Spr0813 was increased sixfold. The corresponding DNA sequence revealed a nonsense mutation (C1744T) in spr0813, leading to the formation of a truncated permease lacking 2 of the 10 predicted transmembrane helices. As demonstrated by deletion and transformation analysis and reconstructing the spr0813(C1744T) mutation in the wild-type background, this nucleotide exchange was sufficient to cause reduced susceptibility to vancoresmycin and higher amounts of spr0812-spr0813 mRNA. Mapping and reporter assays of the cognate promoter P(abc) showed that spr0812 and spr0813 are cotranscribed with a preceding small gene and that the spr0813(C1744T) mutation does not affect the activity of P(abc). Due to the similarity of Spr0812-Spr0813 to bacitracin transporters of Streptococcus mutans and Bacillus spp., the bacitracin susceptibility of spr0813 mutants was examined. Both the spr0813(C1744T) nonsense mutation and the deletion of the transporter genes led to a clearly increased sensitivity to bacitracin. Thus, the intact transporter is required for intrinsic resistance to bacitracin, whereas reduced vancoresmycin susceptibility is mediated by the truncated permease. | 2 | 1 | 19 | CHEMBL_11 | 2011-08-01 |
CHEMBL1137640 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. | 17709466 | 10.1128/aac.00181-07 | nan | Huitric E, Verhasselt P, Andries K, Hoffner SE. | 2007 | 51 | 11 | 4202 | 4204 | PUBLICATION | The diarylquinoline R207910 is in clinical development for tuberculosis treatment. The MIC(50) for 41 drug-susceptible and 44 multidrug-resistant Mycobacterium tuberculosis clinical isolates was 0.032 microg/ml. Out of 20 additional mycobacterial species, three were found to be naturally resistant to R207910 and were shown to exhibit a polymorphism in their atpE genes. | 1 | 22 | 40 | CHEMBL_2 | 2009-11-30 |
CHEMBL3112529 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE. | 24461562 | 10.1016/j.bmc.2013.12.058 | nan | Veleti SK, Lindenberger JJ, Ronning DR, Sucheck SJ. | 2014 | 22 | 4 | 1404 | 1411 | PUBLICATION | The emergence of extensively drug-resistant tuberculosis (XDR-TB) necessitates the need to identify new anti-tuberculosis drug targets as well as to better understand essential biosynthetic pathways. GlgE is a Mycobacterium tuberculosis (Mtb) encoded maltosyltransferase involved in α-glucan biosynthesis. Deletion of GlgE in Mtb results in the accumulation of M1P within cells leading to rapid death of the organism. To inhibit GlgE a maltose-C-phosphonate (MCP) 13 was designed to act as an isosteric non-hydrolysable mimic of M1P. MCP 13, the only known inhibitor of Mtb GlgE, was successfully synthesized using a Wittig olefination as a key step in transforming maltose to the desired product. MCP 13 inhibited Mtb GlgE with an IC₅₀=230 ± 24 μM determined using a coupled enzyme assay which measures orthophosphate release. The requirement of M1P for the assay necessitated the development of an expedited synthetic route to M1P from an intermediate used in the MCP 13 synthesis. In conclusion, we designed a substrate analogue of M1P that is the first to exhibit Mtb GlgE inhibition. | 1 | 1 | 1 | CHEMBL_19 | 2014-07-03 |
CHEMBL1275514 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Surveillance of community-based reservoirs reveals the presence of CTX-M, imported AmpC, and OXA-30 beta-lactamases in urine isolates of Klebsiella pneumoniae and Escherichia coli in a U.S. community. | 18663030 | 10.1128/aac.00877-08 | nan | Hanson ND, Moland ES, Hong SG, Propst K, Novak DJ, Cavalieri SJ. | 2008 | 52 | 10 | 3814 | 3816 | PUBLICATION | beta-Lactamases produced by urine isolates from patients in long-term care facilities (LTCFs), outpatient, clinics, and one hospital in a U.S. community were characterized. A total of 1.3% of all Escherichia coli and Klebsiella pneumoniae isolates collected from patients in 30 LTCFs and various outpatient clinics produced extended-spectrum beta-lactamases (ESBLs) and/or imported AmpC beta-lactamases. | 2 | 2 | 88 | CHEMBL_10 | 2011-05-26 |
CHEMBL1125774 | Journal of medicinal chemistry. | 1 | Scientific Literature | 3-Methyl-2H-1-benzopyran potassium channel activators. | 1920358 | 10.1021/jm00114a017 | nan | Gericke R, Harting J, Lues I, Schittenhelm C. | 1991 | 34 | 10 | 3074 | 3085 | PUBLICATION | By aldol condensation of 4-chromanones with paraformaldehyde, 3-alkylenechromanones 10 were obtained which gave 3-alkylchromenes following reduction and dehydration. Subsequent 3-chloroperbenzoic acid oxidation produced the versatile epoxide intermediates 15, from which 3,4-epoxy-3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile (15a) was resolved into its enantiomers by entrainment. In addition to the methyl group, the benzyl, alkyloxymethyl, and 2-nitroethyl residues could be introduced in the 3-position. Treatment of 15a with 2-pyridone simultaneously gave N- and O-substituted products 19a and 20. 19a easily gave 4-(1,2-dihydro-2-oxo-1-pyridyl)chromene 21 by treatment with base. The corresponding pyrrolidinone compounds 26 and 27 were obtained by a slightly modified procedure. Reaction with 2,4-dihydroxypyridine or 3,6-pyridazinediol resulted in the exclusive formation of 4-(heterocyclyloxy)chromanols (31 and 32). Treatment of 15a with 3-amino-6-pyridazinol gave 4-(3-amino-1,6-dihydro-6-oxo-1-pyridazinyl)chromanol derivative 34 lacking an NH bridge. This could be established after methylation of the ring-nitrogen atom (----35). Trans-configurated 3-methyl-4-pyridone compound 36 was obtained by addition of methyllithium to chromene 3. Hyperpolarizing and antispasmodic or relaxing effects of the compounds were determined in organ bath studies using pig coronary arteries precontracted with acetylcholine or rabbit main pulmonary arteries precontracted with noradrenaline. In the 3-methyl series the classical pyridone and pyrrolidinone structures (9, 21, 26, 27) were only weakly active or inactive, but the corresponding 4-(heterocyclyloxy) and 4-(heterocyclylamino) derivatives (31, 32, 35) were even more potent than the demethyl analogues. In conformation/activity investigations it was found that the activity of the 4-substituted benzopyran derivatives seems to be dependent on the relative orientation of their ring systems. | 29 | 2 | 68 | CHEMBL_1 | 2009-09-03 |
CHEMBL1221200 | Nature chemical biology. | 1 | Scientific Literature | Diarylquinolines target subunit c of mycobacterial ATP synthase. | 17496888 | 10.1038/nchembio884 | nan | Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R, Ristic Z, Lill H, Dorange I, Guillemont J, Bald D, Andries K. | 2007 | 3 | 6 | 323 | 324 | PUBLICATION | The diarylquinoline R207910 (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. Though R207910-resistant mycobacteria bear mutations in ATP synthase, the compound's precise target is not known. Here we establish by genetic, biochemical and binding assays that the oligomeric subunit c (AtpE) of ATP synthase is the target of R207910. Thus targeting energy metabolism is a new, promising approach for antibacterial drug discovery. | 3 | 9 | 50 | CHEMBL_9 | 2011-01-20 |
CHEMBL1159079 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Pharmacophore modeling and virtual screening for designing potential 5-lipoxygenase inhibitors. | 20045317 | 10.1016/j.bmcl.2009.12.047 | nan | Aparoy P, Kumar Reddy K, Kalangi SK, Chandramohan Reddy T, Reddanna P. | 2010 | 20 | 3 | 1013 | 1018 | PUBLICATION | Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inflammatory disorders such as asthma. In this study, chemical feature based pharmacophore models of inhibitors of 5-LOX have been developed with the aid of HipHop and HypoGen modules within Catalyst program package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.97), consists of two hydrogen-bond acceptors, one hydrophobic feature and one ring aromatic feature. Hypo1 was further validated by test set and cross validation method. The application of the model shows great success in predicting the activities of 65 known 5-LOX inhibitors in our test set with a correlation coefficient of 0.85 with a cross validation of 95% confidence level, proving that the model is reliable in identifying structurally diverse compounds for inhibitory activity against 5-LOX. Furthermore, Hypo1 was used as a 3D query for screening Maybridge and NCI databases within catalyst and also drug like compounds obtained from Enamine Ltd, which follow Lipinski's rule of five. The hit compounds were subsequently subjected to filtering by docking and visualization, to identify the potential lead molecules. Finally 5 potential lead compounds, identified in the above process, were evaluated for their inhibitory activities. These studies resulted in the identification of two compounds with potent inhibition of 5-LOX activity with IC(50) of 14 microM and 35 microM, respectively. These studies thus validate the pharmacophore model generated and suggest the usefulness of the model in screening of various small molecule libraries and identification of potential lead compounds for 5-LOX inhibition. | 83 | 1 | 83 | CHEMBL_5 | 2010-06-24 |
CHEMBL1833871 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | 3D QSAR and docking study of flavone derivatives as potent inhibitors of influenza H1N1 virus neuraminidase. | 21843936 | 10.1016/j.bmcl.2011.07.071 | nan | Gao L, Zu M, Wu S, Liu AL, Du GH. | 2011 | 21 | 19 | 5964 | 5970 | PUBLICATION | Although several flavonoids have been reported to exert inhibitory effects on influenza H1N1 neuraminidase (NA), little is known about the structure-activity relationship and binding mode. Three dimensional QSAR (quantitative structure-activity relationship) and molecular docking approaches were applied to explore the structural requisites of flavone derivatives for NA inhibitory activity. A meaningful QSAR model with R(2) of 0.5968, Q(2) of 0.6457, and Pearson-R value of 0.8679, was constructed. From the QSAR model, it could be seen how 6-OH, 3'-OH, 4'-OH, and 8-position substituent affect the NA inhibitory activity. Molecular docking study between the most active compound and NA suggested that hydrogen bonds, hydrophobic and electrostatic interactions were closely related to NA inhibitory activity, 5-OH and 7-OH may be essential for this activity. The results provide a set of useful guidelines for the rational design of novel NA inhibitors. | 36 | 1 | 106 | CHEMBL_13 | 2012-02-21 |
CHEMBL1129577 | Journal of medicinal chemistry. | 1 | Scientific Literature | Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. | 8576910 | 10.1021/jm950956y | nan | Barbachyn MR, Hutchinson DK, Brickner SJ, Cynamon MH, Kilburn JO, Klemens SP, Glickman SE, Grega KC, Hendges SK, Toops DS, Ford CW, Zurenko GE. | 1996 | 39 | 3 | 680 | 685 | PUBLICATION | During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent. | 5 | 6 | 26 | CHEMBL_1 | 2009-09-03 |
CHEMBL1821659 | ACS medicinal chemistry letters. | 1 | Scientific Literature | N-Benzyl-3-sulfonamidopyrrolidines are a New Class of Bacterial DNA Gyrase Inhibitors. | 21552338 | 10.1021/ml1002822 | nan | Foss MH, Hurley KA, Sorto N, Lackner LL, Thornton KM, Shaw JT, Weibel DB. | 2011 | 2 | 4 | 289 | 292 | PUBLICATION | This paper characterizes N-benzyl-3-sulfonamidopyrrolidines (gyramides) as DNA gyrase inhibitors. Gyramide A was previously shown to exhibit antimicrobial activity that suggested it inhibited bacterial cell division. In this study, we conducted target identification studies and identified DNA gyrase as the primary target of gyramide A. The gyramide A resistance-determining region in DNA gyrase is adjacent to the DNA cleavage gate and is a new site for inhibitor design. We studied the antibiotic effects of gyramides A-C in combination with the Gram-negative efflux pump inhibitor MC-207,110 (60 μM). The gyramides had a minimum inhibitory concentration of 10-40 μM against Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, and Streptococcus pneumoniae; the compounds were ineffective against Enterococcus faecalis. The IC(50) of gyramides A-C against E. coli DNA gyrase was 0.7- 3.3 μM. The N-benzyl-3-sulfonamidopyrrolidines described in this manuscript represent a starting point for development of antibiotics that bind a new site in DNA gyrase. | 6 | 8 | 73 | CHEMBL_13 | 2012-02-21 |
CHEMBL1255443 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | CEM-101 activity against Gram-positive organisms. | 20176910 | 10.1128/aac.01662-09 | nan | Woosley LN, Castanheira M, Jones RN. | 2010 | 54 | 5 | 2182 | 2187 | PUBLICATION | The in vitro activity of CEM-101, a new fluoroketolide, was determined against Gram-positive organisms with various macrolide susceptibility profiles. Experiments for determination of the MICs and minimum bactericidal concentrations (MBCs), timed killing, single-step and multistep mutation rates, the erythromycin induction of resistance, postantibiotic effect (PAE), and drug interactions were performed for CEM-101; and the results were compared to those obtained with telithromycin, macrolides, and lincosamides. The MBCs of CEM-101 remained lower overall than those of telithromycin, and CEM-101 displayed a 2-fold greater potency than the ketolide. Timed-killing curve testing showed that CEM-101 had greater bactericidal activity than telithromycin (a >or=3-log(10)-CFU/ml decrease in the initial inoculum at 24 h) against the staphylococcal isolates tested. The propensity of CEM-101 to cause resistance was low, as determined from the rates of resistance determined in single-step mutational studies (<10(-8) or 10(-9)). In multipassaging studies, mutants of two strains (both of which were USA300 isolates) resistant to CEM-101 emerged. That number was comparable to the number resistant to clindamycin but less than the number resistant to telithromycin. Erythromycin induced CEM-101 resistance in Staphylococcus aureus and Streptococcus pneumoniae, similar to telithromycin; however, in seven of eight beta-hemolytic streptococci, CEM-101 resistance induction was not observed. CEM-101 showed a significant concentration- and exposure-dependent PAE against the strains tested, with the values ranging from 2.3 to 6.1 h for Gram-positive organisms (these times were longer than those for telithromycin). No antagonism was found in synergy analyses, with enhanced inhibition being most noted for combinations with CEM-101 and ceftriaxone, gentamicin, and trimethoprim-sulfamethoxazole. Overall, this new antimicrobial agent (CEM-101) showed good antimicrobial characteristics compared with those of the agents in its class and exhibited measured parameter values similar or superior to those of utilized comparators, indicating that CEM-101 warrants further clinical evaluation. | 4 | 10 | 49 | CHEMBL_10 | 2011-05-26 |
CHEMBL1255453 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. | 20194704 | 10.1128/aac.00019-10 | nan | Kosowska-Shick K, McGhee PL, Appelbaum PC. | 2010 | 54 | 5 | 1670 | 1677 | PUBLICATION | We compared the affinities of ceftaroline for all penicillin-binding proteins (PBPs) with those of ceftriaxone and cefotaxime in 6 Staphylococcus aureus and 7 Streptococcus pneumoniae isolates with various resistance phenotypes. Ceftaroline MICs were <or=1 microg/ml against all S. aureus isolates and were <or=0.25 microg/ml for 4 of 7 isolates of S. pneumoniae. Ceftaroline affinities for penicillin-susceptible S. pneumoniae strains were in the order PBP2X and -3 > PBP1A, -1B, and -2A > PBP2B, and ceftaroline had >or=4-fold higher 50% inhibitory concentrations (IC(50)s) (0.1 to 4 microg/ml) for PBP2X, -2A, -2B, and -3 than those for the other cephalosporins tested. Among 3 penicillin-resistant S. pneumoniae strains, ceftaroline had a high affinity for PBP2X (IC(50), 0.1 to 1 microg/ml), a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B (IC(50), 0.5 to 4 microg/ml) and PBP1A (IC(50), 0.125 to 0.25 microg/ml) as well, both of which are also known as major targets for PBP binding activity of cephalosporins. Ceftaroline PBP affinities in methicillin-susceptible S. aureus strains were greater than or equal to those of the 3 other beta-lactams tested. Ceftaroline bound to PBP2a in methicillin-resistant S. aureus (IC(50), 0.01 to 1 microg/ml) with up to 256-fold-higher affinity than those of other agents. Ceftaroline demonstrated very good PBP affinity against all S. aureus and S. pneumoniae strains tested, including resistant isolates. | 4 | 7 | 240 | CHEMBL_10 | 2011-05-26 |
CHEMBL1641428 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Inhibition of the β-carbonic anhydrase from Streptococcus pneumoniae by inorganic anions and small molecules: Toward innovative drug design of antiinfectives? | 21163660 | 10.1016/j.bmc.2010.11.031 | nan | Burghout P, Vullo D, Scozzafava A, Hermans PW, Supuran CT. | 2011 | 19 | 1 | 243 | 248 | PUBLICATION | The Gram-positive bacterium Streptococcus pneumoniae is a human respiratory tract pathogen that contributes significantly to global mortality and morbidity. It was recently shown that this bacterial pathogen depends on a conserved β-carbonic anhydrase (CA, EC 4.2.1.1) for in vitro growth in environmental ambient air and during intracellular survival in host cells. Hence, it is to be expected that this pneumococcal carbonic anhydrase (PCA) contributes to transmission and pathogenesis of the bacterium, making it a potential therapeutic target. In this study, purified recombinant PCA has been further characterized kinetically and for inhibition with a series of inorganic anions and small molecules useful as leads. PCA has appreciable activity as catalyst for the hydration of CO(2) to bicarbonate, with a k(cat) of 7.4×10(5)s(-1) and k(cat)/K(m) of 6.5×10(7) M(-1)s(-1) at an optimum pH of 8.4. Inorganic anions such as chloride, bromide, iodide, cyanate, selenocyanate, trithiocarbonate, and cyanide were effective inhibitors of PCA (K(I)s of 21-98μM). Sulfamide, sulfamic acid, phenylboronic, phenylarsonic acid, and diethyldithiocarbamate showed inhibition constants in the low micromolar/submicromolar range (K(I)s of 0.61-6.68μM), whereas that of the sulfonamide acetazolamide was in the nanomolar range (K(I)s 89nM). In conclusion, our results show that PCA can effectively be inhibited by a range of molecules that could be interesting leads for obtaining more potent PCA inhibitors. PCA might be a novel target for designing antimicrobial drugs with a new mechanism of action. | 34 | 4 | 67 | CHEMBL_11 | 2011-08-01 |
CHEMBL1152331 | Journal of natural products. | 1 | Scientific Literature | seco-Abietane diterpenoids, a phenylethanoid derivative, and antitubercular constituents from Callicarpa pilosissima. | 19193025 | 10.1021/np800721f | nan | Chen JJ, Wu HM, Peng CF, Chen IS, Chu SD. | 2009 | 72 | 2 | 223 | 228 | PUBLICATION | Six new compounds, including five new seco-abietane diterpenoids, 12-deoxy-seco-hinokiol methyl ester (1), 12-deoxy-11,12-dihydro-seco-hinokiol methyl ester (2), callicarpic acid A (3), 9alpha-hydroxycallicarpic acid A (4), and callicarpic acid B (5), and a new phenylethanoid derivative, 4-hydroxyphenethyl tetradecanoate (6), have been isolated from the leaves and twigs of Callicarpa pilosissima, together with 14 known compounds (7-20). The structures of these new compounds were determined through analyses of physical data. 12-Deoxy-11,12-dihydro-seco-hinokiol methyl ester (2), callicarpic acid B (5), and alpha-tocopherol trimer B (15) exhibit antitubercular activities (MICs <or= 63.6 microM) against Mycobacterium tuberculosis H(37)Rv in vitro. | 18 | 1 | 18 | CHEMBL_3 | 2010-04-16 |
CHEMBL1145050 | Journal of medicinal chemistry. | 1 | Scientific Literature | Discovery of (3S)-amino-(4R)-ethylpiperidinyl quinolones as potent antibacterial agents with a broad spectrum of activity and activity against resistant pathogens. | 12904069 | 10.1021/jm030272n | nan | Hu XE, Kim NK, Gray JL, Almstead JI, Seibel WL, Ledoussal B. | 2003 | 46 | 17 | 3655 | 3661 | PUBLICATION | Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed by using low energy conformation analysis and synthesized by applying a conventional coupling reaction of the quinolone nuclei with new piperidine side chains. These compounds were tested in MIC assays and found to be highly potent against Gram-positive and Gram-negative organisms. In particular, the new compounds exhibited high activity against the resistant pathogens Staphylococcus aureus (MRCR) and Streptococcus pneumoniae (PR). Importantly, when the (3S)-amino-(4R)-ethylpiperidinyl quinolones were compared with marketed quinolones sharing the same quinolone nuclei but different side chains at the C-7 position, the new quinolones showed superior activity against Gram-positive organisms, including resistant pathogens. | 17 | 6 | 124 | CHEMBL_1 | 2009-09-03 |
CHEMBL1146805 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Carbonic anhydrase inhibitors. Inhibition of cytosolic isozyme XIII with aromatic and heterocyclic sulfonamides: a novel target for the drug design. | 15203157 | 10.1016/j.bmcl.2004.04.106 | nan | Lehtonen JM, Parkkila S, Vullo D, Casini A, Scozzafava A, Supuran CT. | 2004 | 14 | 14 | 3757 | 3762 | PUBLICATION | The inhibition of the newly discovered cytosolic carbonic anhydrase isozyme XIII (CA XIII) has been investigated with a series of aromatic and heterocyclic sulfonamides, including some of the clinically used derivatives, such as acetazolamide, methazolamide, dichlorophenamide, dorzolamide, and valdecoxib. Inhibition data for the physiologically relevant isozymes I and II (cytosolic forms) and the tumor associated isozyme IX (transmembrane) were also provided for comparison. A very interesting and unusual inhibition profile against CA XIII with these sulfonamides has been observed. The clinically used compounds (except valdecoxib, which was a weak CA XIII inhibitor) potently inhibit CA XIII, with Ki's in the range of 17-23 nM, whereas sulfanilamide, halogenated sulfanilamides, homosulfanilamide, 4-aminoethylbenzenesulfonamide, and orthanilamide were slightly less effective, with Ki's in the range of 32-56 nM. Several low nanomolar (Ki's in the range of 1.3-2.4 nM) CA XIII inhibitors have also been detected, all of them belonging to the sulfanilyl-sulfonamide type of inhibitors, of which aminobenzolamide is the best known representative. Because CA XIII is an active isozyme predominantly expressed in salivary glands, kidney, brain, lung, gut, uterus, and testis, where it probably plays an important role in pH regulation, its inhibition by sulfonamides may lead to novel therapeutic applications for this class of pharmacological agents. | 17 | 4 | 68 | CHEMBL_1 | 2009-09-03 |
CHEMBL1833842 | European journal of medicinal chemistry. | 1 | Scientific Literature | 1,3-Dihydro-2H-indol-2-ones derivatives: design, synthesis, in vitro antibacterial, antifungal and antitubercular study. | 21981980 | 10.1016/j.ejmech.2011.09.023 | nan | Akhaja TN, Raval JP. | 2011 | 46 | 11 | 5573 | 5579 | PUBLICATION | 1,3-dihydro-2H-indol-2-ones derivatives are reported to exhibit a wide variety of biodynamic activities such as antituberculer, anti HIV, fungicidal, antibacterial, anticonvulsant. These valid observations led us to synthesize some new indole-2-one derivative. Thus, herein we report synthesis of various 5-substituted-3-[{5-(6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4 tetrahydro pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl}imino]-1,3-dihydro-2H-indol-2-one derivatives 4a-l using one pot multicomponent-Biginelli reaction via CaCl(2) catalyst. Structures and purity of these compounds were confirmed by elemental, IR, ((1)H &(13)C) NMR and Mass spectral analysis. Newly synthesized compounds were also tested for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H(37)Rv, in vitro antibacterial activity against selected human pathogens viz. Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Staphylococcus aureus, Staphylococcus pyogenus, Bacillus subtilis and antifungal activity against Candida albicans, Aspergillus niger, Aspergillus clavatus strains. | 21 | 11 | 189 | CHEMBL_13 | 2012-02-21 |
CHEMBL1649539 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Pharmacokinetics-pharmacodynamics of pyrazinamide in a novel in vitro model of tuberculosis for sterilizing effect: a paradigm for faster assessment of new antituberculosis drugs. | 19451303 | 10.1128/aac.01681-08 | nan | Gumbo T, Dona CS, Meek C, Leff R. | 2009 | 53 | 8 | 3197 | 3204 | PUBLICATION | There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log(10) CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. The sterilizing effect was linked to the pyrazinamide ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC (r(2) = 0.80 to 0.90), with 90% of the maximal effect being achieved by an AUC(0-24)/MIC of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r(2) = 0.73 to 0.91). Monte Carlo simulations of 10,000 patients demonstrated that the currently recommended pyrazinamide doses (15 to 30 mg/kg of body weight/day) achieved the AUC(0-24)/MIC of 209.08 in the epithelial lining fluid of only 15.1 to 53.3% of patients. Doses of >60 mg/kg per day performed better. Our vitro model for the sterilizing effect, together with Monte Carlo simulations, can be used for the faster identification of the clinical doses that are needed to achieve a sterilizing effect and that can then be studied in clinical trials. | 1 | 3 | 10 | CHEMBL_11 | 2011-08-01 |
CHEMBL1151975 | Journal of natural products. | 1 | Scientific Literature | Isolation, structure, and antibacterial activities of lucensimycins D-G, discovered from Streptomyces lucensis MA7349 using an antisense strategy. | 19115838 | 10.1021/np8005106 | nan | Singh SB, Zink DL, Dorso K, Motyl M, Salazar O, Basilio A, Vicente F, Byrne KM, Ha S, Genilloud O. | 2009 | 72 | 3 | 345 | 352 | PUBLICATION | Bacterial resistance to existing antibiotics continues to grow, necessitating the discovery of new compounds of this type. Antisense-based whole-cell target-based screening is a new and highly sensitive antibiotic discovery approach that has led to a number of new natural product antibiotics. Screening with a rpsD-sensitized strain led to the discovery of a number of natural product polyketides from Streptomyces lucensis. Complete workup of the fermentation extract of this strain allowed for the isolation of seven new compounds, lucensimycins A-G (1-3, 4a, 5-7), with varying degrees of antibacterial activities. Lucensimycin E (5) exhibited the best activity and showed MIC values of 32 microg/mL against Staphylococcus aureus and 8 microg/mL against Streptococcus pneumoniae. The isolation, structure elucidation, and antibacterial activities of four new members, lucensimycins D-G, are described. Lucensimycins D (4a) and E (5) are N-acetyl-l-cysteine adducts of lucensimycin A (1). Semisynthesis of lucensimycins D and E from lucensimycin A has also been described. Lucensimycins F and G are myo-inositolyl-alpha-2-amino-2-deoxy-l-idosyl amide derivatives of lucensimycins D and E, respectively. The relative configuration of these compounds was determined, in part, by molecular dynamics simulations. | 10 | 8 | 48 | CHEMBL_3 | 2010-04-16 |
CHEMBL1649268 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Comparative in vitro activity profile of oritavancin against recent gram-positive clinical isolates. | 19738026 | 10.1128/aac.00952-09 | nan | Arhin FF, Draghi DC, Pillar CM, Parr TR, Moeck G, Sahm DF. | 2009 | 53 | 11 | 4762 | 4771 | PUBLICATION | Oritavancin activity was tested against 15,764 gram-positive isolates collected from 246 hospital centers in 25 countries between 2005 and 2008. Organisms were Staphylococcus aureus (n = 9,075), coagulase-negative staphylococci (n = 1,664), Enterococcus faecalis (n = 1,738), Enterococcus faecium (n = 819), Streptococcus pyogenes (n = 959), Streptococcus agalactiae (n = 415), group C, G, and F streptococci (n = 84), and Streptococcus pneumoniae (n = 1,010). Among the evaluated staphylococci, 56.7% were resistant to oxacillin. The vancomycin resistance rate among enterococci was 21.2%. Penicillin-resistant and -intermediate rates were 14.7% and 21.4%, respectively, among S. pneumoniae isolates. Among nonpneumococcal streptococci, 18.5% were nonsusceptible to erythromycin. Oritavancin showed substantial in vitro activity against all organisms tested, regardless of resistance profile. The maximum oritavancin MIC against all staphylococci tested (n = 10,739) was 4 microg/ml; the MIC(90) against S. aureus was 0.12 microg/ml. Against E. faecalis and E. faecium, oritavancin MIC(90)s were 0.06 and 0.12, respectively. Oritavancin was active against glycopeptide-resistant enterococci, including VanA strains (n = 486), with MIC(90)s of 0.25 and 1 microg/ml against VanA E. faecium and E. faecalis, respectively. Oritavancin showed potent activity against streptococci (n = 2,468); MIC(90)s for the different streptococcal species were between 0.008 and 1 microg/ml. These data are consistent with previous studies with respect to resistance rates of gram-positive isolates and demonstrate the spectrum and in vitro activity of oritavancin against a wide variety of contemporary gram-positive pathogens, regardless of resistance to currently used drugs. The data provide a foundation for interpreting oritavancin activity and potential changes in susceptibility over time once oritavancin enters into clinical use. | 17 | 10 | 979 | CHEMBL_11 | 2011-08-01 |
CHEMBL1147478 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Phosphonate inhibitors of antigen 85C, a crucial enzyme involved in the biosynthesis of the Mycobacterium tuberculosis cell wall. | 15177473 | 10.1016/j.bmcl.2004.04.052 | nan | Gobec S, Plantan I, Mravljak J, Wilson RA, Besra GS, Kikelj D. | 2004 | 14 | 13 | 3559 | 3562 | PUBLICATION | The first phosphonate inhibitors of antigen 85C--a major protein component of the Mycobacterium tuberculosis cell wall possessing mycolyltransferase activity were prepared using structure-based design. These potential novel antituberculosis agents, consisting of a phosphonate moiety, hydrophobic alkyl chain and a simple trehalose-mimicking aromatic structure, were designed as tetrahedral transition-state analogue inhibitors of antigen 85C, which catalyzes the key mycolyltransferase reaction involved in cell wall biosynthesis. | 17 | 1 | 17 | CHEMBL_1 | 2009-09-03 |
CHEMBL1671750 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Emergence and molecular characterization of extensively drug-resistant Mycobacterium tuberculosis clinical isolates from the Delhi Region in India. | 20713679 | 10.1128/aac.00661-10 | nan | Khanna A, Raj VS, Tarai B, Sood R, Pareek PK, Upadhyay DJ, Sharma P, Rattan A, Saini KS, Singh H. | 2010 | 54 | 11 | 4789 | 4793 | PUBLICATION | We screened 194 Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in Delhi and neighboring regions in India to identify the prevalence of extensive drug resistance (XDR) in clinical isolates. Among these, 104 isolates were found to be multidrug resistant (MDR), and 6 were identified as XDR isolates, which was later confirmed by antimicrobial susceptibility testing against the respective drug screening panel. Genotyping was carried out by amplifying and sequencing the following genes: rpoB (rifampin), katG (isoniazid), gyrA (fluoroquinolones), and rrs (amikacin, kanamycin, and capreomycin). Our analyses indicated that mutations at the hot spots of these genes were positively correlated with drug resistance in clinical isolates. The key mutation observed for rpoB was in the codon for amino acid position 531 (S531L), and other mutations were seen in the hot spot, including those encoding Q510P, L511H, D516V, and H526Y mutations. We identified S315T and R463L substitutions encoded in the katG locus. An S95T substitution encoded in the gyrA locus was the most common mutation observed in fluoroquinolone-resistant isolates. In addition, we saw D94G and D94N mutations encoded in the QRDR region. The 16S rRNA (rrs) gene encoded mainly the A1401G mutation and an additional mutation, G1484T, resulting in ribosomal modifications. Taken together, the data in this report clearly establish the presence of phenotypically distinct XDR strains in India by molecular profiling and further identify specific mutational hot spots within key genes of XDR-TB strains. | 13 | 1 | 126 | CHEMBL_11 | 2011-08-01 |
CHEMBL1156544 | Journal of natural products. | 1 | Scientific Literature | Bioactive brominated metabolites from the red sea sponge Suberea mollis. | 18656986 | 10.1021/np800142n | nan | Abou-Shoer MI, Shaala LA, Youssef DT, Badr JM, Habib AA. | 2008 | 71 | 8 | 1464 | 1467 | PUBLICATION | Reinvestigation of the Red Sea sponge Suberea mollis afforded two new bromotyrosine-derived alkaloids, subereamollines A (1) and B (2), two new brominated phenolic compounds, subereaphenols B (7) and C (9), and the known compounds aerothionin (3), homoaerothionin (4), 11,19-dideoxyfistularin-3 (5), aeroplysinin-1 (6), and aeroplysinin-2 (8). The structure determination of the isolated compounds was assigned using one- and two-dimensional NMR spectra and HRFABMS data. The antimicrobial and antioxidant activities of the isolated compounds have been evaluated. Aeroplysinin-1 displayed significant antimicrobial activity against S. aureus, P. aerugenosa, and K. pneumoniae. The isolated compounds were examined for their antioxidant activity using a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) solution-based chemical assay. Among the tested compounds, only subereaphenols B and C displayed a significant effect. | 13 | 4 | 41 | CHEMBL_2 | 2009-11-30 |
CHEMBL1155341 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antibacterial activity of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones. | 19646867 | 10.1016/j.bmcl.2009.07.087 | nan | Zhu B, Marinelli BA, Goldschmidt R, Foleno BD, Hilliard JJ, Bush K, Macielag MJ. | 2009 | 19 | 17 | 4933 | 4936 | PUBLICATION | A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon-carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae. | 22 | 3 | 136 | CHEMBL_4 | 2010-05-18 |
CHEMBL1287649 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and anti-tubercular and antimicrobial activities of some 2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one N-isonicotinoylhydrazone derivatives. | 20822833 | 10.1016/j.ejmech.2010.08.024 | nan | Sankar C, Pandiarajan K. | 2010 | 45 | 11 | 5480 | 5485 | PUBLICATION | In this study, seven 2r,4c-diaryl-3-azabicyclo[3.3.1]nonan-9-one N-isonicotinoylhydrazones 8-14 were synthesized. The structure and stereochemistry of these compounds were established by IR and NMR spectral data. The purities were checked by elemental analysis. The synthesized compounds adopt twin-chair conformation with equatorial orientations of the aryl groups. The compounds were evaluated for their in vitro anti-tubercular and antimicrobial activities. The initial screen was conducted against Mycobacterium tuberculosis H(37)Rv (ATTCC 27294) and INH-TB by luciferase reporter phage assay method. All the synthesized compounds showed very good activity against MTB and INH-TB. Though all the compounds showed good antimicrobial activity only 11 (Ar = p-chlorophenyl), 12 (Ar = p-fluorophenyl), 13 (Ar = m-chlorophenyl) and 14 (Ar = m-methoxyphenyl) exhibited activity against all the tested (bacterial and fungal) microorganisms. The results suggest that the formation of hydrogen bonds may play a significant role in drug action. | 11 | 9 | 117 | CHEMBL_10 | 2011-05-26 |
CHEMBL1157988 | Journal of natural products. | 1 | Scientific Literature | Loloatins A-D, cyclic decapeptide antibiotics produced in culture by a tropical marine bacterium. | 9917287 | 10.1021/np980219f | nan | Gerard JM, Haden P, Kelly MT, Andersen RJ. | 1999 | 62 | 1 | 80 | 85 | PUBLICATION | Loloatins A (1) to D (4), a family of new cyclic decapeptide antibiotics, have been isolated from laboratory cultures of a tropical marine bacterium recovered from the Great Barrier Reef in Papua New Guinea. The structures of loloatins A-D were elucidated via a combination of spectroscopic analyses and chemical degradation. Loloatins A-D exhibit in vitro antimicrobial activity against methicillin-resistant Staphyloccoccus aureus, vancomycin-resistant enterococci, and drug-resistant Streptococcus pneumoniae. | 4 | 9 | 52 | CHEMBL_2 | 2009-11-30 |
CHEMBL1255469 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro activity of a new isothiazoloquinolone, ACH-702, against Mycobacterium tuberculosis and other mycobacteria. | 20231398 | 10.1128/aac.01603-09 | nan | Molina-Torres CA, Ocampo-Candiani J, Rendón A, Pucci MJ, Vera-Cabrera L. | 2010 | 54 | 5 | 2188 | 2190 | PUBLICATION | In this work, we describe the activity of ACH-702 against clinical isolates of Mycobacterium tuberculosis and six different nontuberculous mycobacteria. The MIC(50) and MIC(90) of both susceptible and drug-resistant M. tuberculosis strains tested were 0.0625 and 0.125 microg/ml, respectively. The MIC(50) and MIC(90) values for Mycobacterium fortuitum isolates were 0.0625 microg/ml in both cases; Mycobacterium avium complex isolates showed MIC(50) and MIC(90) values of 0.25 and 4 microg/ml, respectively. | 1 | 8 | 15 | CHEMBL_10 | 2011-05-26 |
CHEMBL1667745 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antibacterial evaluation of novel clarithromycin derivatives with C-4″ elongated arylalkyl groups against macrolide-resistant strains. | 21159410 | 10.1016/j.ejmech.2010.11.035 | nan | Ma S, Jiao B, Ju Y, Zheng M, Ma R, Liu L, Zhang L, Shen X, Ma C, Meng Y, Wang H, Qi Y, Ma X, Cui W. | 2011 | 46 | 2 | 556 | 566 | PUBLICATION | Novel clarithromycin derivatives with C-4″ elongated arylalkyl groups were designed, synthesized and evaluated to probe the effect of different lengths of their C-4″ side chains on the activity against resistant bacterial strains. These derivatives had excellent activity against erythromycin-susceptible Streptococcus pneumoniae, Streptococcus aureus or Streptococcus pyogenes and some of them exhibited greatly improved activity against erythromycin-resistant strains. Compounds 18 and 16, which had the C-4″ elongated arylalkyl groups with eight atoms from the 4″-oxygen atom to the terminal benzene ring, were the most effective against S. pneumoniae expressing the erm gene and the erm and mef genes. In contrast, the most potent compounds 3, 5, 9, 17 and 18 against S. pneumoniae expressing the mef gene had C-4″ elongated arylalkyl groups with three to eight atoms between the 4″-oxygen atom and the terminal aromatic ring. | 36 | 3 | 288 | CHEMBL_11 | 2011-08-01 |
CHEMBL1255399 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Haemophilus influenzae clinical isolates with plasmid pB1000 bearing blaROB-1: fitness cost and interspecies dissemination. | 20086141 | 10.1128/aac.01489-09 | nan | San Millan A, Garcia-Cobos S, Escudero JA, Hidalgo L, Gutierrez B, Carrilero L, Campos J, Gonzalez-Zorn B. | 2010 | 54 | 4 | 1506 | 1511 | PUBLICATION | Plasmid pB1000 is a mobilizable replicon bearing the bla(ROB-1) beta-lactamase gene that we have recently described in Haemophilus parasuis and Pasteurella multocida animal isolates. Here we report the presence of pB1000 and a derivative plasmid, pB1000', in four Haemophilus influenzae clinical isolates of human origin. Pulsed-field gel electrophoresis showed unrelated patterns in all strains, indicating that the existence of pB1000 in H. influenzae isolates is not the consequence of clonal dissemination. The replicon can be transferred both by transformation and by conjugation into H. influenzae, giving rise to recipients resistant to ampicillin and cefaclor (MICs, > or =64 microg/ml). Stability experiments showed that pB1000 is stable in H. influenzae without antimicrobial pressure for at least 60 generations. Competition experiments between isogenic H. influenzae strains with and without pB1000 revealed a competitive disadvantage of 9% per 10 generations for the transformant versus the recipient. The complete nucleotide sequences of nine pB1000 plasmids from human and animal isolates, as well as the epidemiological data, suggest that animal isolates belonging to the Pasteurellaceae act as an antimicrobial resistance reservoir for H. influenzae. Further, since P. multocida is the only member of this family that can colonize both humans and animals, we propose that P. multocida is the vehicle for the transport of pB1000 between animal- and human-adapted members of the Pasteurellaceae. | 9 | 1 | 54 | CHEMBL_10 | 2011-05-26 |
CHEMBL1795314 | European journal of medicinal chemistry. | 1 | Scientific Literature | Mycobacterium tuberculosis and cholinesterase inhibitors from Voacanga globosa. | 21546135 | 10.1016/j.ejmech.2011.04.025 | nan | Macabeo AP, Vidar WS, Chen X, Decker M, Heilmann J, Wan B, Franzblau SG, Galvez EV, Aguinaldo MA, Cordell GA. | 2011 | 46 | 7 | 3118 | 3123 | PUBLICATION | Globospiramine (1), a new spirobisindole alkaloid possessing an Aspidosperma-Aspidosperma skeleton, together with deoxyvobtusine (2), deoxyvobtusine lactone (3), vobtusine lactone (4) and lupeol (5), were isolated and identified from Voacanga globosa through a bioassay-guided purification. The gross structure and absolute stereochemistry of 1 were established by circular dichroism spectroscopy, HR-MS and unambiguous NMR spectroscopic experiments. In addition, a new biogenetic pathway for the formation of the spiro-Aspidosperma-Aspidosperma skeleton is proposed. Alkaloid 1 showed potent antituberculosis activity against Mycobacterium tuberculosis H(37)Rv as evidenced in microplate Alamar blue assay (MIC = 4 μg/mL) and low-oxygen recovery assay (LORA (MIC = 5.2 μg/mL). The bisindole alkaloids also exhibited promising activity against acetylcholinesterase and, especially butyrylcholinesterase, with deoxyvobtusine (2) (IC(50) = 6.2 μM) as the most strongly inhibiting compound. This study extends the variety of alkaloid structural platforms which exhibit antimycobacterial and anticholinesterase activity. | 9 | 3 | 36 | CHEMBL_13 | 2012-02-21 |
CHEMBL1255447 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Efflux pumps, OprD porin, AmpC beta-lactamase, and multiresistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. | 20194693 | 10.1128/aac.00816-09 | nan | Tomás M, Doumith M, Warner M, Turton JF, Beceiro A, Bou G, Livermore DM, Woodford N. | 2010 | 54 | 5 | 2219 | 2224 | PUBLICATION | Expression of ampC, oprD, mexA, mexC, mexE, and mexX was studied in 25 Pseudomonas aeruginosa isolates from cystic fibrosis patients, including 14 isolates of the Liverpool epidemic strain. Overexpressed mexA or ampC and reduced oprD were associated with beta-lactam resistance. A specific combination of mexR, nalC, and nalD mutations occurred in 11 Liverpool strain isolates, including 7 with upregulated mexA. | 10 | 1 | 320 | CHEMBL_10 | 2011-05-26 |
CHEMBL1255475 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Mutant prevention concentrations of four carbapenems against gram-negative rods. | 20308376 | 10.1128/aac.00033-10 | nan | Credito K, Kosowska-Shick K, Appelbaum PC. | 2010 | 54 | 6 | 2692 | 2695 | PUBLICATION | We tested the propensities of four carbapenems to select for resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii mutants by determining the mutant prevention concentrations (MPCs) for 100 clinical strains with various ss-lactam phenotypes. Among the members of the Enterobacteriaceae family and A. baumannii strains, the MPC/MIC ratios were mostly 2 to 4. In contrast, for P. aeruginosa the MPC/MIC ratios were 4 to > or =16. The MPC/MIC ratios for beta-lactamase-positive K. pneumoniae and E. coli isolates were much higher (range, 4 to >16 microg/ml) than those for ss-lactamase-negative strains. | 5 | 4 | 1204 | CHEMBL_10 | 2011-05-26 |
CHEMBL1157817 | Journal of medicinal chemistry. | 1 | Scientific Literature | 2-aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase I. | 20441173 | 10.1021/jm100306a | nan | Ilies M, Di Costanzo L, North ML, Scott JA, Christianson DW. | 2010 | 53 | 10 | 4266 | 4276 | PUBLICATION | Arginase, a key metalloenzyme of the urea cycle that converts L-arginine into L-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant l-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl)pentanoic acid (A1P, 10), binds to human arginase I with K(d) = 2 microM and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles. | 6 | 4 | 25 | CHEMBL_6 | 2010-08-27 |
CHEMBL1156074 | Journal of medicinal chemistry. | 1 | Scientific Literature | Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study. | 19791806 | 10.1021/jm900950d | nan | Pintér G, Batta G, Kéki S, Mándi A, Komáromi I, Takács-Novák K, Sztaricskai F, Röth E, Ostorházi E, Rozgonyi F, Naesens L, Herczegh P. | 2009 | 52 | 19 | 6053 | 6061 | PUBLICATION | Semisynthetic, lipophilic ristocetin and teicoplanin derivatives were prepared starting from ristocetin aglycon and teicoplanin psi-aglycon (N-acetyl-D-glucosaminyl aglycoteicoplanin). The terminal amino functions of the aglycons were converted into azido form by triflic azide. Copper catalyzed 1,3-dipolar cycloaddition reaction with lipophilic alkynes resulted in the title compounds. Two of the teicoplanin derivatives showed very good MIC and MBC values against various Gram-positive bacteria, including vanA enterococci. The aggregation and interaction of a n-decyl derivative with bacterial cell wall components was studied. One of the lipophilic ristocetin derivatives displayed favorable anti-influenza virus activity. | 16 | 9 | 235 | CHEMBL_4 | 2010-05-18 |
CHEMBL1240440 | European journal of medicinal chemistry. | 1 | Scientific Literature | A bioactive labdane diterpenoid from Curcuma amada and its semisynthetic analogues as antitubercular agents. | 20584563 | 10.1016/j.ejmech.2010.06.006 | nan | Singh S, Kumar JK, Saikia D, Shanker K, Thakur JP, Negi AS, Banerjee S. | 2010 | 45 | 9 | 4379 | 4382 | PUBLICATION | A labdane diterpene dialdehyde was first time isolated from the chloroform extract of rhizomes of Curcuma amada. This compound exhibited antitubercular activity (MIC=500 microg/mL) against Mycobacterium tuberculosis H(37)Rv strain in BACTEC-460 assay. Two of its semisynthetic analogues also exhibited antitubercular activity at 250-500 microg/mL. It is the first report on isolation and antimycobacterial activity of this dialdehyde from C. amada. | 6 | 1 | 6 | CHEMBL_10 | 2011-05-26 |
CHEMBL1155937 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Substituted 3-((Z)-2-(4-nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones as novel anti-MRSA agents: synthesis, SAR, and in-vitro assessment. | 18650090 | 10.1016/j.bmcl.2008.07.007 | nan | Diwakar SD, Bhagwat SS, Shingare MS, Gill CH. | 2008 | 18 | 16 | 4678 | 4681 | PUBLICATION | In search for a new antibacterial agent with improved antimicrobial spectrum and potency, we designed and synthesized a series of novel 3-((Z)-2-(4-nitrophenyl)-2-(1H-tetrazol-5-yl) vinyl)-4H-chromen-4-ones 7a-h by convergent synthesis approach. All the synthesized compounds were assayed for their in-vitro antibacterial activities against gram-negative and gram-positive bacteria. The preliminary structure-activity relationship, to elucidate the essential structure requirements for the antimicrobial activity that results into anti-MRSA (methicillin-resistant S. aureus) potential, has been described. Amongst the synthesized compounds 7d, 7e, 7f and 7h were found to possess activity against methicillin-resistant S. aureus in addition to the activity against other bacterial strains such as E. faecalis, S. pneumoniae, and E. coli. | 12 | 5 | 52 | CHEMBL_2 | 2009-11-30 |
CHEMBL1828595 | European journal of medicinal chemistry. | 1 | Scientific Literature | A facile four-component sequential protocol in the expedient synthesis of novel 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones in water and their antitubercular evaluation. | 21839549 | 10.1016/j.ejmech.2011.07.029 | nan | Gunasekaran P, Perumal S, Yogeeswari P, Sriram D. | 2011 | 46 | 9 | 4530 | 4536 | PUBLICATION | A series of 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones has been synthesized by one-pot, four-component sequential reactions of phenylhydrazine, methyl acetoacetate, aromatic aldehydes and β-naphthol in the presence of p-toluenesulphonic acid in water in good yields. These 2-aryl-5-methyl-2,3-dihydro-1H-3-pyrazolones were screened for in-vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among the 15 compounds screened, 4-[(2,4-dichlorophenyl)(2-hydroxy-1-naphthyl)methyl]-2-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-3-pyrazolone displays the maximum potency with a minimum inhibitory concentration (MIC) of 1.6 μM against MTB, being 2.94 and 4.75 times more active than ciprofloxacin and ethambutol respectively. | 19 | 1 | 21 | CHEMBL_13 | 2012-02-21 |
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