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CHEMBL1132253 | Journal of medicinal chemistry. | 1 | Scientific Literature | Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent. | 10395473 | 10.1021/jm980707k | nan | Atigadda VR, Brouillette WJ, Duarte F, Ali SM, Babu YS, Bantia S, Chand P, Chu N, Montgomery JA, Walsh DA, Sudbeck EA, Finley J, Luo M, Air GM, Laver GW. | 1999 | 42 | 13 | 2332 | 2343 | PUBLICATION | On the basis of the lead compound 4-(N-acetylamino)-3-guanidinobenzoic acid (BANA 113), which inhibits influenza A sialidase with a Ki of 2.5 microM, several novel aromatic inhibitors of influenza sialidases were designed. In this study the N-acetyl group of BANA 113 was replaced with a 2-pyrrolidinone ring, which was designed in part to offer opportunities for introduction of spatially directed side chains that could potentially interact with the 4-, 5-, and/or 6-subsites of sialidase. While the parent structure 1-(4-carboxy-2-guanidinophenyl)pyrrolidin-2-one (8) was only a modest inhibitor of sialidase, the introduction of a hydroxymethyl or bis(hydroxymethyl) substituent at the C5' position of the 2-pyrrolidinone ring resulted in inhibitors (9 and 12, respectively) with low micromolar activity. Crystal structures of these inhibitors in complex with sialidase demonstrated that the substituents at the 5'-position of the 2-pyrrolidinone ring interact in the 4- and/or 5-subsites of the enzyme. Replacement of the guanidine in 12 with a hydrophobic 3-pentylamino group resulted in a large enhancement in binding to produce an inhibitor (14) with an IC50 of about 50 nM against influenza A sialidase, although the inhibition of influenza B sialidase was 2000-fold less. This represents the first reported example of a simple, achiral benzoic acid with potent (low nanomolar) activity as an inhibitor of influenza sialidase. | 11 | 2 | 19 | CHEMBL_1 | 2009-09-03 |
CHEMBL2151014 | European journal of medicinal chemistry. | 1 | Scientific Literature | Facile water promoted synthesis of 1,2,3-triazolyl dihydropyrimidine-2-thione hybrids - highly potent antibacterial agents. | 23151322 | 10.1016/j.ejmech.2012.10.029 | nan | Sangaraiah N, Murugan S, Poovan S, Raja R, Alagusundaram P, Ramakrishnan V, Vellasamy S. | 2012 | 58 | nan | 464 | 469 | PUBLICATION | An elegant and efficient synthesis of hitherto novel 1,2,3-triazolyl dihydropyrimidine-2-thione hybrids has been accomplished for the first time in a green solvent viz. water. The hybrid molecules exhibit significant antibacterial activity when screened against four human pathogens viz. Streptococcus pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi. In comparison to the commercially marketed tetracycline, some of them were equally potent and a few more potent. | 13 | 4 | 52 | CHEMBL_16 | 2013-05-07 |
CHEMBL1921781 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs. | 22024034 | 10.1016/j.bmcl.2011.09.123 | nan | Uh E, Jackson ER, San Jose G, Maddox M, Lee RE, Lee RE, Boshoff HI, Dowd CS. | 2011 | 21 | 23 | 6973 | 6976 | PUBLICATION | The nonmevalonate pathway (NMP) of isoprene biosynthesis is an exciting new route toward novel antibiotic development. Inhibitors against several enzymes in this pathway are currently under examination. A significant liability of many of these agents is poor cell penetration. To overcome and improve our understanding of this problem, we have synthesized a series of lipophilic, prodrug analogs of fosmidomycin and FR900098, inhibitors of the NMP enzyme Dxr. Several of these compounds show improved antibacterial activity against a panel of organisms relative to the parent compound, including activity against Mycobacterium tuberculosis (Mtb). Our results show that this strategy can be an effective way for improving whole cell activity of NMP inhibitors. | 12 | 6 | 96 | CHEMBL_14 | 2012-06-27 |
CHEMBL2057185 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Analogs of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases. | 22704656 | 10.1016/j.bmc.2012.05.022 | nan | Bhat S, Olaleye O, Meyer KJ, Shi W, Zhang Y, Liu JO. | 2012 | 20 | 14 | 4507 | 4513 | PUBLICATION | Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents. | 25 | 3 | 123 | CHEMBL_15 | 2013-01-23 |
CHEMBL2046332 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Substrate analog studies of the ω-regiospecificity of Mycobacterium tuberculosis cholesterol metabolizing cytochrome P450 enzymes CYP124A1, CYP125A1 and CYP142A1. | 22647881 | 10.1016/j.bmc.2012.05.003 | nan | Johnston JB, Singh AA, Clary AA, Chen CK, Hayes PY, Chow S, De Voss JJ, Ortiz de Montellano PR. | 2012 | 20 | 13 | 4064 | 4081 | PUBLICATION | We report the synthesis and evaluation of a series of cholesterol side-chain analogs as mechanistic probes of three important Mycobacterium tuberculosis cytochrome P450 enzymes that selectively oxidize the ω-position of the methyl-branched cholesterol side-chain. To probe the structural requirements for the thermodynamically disfavored ω-regiospecificity we compared the binding of these substrate analogs to each P450, determined the turnover rates, and characterized the enzymatic products. The results are discussed in the context of the structure-activity relationships of the enzymes and how their active sites enforce ω-oxidation. | 26 | 2 | 146 | CHEMBL_15 | 2013-01-23 |
CHEMBL2074280 | British journal of cancer. | 18 | TP-search Transporter Database | Acceleration of MRP-associated efflux of rhodamine 123 by genistein and related compounds. | 8980395 | 10.1038/bjc.1996.658 | nan | Versantvoort CH, Rhodes T, Twentyman PR. | 1996 | 74 | 1 | 1949 | 1954 | PUBLICATION | Multidrug resistance (MDR), caused by overexpression of either P-glycoprotein or the multidrug resistance protein (MRP), is characterised by a decreased cellular drug accumulation due to an enhanced drug efflux. In this study, we examined the effects of genistein and structurally related (iso)flavonoids on the transport of rhodamine 123 (Rh123) and daunorubicin in the MRP-overexpressing MDR lung cancer cell lines COR-L23/R and MOR/R. Genistein, genistin, daidzein and quercetin showed major differences in effects on Rh123 vs daunorubicin transport in the MRP-mediated MDR cell lines: the accumulation of daunorubicin was increased, whereas the accumulation of Rh123 was decreased by the flavonoids. The depolarisation of the membrane potential caused by genistein might be involved in the acceleration of the efflux of Rh123 measured in the MRP-overexpressing cell lines. These observations should be taken into account when using fluorescent dyes as probes for determination of transporter activity as a measure of MDR. | 1 | 2 | 3 | CHEMBL_15 | 2013-01-23 |
CHEMBL1759873 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Novel thiolactone-isatin hybrids as potential antimalarial and antitubercular agents. | 21376591 | 10.1016/j.bmcl.2011.02.008 | nan | Hans RH, Wiid IJ, van Helden PD, Wan B, Franzblau SG, Gut J, Rosenthal PJ, Chibale K. | 2011 | 21 | 7 | 2055 | 2058 | PUBLICATION | The synthesis of a novel series of thiolactone-isatin hybrids led to the discovery of tetracyclic by-products which displayed superior antiplasmodial activity. The tetracycles thus formed the basis of a more focused SAR study. Identified from this series is a compound with an IC(50) of 6.92 μM against the chloroquine-resistant (W2) strain of Plasmodium falciparum. Useful antimalarial SARs delineated include the need for substitution at C-5 of the isatin scaffold and the enhancement of activity by increasing the linker length. In contrast to their antimalarial activity, the tetracycles were devoid of antitubercular activity whereas the advanced intermediates displayed growth inhibitory activity against the H(37)Rv strain of Mycobacterium tuberculosis as revealed by BACTEC, MABA and LORA assays. | 48 | 3 | 251 | CHEMBL_12 | 2011-11-18 |
CHEMBL1130589 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and evaluation of a novel series of phosphodiesterase IV inhibitors. A potential treatment for asthma. | 9873593 | 10.1016/s0960-894x(98)00490-9 | nan | Beasley SC, Cooper N, Gowers L, Gregory JP, Haughan AF, Hellewell PG, Macari D, Miotla J, Montana JG, Morgan T, Naylor R, Runcie KA, Tuladhar B, Warneck JB. | 1998 | 8 | 19 | 2629 | 2634 | PUBLICATION | The synthesis and pharmacological profile of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described. | 12 | 1 | 34 | CHEMBL_1 | 2009-09-03 |
CHEMBL1135294 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of a molecular mimic of the Glc1Man9 oligoside as potential inhibitor of calnexin binding to DeltaF508 CFTR protein. | 11965361 | 10.1016/s0960-894x(02)00151-8 | nan | Cherif S, Leach MR, Williams DB, Monneret C. | 2002 | 12 | 9 | 1237 | 1240 | PUBLICATION | Deletion of phenylalanine at position 508 of the CFTR protein is associated with a severe form of cystic fibrosis. Biosynthetic arrest of the misfolded DeltaF508 CFTR protein in the endoplasmic reticulum is due to prolonged interaction with protein chaperones. In order to overcome this retention and thereby restore the delivery of the protein to the plasma membrane, a molecular mimic of the glycoprotein oligoside moiety has been designed and synthesized. Ability of this mimic to inhibit the binding of the natural Glc1Man9GlcNAc oligoside to calnexin has been measured. | 1 | 1 | 1 | CHEMBL_1 | 2009-09-03 |
CHEMBL1938285 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Novel inhibitors of Mycobacterium tuberculosis dTDP-6-deoxy-L-lyxo-4-hexulose reductase (RmlD) identified by virtual screening. | 22014548 | 10.1016/j.bmcl.2011.09.094 | nan | Wang Y, Hess TN, Jones V, Zhou JZ, McNeil MR, Andrew McCammon J. | 2011 | 21 | 23 | 7064 | 7067 | PUBLICATION | The complex and highly impermeable cell wall of Mycobacterium tuberculosis (Mtb) is largely responsible for the ability of the mycobacterium to resist the action of chemical therapeutics. An L-rhamnosyl residue, which occupies an important anchoring position in the Mtb cell wall, is an attractive target for novel anti-tuberculosis drugs. In this work, we report a virtual screening (VS) study targeting Mtb dTDP-deoxy-L-lyxo-4-hexulose reductase (RmlD), the last enzyme in the L-rhamnosyl synthesis pathway. Through two rounds of VS, we have identified four RmlD inhibitors with half inhibitory concentrations of 0.9-25 μM, and whole-cell minimum inhibitory concentrations of 20-200 μg/ml. Compared with our previous high throughput screening targeting another enzyme involved in L-rhamnosyl synthesis, virtual screening produced higher hit rates, supporting the use of computational methods in future anti-tuberculosis drug discovery efforts. | 49 | 2 | 53 | CHEMBL_14 | 2012-06-27 |
CHEMBL2074073 | British journal of pharmacology. | 18 | TP-search Transporter Database | The organic cation transporter OCT2 mediates the uptake of beta-adrenoceptor antagonists across the apical membrane of renal LLC-PK(1) cell monolayers. | 10960071 | 10.1038/sj.bjp.0703518 | nan | Dudley AJ, Bleasby K, Brown CD. | 2000 | 131 | 1 | 71 | 79 | PUBLICATION | Previous studies have shown that beta-adrenoceptor antagonists may be substrates of organic cation transporters in kidney and lung. In this study we examined the transport of the beta-adrenoreceptor antagonists propranolol and metoprolol, in renal LLC-PK(1) cell monolayers. Experiments with BCECF (2', 7'-bis(2carboxyethyl)-5(6)-carboxyfluorescein) loaded LLC-PK(1) cell monolayers demonstrated that metoprolol and propranolol flux across the basolateral membrane was consistent with non-ionic diffusion. Flux across the apical membrane consisted of both non-ionic diffusion and the uptake of the cationic form of the beta-adrenoceptor antagonists. Uptake of the cationic form of metoprolol across the apical membrane was Na(+)-independent, electrogenic and sensitive to external pH. Furthermore, uptake was sensitive to inhibition by Decynium-22 and the organic cations TEA (tetraethylammonium) and MPP(+) (1-methyl 4-phenylpyridinium). These results, allied with the apical location of the uptake mechanism suggest that beta-adrenoceptor antagonists may be substrates for the organic cation transporter, OCT2. To confirm beta-adrenoceptor antagonists as substrates for OCT2, we demonstrate, in cells transiently transfected with an epitope tagged version of hOCT2 (hOCT2-V5):(1) Decynium-22 sensitive [(14)C]-propranolol uptake, (2) cis-inhibition of OCT2 by a range of beta-adrenoceptor antagonists and (3) metoprolol induced intracellular acidification. | 5 | 1 | 6 | CHEMBL_15 | 2013-01-23 |
CHEMBL2062397 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | N-heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria. | 22796180 | 10.1016/j.bmcl.2012.06.074 | nan | Feng L, Yang KW, Zhou LS, Xiao JM, Yang X, Zhai L, Zhang YL, Crowder MW. | 2012 | 22 | 16 | 5185 | 5189 | PUBLICATION | In an effort to identify novel, broad-spectrum inhibitors against the metallo-β-lactamases (MβLs), several N-heterocyclic derivatives were tested as inhibitors of MβLs CcrA, ImiS, and L1, which are representative enzymes from the distinct MβL subclasses. Three N-heterocyclic dicarboxylic acid derivatives were competitive inhibitors of CcrA and L1, exhibiting K(i) values ≤2 μM, while only 2,4-thiazolidinedicarboxylic acid (1b) was a competitive inhibitor of ImiS. Two 2-mercapto-1,3,4-thiadiazole derivatives were noncompetitive inhibitors of CcrA and ImiS, exhibiting K(i) values <7 μM; however, these same compounds did not inhibit L1. Two 2-mercapto-1,3,4-triazole derivatives were shown not to inhibit any of the tested MβLs. The N-heterocyclic derivatives were tested for antibacterial activity by examining the MIC values for existing antibiotics in the presence/absence of these derivatives. Consistent with the steady-state inhibition data, the inclusion of three N-heterocyclic dicarboxylic acid derivatives resulted in lower MIC values when using Escherichia coli BL21(DE3) cells containing the CcrA or L1 plasmids or Klebsiella pneumoniae (ATCC 700603), while 1b was the only dicarboxylic acid derivative to lower the MIC value of E. coli cells containing the ImiS plasmid. Inclusion of the 2-mercapto-1,3,4-thiadiazole derivatives resulted in lower MIC values for E. coli cells containing ImiS or L1 plasmids; however, these derivatives did not alter the MIC values for K. pneumoniae or E. coli cells containing the L1 plasmid. None of the N-heterocyclic derivatives affected the MIC of two methicillin resistant Staphylococcus aureus (MRSA) strains. Taken together, these studies demonstrate that N-heterocyclic dicarboxylic acids 1a-c and pyridylmercaptothiadiazoles 2a,b are good scaffolds for future broad-spectrum inhibitors of the MβLs. | 7 | 1 | 77 | CHEMBL_15 | 2013-01-23 |
CHEMBL2057135 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis, antitubercular and antimicrobial evaluation of 3-(4-chlorophenyl)-4-substituted pyrazole derivatives. | 22695129 | 10.1016/j.bmcl.2012.05.063 | nan | Pathak RB, Chovatia PT, Parekh HH. | 2012 | 22 | 15 | 5129 | 5133 | PUBLICATION | As a part of our research to develop novel antitubercular and antimicrobial agents, a series of 3-(4-chlorophenyl)-4-substituted pyrazoles have been synthesised. These compounds were tested for antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system, antifungal activity against a pathogenic strain of fungi and antibacterial activity against gram-positive and gram-negative organisms. Among them tested, many compounds showed good to excellent antimicrobial and antitubercular activity. The results suggest that hydrazones, 2-azetidinones and 4-thiazolidinones bearing a core pyrazole scaffold would be potent antimicrobial and antitubercular agents. | 35 | 7 | 223 | CHEMBL_15 | 2013-01-23 |
CHEMBL1765045 | Journal of medicinal chemistry. | 1 | Scientific Literature | Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives. | 21384875 | 10.1021/jm101470k | nan | Lucas S, Negri M, Heim R, Zimmer C, Hartmann RW. | 2011 | 54 | 7 | 2307 | 2319 | PUBLICATION | Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11β-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome. | 39 | 11 | 231 | CHEMBL_12 | 2011-11-18 |
CHEMBL1765019 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Design, synthesis and biological activity of thiazolidine-4-carboxylic acid derivatives as novel influenza neuraminidase inhibitors. | 21382719 | 10.1016/j.bmc.2011.02.019 | nan | Liu Y, Jing F, Xu Y, Xie Y, Shi F, Fang H, Li M, Xu W. | 2011 | 19 | 7 | 2342 | 2348 | PUBLICATION | A series of thiazolidine-4-carboxylic acid derivatives were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus. All the compounds were synthesized in good yields starting from commercially available l-cysteine hydrochloride using a suitable synthetic strategy. These compounds showed moderate inhibitory activity against influenza A neuraminidase. The most potent compound of this series is compound 4f (IC(50)=0.14 μM), which is about sevenfold less potent than oseltamivir and could be used to design novel influenza NA inhibitors that exhibit increased activity based on thiazolidine ring. | 29 | 1 | 29 | CHEMBL_12 | 2011-11-18 |
CHEMBL1770066 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | A green expedient synthesis of pyridopyrimidine-2-thiones and their antitubercular activity. | 21498077 | 10.1016/j.bmcl.2011.03.045 | nan | Rajesh SM, Kumar RS, Libertsen LA, Perumal S, Yogeeswari P, Sriram D. | 2011 | 21 | 10 | 3012 | 3016 | PUBLICATION | The pseudo four-component domino reactions of N-substituted-4-piperidones, substituted aromatic aldehydes and thiourea in the presence of solid sodium ethoxide under solvent-free conditions afforded pyridopyrimidine-2-thiones in almost quantitative yields by simply grinding for 1-2 min. at ambient temperature. The synthesized compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv. Among them, (E)-6-benzyl-8-(2,4-dichlorobenzylidene)-4-(2,4-dichlorophenyl)-3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine-2(1H)-thione (MIC 2.8 μM) displays the maximum activity, being 2.7 and 1.7 times more active than the first line antitubercular drugs ethambutol and ciprofloxacin, respectively, and less active than rifampicin and isoniazid, by 28 and 7 times, respectively. | 40 | 1 | 46 | CHEMBL_12 | 2011-11-18 |
CHEMBL1125561 | Journal of medicinal chemistry. | 1 | Scientific Literature | Inhibition of human leukocyte elastase by N-substituted peptides containing alpha,alpha-difluorostatone residues at P1. | 1479581 | 10.1021/jm00104a004 | nan | Skiles JW, Miao C, Sorcek R, Jacober S, Mui PW, Chow G, Weldon SM, Possanza G, Skoog M, Keirns J. | 1992 | 35 | 26 | 4795 | 4808 | PUBLICATION | A series of tripeptides which contain alpha,alpha-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This redidue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the alpha,alpha-difluoromethylene keton derivative of L-valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding alpha,alpha-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds. Of the tripeptides described the most potent in vitro compound is ethyl N-[N-CBZ-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]- 4(S)-amino-2,2-difluoro-3-oxo-5-methylhexanoate (17B) (IC50 = 0.635 microM). It is presumed that the inhibitor 17b interacts with the S3-S1' binding regions of HLE. Additionally extended binding inhibitors were prepared which interact with the S3-S3' binding subsites of HLE. In order to effect interaction with the S1'-S3' subsites of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the N epsilon of L-lysine were utilized. One of the most potent extended compounds (P3-P3') in vitro is methyl N6-[4(S)-[[N-[N-CBZ-L-valyl-N- (2,3-dihydro-1H-inden-2-yl)glycyl]amino]-2,2-difluoro-3-oxo-5- methylhexanoyl]-2(S)-(acetylamino)-6-aminohexanoate (24b) (IC50 = 0.057 microM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 22c, 5 min prior to HLE challenge (10 micrograms, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described alpha,alpha-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the alpha,alpha-difluoromethylene functionality. | 11 | 2 | 21 | CHEMBL_1 | 2009-09-03 |
CHEMBL1158570 | Journal of natural products. | 1 | Scientific Literature | Secondary metabolites from the roots of Litsea hypophaea and their antitubercular activity. | 20384293 | 10.1021/np100022s | nan | Pan PC, Cheng MJ, Peng CF, Huang HY, Chen JJ, Chen IS. | 2010 | 73 | 5 | 890 | 896 | PUBLICATION | Bioassay-guided fractionation of the roots of Litsea hypophaea led to the isolation of seven new butanolides, namely, litseakolides H-N (1-7), all with the 3R,4S configuration, as well as three new biarylpropanoids, hypophaone (8), hypophaol (9), and hypophane (10), and 15 known compounds. The structures of 1-10 were determined by means of spectroscopic analysis. Litseakolide L (5) and N-trans-feruloylmethoxytyramine (11) showed antitubercular activity against Mycobacterium tuberculosis strain H(37)Rv, with MIC values of 25 and 1.6 microg/mL, respectively. | 7 | 1 | 7 | CHEMBL_6 | 2010-08-27 |
CHEMBL2380284 | Journal of medicinal chemistry. | 1 | Scientific Literature | X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. | 23679862 | 10.1021/jm4004889 | nan | Molodtsov V, Nawarathne IN, Scharf NT, Kirchhoff PD, Showalter HD, Garcia GA, Murakami KS. | 2013 | 56 | 11 | 4758 | 4763 | PUBLICATION | Rifampin, a semisynthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semisynthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the β subunit, blocking the path of the RNA transcript. The C3'-tail of benzoxazinorifamycin fits a cavity between the β subunit and σ factor. We propose that in addition to blocking RNA exit, the benzoxazinorifamycin C3'-tail changes the σ region 3.2 loop position, which influences the template DNA at the active site, thereby reducing the efficiency of transcription initiation. This study supports expansion of structure-activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential. | 5 | 2 | 24 | CHEMBL_18 | 2014-03-12 |
CHEMBL2169761 | Journal of medicinal chemistry. | 1 | Scientific Literature | Exploring the interactions of unsaturated glucuronides with influenza virus sialidase. | 23017008 | 10.1021/jm301145k | nan | Bhatt B, Böhm R, Kerry PS, Dyason JC, Russell RJ, Thomson RJ, von Itzstein M. | 2012 | 55 | 20 | 8963 | 8968 | PUBLICATION | A series of C3 O-functionalized 2-acetamido-2-deoxy-Δ⁴-β-D-glucuronides were synthesized to explore noncharge interactions in subsite 2 of the influenza virus sialidase active site. In complex with A/N8 sialidase, the parent compound (C3 OH) inverts its solution conformation to bind with all substituents well positioned in the active site. The parent compound inhibits influenza virus sialidase at a sub-μM level; the introduction of small alkyl substituents or an acetyl group at C3 is also tolerated. | 13 | 1 | 15 | CHEMBL_16 | 2013-05-07 |
CHEMBL2440109 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids. | 24103427 | 10.1016/j.bmc.2013.09.034 | nan | Rodrigues MO, Cantos JB, D'Oca CR, Soares KL, Coelho TS, Piovesan LA, Russowsky D, da Silva PA, D'Oca MG. | 2013 | 21 | 22 | 6910 | 6914 | PUBLICATION | This work describes the synthesis of a series of fatty acid hydrazide derivatives of isoniazid (INH). The compounds were tested against Mycobacterium tuberculosis H37Rv (ATCC 27294) as well as INH-resistant (ATCC 35822 and 1896 HF) and rifampicin-resistant (ATCC 35338) M. tuberculosis strains. The fatty acid derivatives of INH showed high antimycobacterial potency against the studied strains, which is desirable for a pharmaceutical compound, suggesting that the increased lipophilicity of isoniazid plays an important role in its antimycobacterial activity. | 11 | 1 | 44 | CHEMBL_18 | 2014-03-12 |
CHEMBL1949516 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antimycobacterial evaluation of N-substituted 3-aminopyrazine-2,5-dicarbonitriles. | 22281187 | 10.1016/j.bmcl.2011.12.129 | nan | Zitko J, Jampílek J, Dobrovolný L, Svobodová M, Kuneš J, Doležal M, Doležal M. | 2012 | 22 | 4 | 1598 | 1601 | PUBLICATION | A series of 14 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and two types of Mycobacterium avium. The series comprised of N-substituted 3-aminopyrazine-2,5-dicarbonitriles derived from 3-chloropyrazine-2,5-dicarbonitrile by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines, cycloalkylamines and heterocyclic amines). Noteworthy antimycobacterial activity against M. tuberculosis was found among the alkylamino derivatives, for example, 3-(heptylamino)pyrazine-2,5-dicarbonitrile inhibited M. tuberculosis at MIC=51 μmol/L. 3-(Hexylamino)pyrazine-2,5-dicarbonitrile inhibited M. kansasii at MIC=218 μmol/L. Basic structure-activity relationships are discussed. A comparison between calculated and experimentally determined lipophilicity parameters within the series is included. | 16 | 4 | 83 | CHEMBL_14 | 2012-06-27 |
CHEMBL2401638 | European journal of medicinal chemistry. | 1 | Scientific Literature | Design and synthesis of biquinolone-isoniazid hybrids as a new class of antitubercular and antimicrobial agents. | 23747804 | 10.1016/j.ejmech.2013.05.003 | nan | Jardosh HH, Patel MP. | 2013 | 65 | nan | 348 | 359 | PUBLICATION | Twenty four biquinolone-isoniazid hybrids were designed based on molecular hybridization technique and synthesized via multicomponent cyclocondensation (MCC) approach. All the newly synthesized compounds were screened for their antimicrobial and antitubercular activities. The brine shrimp bioassay was carried out to study the cytotoxicity of the synthesized compounds. Hybrids 7f (MIC = 25 μg/mL); 7a, 7e and 7m (MIC = 50 μg/mL); 7g, 7h and 7k (MIC = 62.5 μg/mL) exhibited excellent antimicrobial activity as compared with standard drugs. Hybrids 7l and 7j displayed 99% inhibition against Mycobacterium tuberculosis bacteria with better LC50 values 35.39 and 34.59 μg/mL, respectively. These results indicate that the synthesized compounds can act as leads for the development of newer antimicrobial and antitubercular compounds. | 33 | 10 | 317 | CHEMBL_18 | 2014-03-12 |
CHEMBL1149954 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of methyl -sialosides N-substituted with large alkanoyl groups, and investigation of their inhibition of agglutination of erythrocytes by influenza A virus | nan | 10.1016/S0960-894X(01)81267-1 | nan | Schmid W, Avila LZ, Williams KW, Whitesides GM | 1993 | 3 | 4 | 747 | 752 | PUBLICATION | nan | 3 | 1 | 3 | CHEMBL_1 | 2009-09-03 |
CHEMBL2406982 | European journal of medicinal chemistry. | 1 | Scientific Literature | Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF. | 23786712 | 10.1016/j.ejmech.2013.05.013 | nan | Hrast M, Turk S, Sosič I, Knez D, Randall CP, Barreteau H, Contreras-Martel C, Dessen A, O'Neill AJ, Mengin-Lecreulx D, Blanot D, Gobec S. | 2013 | 66 | nan | 32 | 45 | PUBLICATION | Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc-L-Ala-γ-D-Glu-meso-DAP (or L-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization toward effective novel antibacterials. | 46 | 4 | 314 | CHEMBL_18 | 2014-03-12 |
CHEMBL2390881 | Journal of medicinal chemistry. | 1 | Scientific Literature | Identification of M. tuberculosis thioredoxin reductase inhibitors based on high-throughput docking using constraints. | 23676086 | 10.1021/jm3015734 | nan | Koch O, Jäger T, Heller K, Khandavalli PC, Pretzel J, Becker K, Flohé L, Selzer PM. | 2013 | 56 | 12 | 4849 | 4859 | PUBLICATION | A virtual screening campaign is presented that led to small molecule inhibitors of thioredoxin reductase of Mycobacterium tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate thioredoxin (Trx). MtTrxR is a promising drug target because it dominates the Trx-dependent hydroperoxide metabolism and the reduction of ribonucleotides, thus facilitating survival and proliferation of M. tuberculosis. Moreover, MtTrxR sufficiently differs from its human homologs to suggest the possibility of selective inhibition if the MtTrxR-Trx interaction site is targeted. To this end, high-throughput docking of 6.5 million virtual compounds to the thioredoxin binding site of MtTrxR combined with constraints as filtering steps was applied. A total of 170 high-scoring compounds yielded 18 compounds that inhibited MtTrxR with IC50 values up to the low micromolar range, thus revealing that the protein-protein interaction site of MtTrxR is indeed druggable. Most importantly, selectivity toward MtTrxR in comparison to human TrxR (HsTrxR) is also demonstrated. | 13 | 3 | 81 | CHEMBL_18 | 2014-03-12 |
CHEMBL1136042 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Design, synthesis, and neuraminidase inhibitory activity of GS-4071 analogues that utilize a novel hydrophobic paradigm. | 12419376 | 10.1016/s0960-894x(02)00732-1 | nan | Hanessian S, Wang J, Montgomery D, Stoll V, Stewart KD, Kati W, Maring C, Kempf D, Hutchins C, Laver WG. | 2002 | 12 | 23 | 3425 | 3429 | PUBLICATION | Structure-based design has led to the synthesis of a novel analogue of GS-4071, an influenza neuraminidase inhibitor, in which the basic amino group has been replaced by a hydrophobic vinyl group. An X-ray co-crystal structure of the new inhibitor (K(i)=45 nM) bound to the active site shows that the vinyl group occupies the same subsite as the amino group in GS-4071. | 8 | 1 | 9 | CHEMBL_1 | 2009-09-03 |
CHEMBL1275488 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Extended-spectrum beta-lactamase production is associated with an increase in cell invasion and expression of fimbrial adhesins in Klebsiella pneumoniae. | 18573929 | 10.1128/aac.00010-08 | nan | Sahly H, Navon-Venezia S, Roesler L, Hay A, Carmeli Y, Podschun R, Hennequin C, Forestier C, Ofek I. | 2008 | 52 | 9 | 3029 | 3034 | PUBLICATION | Extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae strains are suggested to possess higher pathogenic potential than non-ESBL producers. Microbial adherence to and invasion of host cells are critical steps in the infection process, so we examined the expression of type 1 and 3 fimbrial adhesins by 58 ESBL-producing and 152 nonproducing isolates of K. pneumoniae and their abilities to invade ileocecal and bladder epithelial cells. Mannose-sensitive hemagglutination of guinea pig erythrocytes and mannose-resistant hemagglutination of ox erythrocytes were evaluated to determine the strains' abilities to express type 1 and type 3 fimbriae, respectively. Bacterial adhesion to and invasion of epithelial cells were tested by enzyme-linked immunosorbent assay and imipenem killing assay, respectively. The adherence of ESBL- and non-ESBL-producing strains to epithelial cells did not differ significantly (P > 0.05). In contrast, the proportion of strains capable of invading (>5% relative invasion) ileocecal and bladder epithelial cells was significantly higher among ESBL producers (81%, n = 47/58, and 27.6%, n = 16/58, respectively) than among non-ESBL producers (61%, n = 93/152, and 10%, n = 15/152, respectively) (P = 0.0084, odds ratio [OR] = 2.711, 95% confidence interval [CI] = 1.302 to 5.643 and P = 0.0021, OR = 4.79, 95% CI = 1.587 to 7.627). The mean invasion by ESBL producers (5.5% +/- 2.8% and 3.3% +/- 2.7%, respectively) was significantly higher than that by non-ESBL producers (2.9% +/- 2.6% and 1.8% +/- 2%, respectively) (P < 0.0001). Likewise, the proportion of ESBL producers coexpressing both fimbrial adhesins was significantly higher (79.3%; n = 46/58) than that of non-ESBL producers (61.8%; n = 94/152) (P = 0.0214; OR = 2,365; 95% CI = 1.157 to 4.834). Upon acquisition of SHV-12-encoding plasmids, two transconjugants switched on to produce type 3 fimbriae while expression of type 1 fimbriae was not affected. The acquisition of an ESBL plasmid appeared to upregulate the phenotypic expression of one or more genes, resulting in greater invasion ability. | 3 | 1 | 3 | CHEMBL_10 | 2011-05-26 |
CHEMBL1145500 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro bactericidal activity of the antiprotozoal drug miltefosine against Streptococcus pneumoniae and other pathogenic streptococci. | 17353242 | 10.1128/aac.01428-06 | nan | Llull D, Rivas L, García E. | 2007 | 51 | 5 | 1844 | 1848 | PUBLICATION | Miltefosine (hexadecylphosphocholine), the first oral drug against visceral leishmaniasis, triggered pneumococcal autolysis at concentrations higher than 2.5 microM. Bactericidal activity was also observed in cultures of other streptococci, although these failed to undergo lysis. The autolysis elicited by miltefosine can be attributed to triggering of the pneumococcal autolysin LytA. | 4 | 9 | 28 | CHEMBL_1 | 2009-09-03 |
CHEMBL1143085 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors. | 18457948 | 10.1016/j.bmcl.2008.04.038 | nan | am Ende CW, Knudson SE, Liu N, Childs J, Sullivan TJ, Boyne M, Xu H, Gegina Y, Knudson DL, Johnson F, Peloquin CA, Slayden RA, Tonge PJ. | 2008 | 18 | 10 | 3029 | 3033 | PUBLICATION | Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values. | 26 | 3 | 91 | CHEMBL_1 | 2009-09-03 |
CHEMBL1137386 | Journal of medicinal chemistry. | 1 | Scientific Literature | Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. | 17034137 | 10.1021/jm060715y | nan | He X, Alian A, Stroud R, Ortiz de Montellano PR. | 2006 | 49 | 21 | 6308 | 6323 | PUBLICATION | In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA. | 107 | 2 | 168 | CHEMBL_1 | 2009-09-03 |
CHEMBL2086335 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Three new 12-carbamoylated streptothricins from Streptomyces sp. I08A 1776. | 22939698 | 10.1016/j.bmcl.2012.08.003 | nan | Gan M, Zheng X, Liu Y, Guan Y, Xiao C. | 2012 | 22 | 19 | 6151 | 6154 | PUBLICATION | Two new streptothricins (1 and 2) and a new streptothricin acid derivative (3), all with the carbamoyl group substituted at C-12 of the gulosamine moiety, together with the known N(β)-acetylstreptothricin D acid (4), have been isolated from the culture broth of Streptomyces sp. I08A 1776. The structures of the new compounds were determined by MS, CD, and 1D and 2D NMR spectroscopic data analysis. The isolated compounds were evaluated for antibacterial and antifungal activities. Streptothricin E (6) showed potent activity against the clinically isolated extensively drug-resistant Mycobacterium tuberculosis with MIC values of 0.25-0.5μg/mL. | 9 | 9 | 101 | CHEMBL_15 | 2013-01-23 |
CHEMBL2321809 | Journal of medicinal chemistry. | 1 | Scientific Literature | Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase. | 23252553 | 10.1021/jm301490d | nan | Winkler ML, Rodkey EA, Taracila MA, Drawz SM, Bethel CR, Papp-Wallace KM, Smith KM, Xu Y, Dwulit-Smith JR, Romagnoli C, Caselli E, Prati F, van den Akker F, Bonomo RA. | 2013 | 56 | 3 | 1084 | 1097 | PUBLICATION | Inhibitor resistant (IR) class A β-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV β-lactamase, from Klebsiella pneumoniae , results in resistance to ampicillin/clavulanate. After site-saturation mutagenesis of Lys-234 in SHV, microbiological and biochemical characterization of the resulting β-lactamases revealed that only -Arg conferred resistance to ampicillin/clavulanate. X-ray crystallography revealed two conformations of Arg-234 and Ser-130 in SHV K234R. The movement of Ser-130 is the principal cause of the observed clavulanate resistance. A panel of boronic acid inhibitors was designed and tested against SHV-1 and SHV K234R. A chiral ampicillin analogue was discovered to have a 2.4 ± 0.2 nM K(i) for SHV K234R; the chiral ampicillin analogue formed a more complex hydrogen-bonding network in SHV K234R vs SHV-1. Consideration of the spatial position of Ser-130 and Lys-234 and this hydrogen-bonding network will be important in the design of novel antibiotics targeting IR β-lactamases. | 12 | 2 | 88 | CHEMBL_17 | 2013-08-29 |
CHEMBL1777730 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Antimycobacterial activity of novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrids generated by chemoselective 1,3-dipolar cycloadditions of nitrile oxides. | 21592801 | 10.1016/j.bmc.2011.04.033 | nan | Ranjith Kumar R, Perumal S, Menéndez JC, Yogeeswari P, Sriram D. | 2011 | 19 | 11 | 3444 | 3450 | PUBLICATION | The 1,3-dipolar cycloaddition of nitrile oxides generated in situ from benzohydroximinoyl chloride and triethylamine to 2-aminopyranopyridine-3-carbonitriles and 2-aminochromene-3-carbonitriles occurred chemoselectively furnishing novel 1,2,4-oxadiazole-pyranopyridine/chromene hybrid heterocycles in moderate yields. In vitro screening of these compounds against Mycobacterium tuberculosis H37Rv (MTB) disclosed that the 1,2,4-oxadiazole-pyranopyridine hybrids display enhanced activity relative to the 1,2,4-oxadiazole-chromene hybrids. Among the compounds screened, 3-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-4-(2,4-dichlorophenyl)-8-[(E)-(2,4-dichlorophenyl)-methylidene]-6-methyl-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridin-2-amine (MIC: 0.31 μM) is 1.2, 15.2 and 24.6 times more active than standard antitubercular drugs, viz. isoniazid, ciprofloxacin and ethambutol, respectively. | 25 | 1 | 25 | CHEMBL_12 | 2011-11-18 |
CHEMBL1140631 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Carbonic anhydrases as targets for medicinal chemistry. | 17475500 | 10.1016/j.bmc.2007.04.020 | nan | Supuran CT, Scozzafava A. | 2007 | 15 | 13 | 4336 | 4350 | PUBLICATION | Carbonic anhydrases (CAs, EC 4.2.1.1) are zinc enzymes acting as efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate. 16 different alpha-CA isoforms were isolated in mammals, where they play crucial physiological roles. Some of them are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII, CA XIV and CA XV), CA VA and CA VB are mitochondrial, and CA VI is secreted in saliva and milk. Three acatalytic forms are also known, the CA related proteins (CARP), CARP VIII, CARP X and CARP XI. Representatives of the beta-delta-CA family are highly abundant in plants, diatoms, eubacteria and archaea. The catalytic mechanism of the alpha-CAs is understood in detail: the active site consists of a Zn(II) ion co-ordinated by three histidine residues and a water molecule/hydroxide ion. The latter is the active species, acting as a potent nucleophile. For beta- and gamma-CAs, the zinc hydroxide mechanism is valid too, although at least some beta-class enzymes do not have water directly coordinated to the metal ion. CAs are inhibited primarily by two classes of compounds: the metal complexing anions and the sulfonamides/sulfamates/sulfamides possessing the general formula RXSO(2)NH(2) (R=aryl; hetaryl; perhaloalkyl; X=nothing, O or NH). Several important physiological and physio-pathological functions are played by CAs present in organisms all over the phylogenetic tree, related to respiration and transport of CO(2)/bicarbonate between metabolizing tissues and the lungs, pH and CO(2) homeostasis, electrolyte secretion in a variety of tissues/organs, biosynthetic reactions, such as the gluconeogenesis and ureagenesis among others (in animals), CO(2) fixation (in plants and algae), etc. The presence of these ubiquitous enzymes in so many tissues and in so different isoforms represents an attractive goal for the design of inhibitors with biomedical applications. Indeed, CA inhibitors are clinically used as antiglaucoma drugs, some other compounds being developed as antitumour agents/diagnostic tools for tumours, antiobesity agents, anticonvulsants and antimicrobials/antifungals (inhibitors targeting alpha- or beta-CAs from pathogenic organisms such as Helicobacter pylori, Mycobacterium tuberculosis, Plasmodium falciparum, Candida albicans, etc.). | 22 | 13 | 138 | CHEMBL_1 | 2009-09-03 |
CHEMBL1143834 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Activity of Garenoxacin against Macrolide-Susceptible and -Resistant Mycoplasma pneumoniae. | 17387152 | 10.1128/aac.01561-06 | nan | Yamazaki T, Sasaki T, Takahata M. | 2007 | 51 | 6 | 2278 | 2279 | PUBLICATION | nan | 5 | 1 | 35 | CHEMBL_1 | 2009-09-03 |
CHEMBL1770148 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Dual function inhibitors of relevance to chronic obstructive pulmonary disease. | 21511470 | 10.1016/j.bmcl.2010.12.033 | nan | Dou D, He G, Alliston KR, Groutas WC. | 2011 | 21 | 10 | 3177 | 3180 | PUBLICATION | The general strategy and rationale underlying the design of COPD therapeutics that possess protease inhibitory activity and are also capable of releasing a species that attenuates inflammation by inhibiting caspase-1, are described. The synthesis and in vitro biochemical evaluation of a dual function molecule that sequentially inhibits HNE and caspase-1 in a time-dependent manner is reported. | 1 | 3 | 4 | CHEMBL_12 | 2011-11-18 |
CHEMBL1142088 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Cumulative effects of several nonenzymatic mechanisms on the resistance of Pseudomonas aeruginosa to aminoglycosides. | 17194835 | 10.1128/aac.00704-06 | nan | El'Garch F, Jeannot K, Hocquet D, Llanes-Barakat C, Plésiat P. | 2007 | 51 | 3 | 1016 | 1021 | PUBLICATION | Screening of a Tn5-Hg insertional library (12,000 clones) constructed in wild-type Pseudomonas aeruginosa strain PAO1 identified four genes (namely, galU, nuoG, mexZ, and rplY) whose disruption individually led to increased resistance to aminoglycosides (means of twofold). Inactivation of these genes was associated with (i) impaired outer membrane uptake, (ii) reduced active transport, (iii) increased MexXY-OprM-mediated active efflux, and (iv) alteration of target of aminoglycosides, respectively. In addition, suppression of the gene rplY, which codes for ribosomal protein L25, was found to result in both moderate upregulation of the efflux system MexXY-OprM and hypersusceptibility to beta-lactam antibiotics. Construction of double, triple, and quadruple mutants demonstrated cumulative effects of the different mechanisms on aminoglycoside resistance, with MICs increasing from 16- to 64-fold in the quadruple mutant compared to the wild-type strain PAO1. Altogether, these results illustrate how P. aeruginosa may gradually develop high resistance to these antibiotics via intrinsic (i.e., nonenzymatic) mechanisms, as in cystic fibrosis patients. | 7 | 1 | 147 | CHEMBL_1 | 2009-09-03 |
CHEMBL3352027 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Pharmacologically active metabolites, combination screening and target identification-driven drug repositioning in antituberculosis drug discovery. | 24997576 | 10.1016/j.bmc.2014.06.012 | nan | Kigondu EM, Wasuna A, Warner DF, Chibale K. | 2014 | 22 | 16 | 4453 | 4461 | PUBLICATION | There has been renewed interest in alternative strategies to address bottlenecks in antibiotic development. These include the repurposing of approved drugs for use as novel anti-infective agents, or their exploitation as leads in drug repositioning. Such approaches are especially attractive for tuberculosis (TB), a disease which remains a leading cause of morbidity and mortality globally and, increasingly, is associated with the emergence of drug-resistance. In this review article, we introduce a refinement of traditional drug repositioning and repurposing strategies involving the development of drugs that are based on the active metabolite(s) of parental compounds with demonstrated efficacy. In addition, we describe an approach to repositioning the natural product antibiotic, fusidic acid, for use against Mycobacterium tuberculosis. Finally, we consider the potential to exploit the chemical matter arising from these activities in combination screens and permeation assays which are designed to confirm mechanism of action (MoA), elucidate potential synergies in polypharmacy, and to develop rules for drug permeability in an organism that poses a special challenge to new drug development. | 18 | 2 | 124 | CHEMBL_21 | 2016-02-01 |
CHEMBL3352819 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors. | 24997577 | 10.1016/j.bmc.2014.06.020 | nan | Park BS, Al-Sanea MM, Abdelazem AZ, Park HM, Roh EJ, Park HM, Yoo KH, Sim T, Tae JS, Lee SH. | 2014 | 22 | 15 | 3871 | 3878 | PUBLICATION | Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC₅₀ values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC₅₀ values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC₅₀=13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value=0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM. | 17 | 27 | 47 | CHEMBL_21 | 2016-02-01 |
CHEMBL2086295 | European journal of medicinal chemistry. | 1 | Scientific Literature | The design, synthesis, in silico ADME profiling, antiplasmodial and antimycobacterial evaluation of new arylamino quinoline derivatives. | 23064162 | 10.1016/j.ejmech.2012.08.047 | nan | Tukulula M, Little S, Gut J, Rosenthal PJ, Wan B, Franzblau SG, Chibale K. | 2012 | 57 | nan | 259 | 267 | PUBLICATION | A series of new arylamino quinoline derivatives was designed based on the quinine and mefloquine scaffolds and evaluated in vitro for antiplasmodial and antimycobacterial activities. A number of these compounds exhibited significant activity against the drug-sensitive 3D7 and drug-resistant K1 strains of Plasmodium falciparum. Furthermore, two compounds, 4.12b and 4.12d, also showed 94 and 98% growth inhibitory activity against non-replicating and replicating Mycobacterium tuberculosis strains, respectively. | 16 | 3 | 101 | CHEMBL_15 | 2013-01-23 |
CHEMBL3102838 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis of RCAI-172 (C6 epimer of RCAI-147) and its biological activity. | 24360828 | 10.1016/j.bmc.2013.12.009 | nan | Shiozaki M, Tashiro T, Koshino H, Shigeura T, Watarai H, Taniguchi M, Mori K. | 2014 | 22 | 2 | 827 | 833 | PUBLICATION | RCAI-147 is one of the hydroxylated analogues of KRN7000 which is known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) and releases both T helper 1 (Th1) cytokines such as IFN-γ and T helper 2 (Th2) cytokines such as IL-4. KRN7000 has been anticipated as an antitumor drug or an adjuvant for viral infection such as influenza, because of its strong secretion of IFN-γ. In an interesting twist, it has been obvious in our previous paper that RCAI-147 induces much more Th2 cytokines (IL-4) than Th1 cytokines (IFN-γ) from iNKT cells compared to KRN7000, and shows fairly good result in the experimental autoimmune encephalomyelitis (EAE) test. Therefore, synthesis of RCAI-172 (C6-OH epimer of RCAI-147) was attempted to examine the biological activity. As a result, RCAI-172 was synthesized and its biological activity biased to Th2 response largely compared to that of KRN7000. However, this level decreased to approximately 61% compared to that of RCAI-147. And the clinical score of RCAI-172 for EAE suppression was disappointing. There exist seven chiral centers in the aglycon part of RCAI-172, and even though the change of configuration is just one position (C6-OH), the effect on both Th1/Th2 response and EAE test is fairly large. | 6 | 1 | 19 | CHEMBL_19 | 2014-07-03 |
CHEMBL3352501 | European journal of medicinal chemistry. | 1 | Scientific Literature | SAR analysis of new anti-TB drugs currently in pre-clinical and clinical development. | 25173852 | 10.1016/j.ejmech.2014.08.066 | nan | Poce G, Cocozza M, Consalvi S, Biava M. | 2014 | 86 | nan | 335 | 351 | PUBLICATION | Despite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality worldwide, causing an estimated 8.6 million new cases and 1.3 million deaths in 2012. Multi-drug resistant-TB strains no longer respond to first-line drugs and are inexorably spreading with an estimated 650,000 cases as well as extensively-drug resistant-TB strains, which are resistant to any fluoroquinolone and at least one of the second-line drugs, with 60,000 cases. Thus the discovery and development of new medicines is a major keystone for tuberculosis treatment and control. After decades of dormancy in the field of TB drug development, recent efforts from various groups have generated a promising TB drug pipeline. Several new therapeutic agents are concurrently studied in clinical trials together with much activity in the hittolead and lead optimization stages. In this article we will review the recent advances in TB drug discovery with a special focus on structure activity relationship studies of the most advanced compound classes. | 21 | 7 | 41 | CHEMBL_21 | 2016-02-01 |
CHEMBL3297718 | European journal of medicinal chemistry. | 1 | Scientific Literature | Ultrasound-assisted one-pot four-component synthesis of novel 2-amino-3-cyanopyridine derivatives bearing 5-imidazopyrazole scaffold and their biological broadcast. | 25010936 | 10.1016/j.ejmech.2014.06.071 | nan | Kalaria PN, Satasia SP, Avalani JR, Raval DK. | 2014 | 83 | nan | 655 | 664 | PUBLICATION | An alternative and environmentally caring way for the synthesis of novel 2-amino-3-cyanopyridine derivatives bearing 5-imidazopyrazole nucleus is reported by one-pot four-component cyclocondensation reaction of substituted 5-(1H-imidazol/4-methyl-1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3a-b), malononitrile (4), ammonium acetate (5) and aromatic (6a-f)/heterocyclic methyl ketones (7a-d) under ultrasonic irradiation. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against a panel of pathogenic stains of bacteria and fungi, in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv stain and in vitro antioxidant activity by ferric-reducing antioxidant power method. Compounds 8e, 8h, 8l, 9c, 9g and 9h exhibited excellent antibacterial activity and compounds 3a, 8k, 9a and 9bshowed moderate antituberculosis activity as compared with the first line drugs. Majority of the compounds showed excellent antioxidant activity. This approaches claimed to be an environment friendly protocol as it afforded numerous advantages i.e. excellent yields, cleaner reaction profile and shorter reaction time. | 26 | 10 | 244 | CHEMBL_20 | 2015-01-14 |
CHEMBL2146477 | ACS medicinal chemistry letters. | 1 | Scientific Literature | Antimicrobial Activity of Adenine-Based Inhibitors of NAD(+)-Dependent DNA Ligase. | 24900527 | 10.1021/ml300169x | nan | Buurman ET, Laganas VA, Liu CF, Manchester JI. | 2012 | 3 | 8 | 663 | 667 | PUBLICATION | The relationship between enzyme inhibition and antimicrobial potency of adenine-based NAD(+)-dependent DNA ligase (LigA) inhibitors was investigated using a strain of the Gram-negative pathogen Haemophilus influenzae lacking its major AcrAB-TolC efflux pump and the Gram-positive pathogen Streptococcus pneumoniae. To this end, biochemical inhibitors not mediating their antibacterial mode of action (MOA) via LigA were removed from the analysis. In doing so, a significant number of compounds were identified that acted via inhibition of LigA in S. pneumoniae but not in H. influenzae, despite being inhibitors of both isozymes. Deviations from the line correlating antimicrobial and biochemical potencies of LigA inhibitors with the correct MOA were observed for both species. These deviations, usually corresponding to higher MIC/IC50 ratios, were attributed to varying compound permeance into the cell. | 8 | 3 | 40 | CHEMBL_16 | 2013-05-07 |
CHEMBL1926563 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis, antimicrobial, antimycobacterial and structure-activity relationship of substituted pyrazolo-, isoxazolo-, pyrimido- and mercaptopyrimidocyclohepta[b]indoles. | 22119150 | 10.1016/j.ejmech.2011.10.046 | nan | Yamuna E, Kumar RA, Zeller M, Rajendra Prasad KJ. | 2012 | 47 | nan | 228 | 238 | PUBLICATION | A new class of heterocycles, specifically substituted pyrazolo-, isoxazolo- and pyrimidocyclohepta[b]indoles, has been prepared by condensation of substituted 7-(hydroxymethylene)-7,8,9,10-tetrahydrocyclohepta[b]indol-6(5H)-ones with hydrazine hydrate, hydroxylamine hydrochloride, phenylhydrazine, urea and thiourea, respectively. The structures of the compounds were established by IR, (1)H NMR, (13)C NMR, mass spectral analysis, X-ray diffraction, and the compounds have been screened for in vitro antimicrobial and antimycobacterial against Mycobacterium tuberculosis H37Rv (MTB). Among the compounds screened, five substances were found to have an MIC of 3.12 μg/ml or greater against MTB. Structure-activity relationship (SAR) analyses and in silico drug relevant properties (HBD, HBA, PSA, c Log P, M.wt) confirmed that the compounds are potential lead compounds for future drug discovery studies. | 32 | 8 | 338 | CHEMBL_14 | 2012-06-27 |
CHEMBL2407016 | Journal of medicinal chemistry. | 1 | Scientific Literature | DXR inhibition by potent mono- and disubstituted fosmidomycin analogues. | 23819803 | 10.1021/jm4006498 | nan | Jansson AM, Więckowska A, Björkelid C, Yahiaoui S, Sooriyaarachchi S, Lindh M, Bergfors T, Dharavath S, Desroses M, Suresh S, Andaloussi M, Nikhil R, Sreevalli S, Srinivasa BR, Larhed M, Jones TA, Karlén A, Mowbray SL. | 2013 | 56 | 15 | 6190 | 6199 | PUBLICATION | The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM. | 26 | 4 | 78 | CHEMBL_18 | 2014-03-12 |
CHEMBL1921682 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agents. | 22071303 | 10.1016/j.bmcl.2011.10.057 | nan | Ahsan MJ, Samy JG, Khalilullah H, Nomani MS, Saraswat P, Gaur R, Singh A. | 2011 | 21 | 24 | 7246 | 7250 | PUBLICATION | In the present investigation, a series of 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-oxadiazol-2-yl)methyl]amino}-1,2-dihydro-3H-pyrazol-3-one were subjected to molecular properties prediction, drug-likeness by Molinspiration (Molinspiration, 2008) and MolSoft (MolSoft, 2007) software, lipophilicity and solubility parameters using ALOGPS 2.1 program. The compounds followed the Lipinski 'Rule of five' were synthesized for antimicrobial and antitubercular screening as oral bioavailable drugs/leads. Maximum drug-likeness model score (0.95) was found for compound, 4a. All the synthesized compounds were characterized by IR, NMR and mass spectral analysis followed by antimicrobial and antimycobacterial screening. Among the title compounds, compound 4d showed pronounced activity against Mycobacterium tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis (INHR-TB) with minimum inhibitory concentrations (MICs) 0.78μM and 1.52 μM, respectively. The compound, 4a showed maximum activity against all bacterial strains with MIC 4-8 μg/mL comparable to standard drug ciprofloxacin, while the compounds, 4e and 4k showed maximum antifungal activity with MIC 8-16 μg/mL less active than standard drug fluconazole. | 17 | 8 | 136 | CHEMBL_14 | 2012-06-27 |
CHEMBL1149869 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Antifungal and antimycobacterial activity of 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives. | 18321714 | 10.1016/j.bmc.2008.02.055 | nan | Zampieri D, Mamolo MG, Laurini E, Scialino G, Banfi E, Vio L. | 2008 | 16 | 8 | 4516 | 4522 | PUBLICATION | 1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives were synthesized and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of Candida albicans and an interesting antitubercular activity against Mycobacterium tuberculosis H(37)Rv reference strain. | 23 | 2 | 65 | CHEMBL_2 | 2009-11-30 |
CHEMBL2073857 | Cancer letters. | 18 | TP-search Transporter Database | Increased sensitivity to vincristine of MDR cells by the leukotriene D4 receptor antagonist, ONO-1078. | 9751271 | 10.1016/s0304-3835(98)00132-3 | nan | Nagayama S, Chen ZS, Kitazono M, Takebayashi Y, Niwa K, Yamada K, Tani A, Haraguchi M, Sumizawa T, Furukawa T, Aikou T, Akiyama S. | 1998 | 130 | 1 | 175 | 182 | PUBLICATION | The leukotriene D4 (LTD4) receptor antagonist, 4-oxo-8-[p-(4-phenylbutyloxy)benzoylamino]-2-(tetrazol-5-yl) -4H-1-benzopyran hemihydrate (ONO-1078) is used for the treatment of allergic asthma and other immediate hypersensitivity diseases. We examined the effect of ONO-1078 on the sensitivity to vincristine (VCR) of MRP overexpressing multidrug-resistant CV60 and its parental drug-sensitive KB-3-1 cell lines. The sensitivity to VCR of KB-3-1 and CV60 cells was increased 13- and 15-fold, respectively, by ONO-1078 at the maximum non-toxic concentration (100 microM). The VCR sensitivity of multidrug-resistant KB-C2 cells that overexpressed P-gp was increased 2.6-fold by ONO-1078. The accumulation of VCR in KB-3-1, CV60 and KB-C2 cells was significantly increased by ONO-1078. The efflux of VCR from KB-3-1 cells was not inhibited, but that from CV60 cells was enhanced compared with that from KB-3-1 cells and was partially inhibited by ONO-1078. ONO-1078 competitively inhibited the ATP-dependent [3H]LTC4 uptake in membrane vesicles isolated from CV60 cells. These findings suggest that ONO-1078 inhibits the transporting activity of MRP and that ONO-1078 increases the sensitivity to VCR of KB-3-1 cells by increasing the VCR uptake in the cells. | 1 | 1 | 1 | CHEMBL_15 | 2013-01-23 |
CHEMBL1143836 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. | 17387156 | 10.1128/aac.01509-06 | nan | Tumbarello M, Sanguinetti M, Montuori E, Trecarichi EM, Posteraro B, Fiori B, Citton R, D'Inzeo T, Fadda G, Cauda R, Spanu T. | 2007 | 51 | 6 | 1987 | 1994 | PUBLICATION | Bloodstream infections (BSI) caused by extended-spectrum beta-lactamase (ESBL)-producing organisms markedly increase the rates of treatment failure and death. We conducted a retrospective cohort analysis to identify risk factors for mortality in adult in-patients with BSI caused by ESBL-producing Enterobacteriaceae (ESBL-BSI). Particular attention was focused on defining the impact on the mortality of inadequate initial antimicrobial therapy (defined as the initiation of treatment with active antimicrobial agents >72 h after collection of the first positive blood culture). A total of 186 patients with ESBL-BSI caused by Escherichia coli (n = 104), Klebsiella pneumoniae (n = 58), or Proteus mirabilis (n = 24) were identified by our microbiology laboratory from 1 January 1999 through 31 December 2004. The overall 21-day mortality rate was 38.2% (71 of 186). In multivariate analysis, significant predictors of mortality were inadequate initial antimicrobial therapy (odds ratio [OR] = 6.28; 95% confidence interval [CI] = 3.18 to 12.42; P < 0.001) and unidentified primary infection site (OR = 2.69; 95% CI = 1.38 to 5.27; P = 0.004). The inadequately treated patients (89 of 186 [47.8%]) had a threefold increase in mortality compared to the adequately treated group (59.5% versus 18.5%; OR = 2.38; 95% CI = 1.76 to 3.22; P < 0.001). The regimens most commonly classified as inadequate were based on oxyimino cephalosporin or fluoroquinolone therapy. Prompt initiation of effective antimicrobial treatment is essential in patients with ESBL-BSI, and empirical decisions must be based on a sound knowledge of the local distribution of pathogens and their susceptibility patterns. | 10 | 3 | 90 | CHEMBL_1 | 2009-09-03 |
CHEMBL1145247 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | 4-Alkyl and 4,4'-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives as new inhibitors of bacterial cell wall biosynthesis. | 15863310 | 10.1016/j.bmcl.2005.03.058 | nan | Kutterer KM, Davis JM, Singh G, Yang Y, Hu W, Severin A, Rasmussen BA, Krishnamurthy G, Failli A, Katz AH. | 2005 | 15 | 10 | 2527 | 2531 | PUBLICATION | Over 195 4-alkyl and 4,4-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives were synthesized, utilizing microwave accelerated synthesis, for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good activity against MurB in vitro and low MIC values against gram-positive bacteria, particularly penicillin-resistant Streptococcus pneumoniae (PRSP). Derivative 7l demonstrated antibacterial activity against both gram-positive and gram-negative bacteria. Derivatives 7f and 10a also demonstrated potent nanomolar Kd values in their binding to MurB. | 28 | 8 | 330 | CHEMBL_1 | 2009-09-03 |
CHEMBL1157195 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis, cytotoxic activity, and SAR analysis of the derivatives of taxchinin A and brevifoliol. | 18381240 | 10.1016/j.bmc.2008.03.041 | nan | Zhao Y, Guo N, Lou LG, Cong YW, Peng LY, Zhao QS. | 2008 | 16 | 9 | 4860 | 4871 | PUBLICATION | Twenty-one derivatives of taxchinin A (1) and brevifoliol (2) were synthesized and evaluated for cytotoxicity against human non-small lung cancer (A549) cell line. Nine derivatives showed potent activity with IC(50) values from 0.48 to 6.22microM. 5-Oxo-13-TBDMS-taxchinin A (11) and 5-oxo-13,15-epoxy-13-epi-taxchinin A (15) are the most potent derivatives, with IC(50) at 0.48 and 0.75microM, respectively. The structure-activity relationship (SAR) of these compounds established that exocyclic unsaturated ketone at ring C is the key structural element for the activity, while the alpha,beta-unsaturated ketone positioned at ring A has no effect for the activity. The significant cytotoxicity of derivatives 11 and 15 may be due to the conformational change in the taxane rings. The 3D-QSAR study was conducted on this series of compounds, which provided optimal predictive comparative molecular field (CoMFA) model with cross-validated r(2) (q(2)) value of 0.64. | 23 | 1 | 23 | CHEMBL_2 | 2009-11-30 |
CHEMBL1944533 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and evaluation of anti-tubercular and antibacterial activities of new 4-(2,6-dichlorobenzyloxy)phenyl thiazole, oxazole and imidazole derivatives. Part 2. | 22264895 | 10.1016/j.ejmech.2012.01.007 | nan | Lu X, Liu X, Wan B, Franzblau SG, Chen L, Zhou C, You Q. | 2012 | 49 | nan | 164 | 171 | PUBLICATION | A series of substituted 4-(2,6-dichlorobenzyloxy)phenyl thiazole, oxazole and imidazole derivatives were synthesized. The derivatives were screened for in vitro anti-tubercular activities against Mycobacterium tuberculosis H37Rv using the Microplate Alamar Blue Assay (MABA), and antibacterial activities with agar dilution method against clinical S. aureus, E. coli, S. pneumoniae and penicilin-resistant S. pneumoniae. Among 15 compounds, several thiazole derivatives exhibited good anti-tubercular activities with MIC values between 1 μM and 61.2 μM, and potent activities against S. pneumoniae with MIC values less than 0.134 μM. These studies suggest that the thiazole scaffold may serve as a new promising template for further elaboration as anti-tubercular and antibacterial drugs. | 20 | 4 | 70 | CHEMBL_14 | 2012-06-27 |
CHEMBL2034835 | European journal of medicinal chemistry. | 1 | Scientific Literature | A solvent free, four-component synthesis and 1,3-dipolar cycloaddition of 4(H)-pyrans with nitrile oxides: synthesis and discovery of antimycobacterial activity of enantiomerically pure 1,2,4-oxadiazoles. | 22575534 | 10.1016/j.ejmech.2012.04.021 | nan | Almansour AI, Suresh Kumar R, Arumugam N, Sriram D. | 2012 | 53 | nan | 416 | 423 | PUBLICATION | Four-component reactions of (R)-1-(1-phenylethyl)tetrahydro-4(1H)-pyridinone, aromatic aldehydes and malononitrile in a 1:2:1 molar ratio in the presence of solid sodium ethoxide under solvent free conditions afforded an inseparable mixture of two diastereomeric 4(H)-pyrans in near quantitative yields. These compounds upon 1,3-dipolar cycloaddition with nitrile oxides furnished two enantiomerically pure 1,2,4-oxadiazoles in moderate yields, which were screened for in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the compounds screened, compound 10h was found to be the most active in vitro with a MIC value of 0.07 and 0.14 μM against MTB and MDR-TB respectively. | 14 | 1 | 56 | CHEMBL_15 | 2013-01-23 |
CHEMBL3352715 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c. | 24894561 | 10.1016/j.bmcl.2014.05.022 | nan | Singh K, Kumar M, Pavadai E, Naran K, Warner DF, Ruminski PG, Chibale K. | 2014 | 24 | 14 | 2985 | 2990 | PUBLICATION | New verapamil analogues were synthesized and their inhibitory activities against Mycobacterium tuberculosis H37Rv determined in vitro alone and in combination with rifampicin (RIF). Some analogues showed comparable activity to verapamil and exhibited better synergies with RIF. Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues. | 23 | 1 | 82 | CHEMBL_21 | 2016-02-01 |
CHEMBL2331373 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antitubercular activity of amino alcohol fused spirochromone conjugates. | 23357635 | 10.1016/j.bmcl.2012.12.073 | nan | Mujahid M, Gonnade RG, Yogeeswari P, Sriram D, Muthukrishnan M. | 2013 | 23 | 5 | 1416 | 1419 | PUBLICATION | A series of 21 new amino alcohol fused spirochromone conjugates have been synthesized, characterized with analytical data and evaluated their antimycobacterial activity against Mycobacterium tuberculosis (virulent strain H37Rv) in vitro. Some of the compounds exerted significant inhibition, in particular, compound 4f found to be the most potent derivative exhibiting MIC=3.13 μg/mL. | 23 | 1 | 23 | CHEMBL_17 | 2013-08-29 |
CHEMBL1932922 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazole derivatives. | 22104148 | 10.1016/j.bmcl.2011.10.059 | nan | Khunt RC, Khedkar VM, Chawda RS, Chauhan NA, Parikh AR, Coutinho EC. | 2012 | 22 | 1 | 666 | 678 | PUBLICATION | As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system. A 3D-QSAR study based on CoMFA and CoMSIA was performed on these pyrazole derivatives to correlate their chemical structures with the observed activity against M. tuberculosis. The CoMFA model provided a significant correlation of steric and electrostatic fields with the biological activity while the CoMSIA model could additionally shed light on the role of hydrogen bonding and hydrophobic features. The important features identified in the 3D-QSAR models have been used to propose new molecules whose activities are predicted higher than the existing systems. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antitubercular agents. | 51 | 1 | 204 | CHEMBL_14 | 2012-06-27 |
CHEMBL2311404 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides. | 23202851 | 10.1016/j.ejmech.2012.10.054 | nan | Liang JH, An K, Lv W, Cushman M, Wang H, Xu YC. | 2013 | 59 | nan | 54 | 63 | PUBLICATION | A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS(B)-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar=4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS(B)-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9. | 17 | 7 | 269 | CHEMBL_17 | 2013-08-29 |
CHEMBL1148671 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antibacterial activity of C12 des-methyl ketolides. | 16784845 | 10.1016/j.bmcl.2006.05.104 | nan | Lin X, Rico AC, Chu DT, Carroll GL, Barker L, Shawar R, Desai MC, Plattner JJ. | 2006 | 16 | 17 | 4692 | 4696 | PUBLICATION | Synthesis of C(12) des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C(12) stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant erm- and mef-containing strains of Streptococcus pneumoniae. | 23 | 6 | 345 | CHEMBL_1 | 2009-09-03 |
CHEMBL1121662 | Journal of medicinal chemistry. | 1 | Scientific Literature | A comparison of mutagenic and carcinogenic activities of aniline mustards. | 7277394 | 10.1021/jm00139a018 | nan | Leo A, Panthananickal A, Hansch C, Theiss J, Shimkin M, Andrews AW. | 1981 | 24 | 7 | 859 | 864 | PUBLICATION | A set of 15 derivatives of aniline mustard (I) was tested to give a quantitative measure of mutagenicity in Salmonella typhimurium TA-1535 and TA-100 and also carcinogenicity as lung tumors in strain-A mice. The structural variation in the set was chosen to minimize collinearity between hydrophobic, electronic, and molar refractive properties. By these measures, there was not a direct relationship between mutagenicity and carcinogenicity; in fact, since the 4-OPh analogue ranked highest in mutagenicity and among the lowest in carcinogenicity, while the reverse was noted for the 3,5-(NHCONH2)2 analogue, an inverse relationship was marginally significant. S-9 activation was required in the Ames test using TA-100, and the dose-response curve, prior to toxicity, appeared biphasic. | 15 | 1 | 60 | CHEMBL_1 | 2009-09-03 |
CHEMBL1141943 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antitubercular activity of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes. | 16171992 | 10.1016/j.bmcl.2005.08.045 | nan | Panda G, Shagufta, Srivastava AK, Sinha S. | 2005 | 15 | 23 | 5222 | 5225 | PUBLICATION | A series of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes were synthesized from nucleophilic opening of oxirane with different amines. These compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H(37)R(v) in vitro and showed MIC in the range of 3.12-25microg/ml. | 17 | 1 | 34 | CHEMBL_1 | 2009-09-03 |
CHEMBL1944570 | ACS medicinal chemistry letters. | 1 | Scientific Literature | Discovery of 4''-ether linked azithromycin-quinolone hybrid series: influence of the central linker on the antibacterial activity. | 24900314 | 10.1021/ml100253p | nan | Pavlović D, Mutak S. | 2011 | 2 | 5 | 331 | 336 | PUBLICATION | A series of novel C-4''-substituted azithromycins was synthesized and evaluated for in vitro antibacterial activity against a panel of representative erythromycin-susceptible and macrolide-lincosamide-streptogramin (MLS) resistant pathogens. In summary, azithromycin and quinolone substructures merged in a mutually SAR-compatible design gave rise to a new class of antimicrobials with an improved spectrum and potency over azithromycin. Prototypical analogues 7f and 8f display an improved potency versus azithromycin against Gram-positive and fastidious Gram-negative pathogens. In particular, these new leads maintain activity against MLS-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes. In addition, they represent an improvement over telithromycin (1) and cethromycin (2) against the fastidious Gram-negative pathogen Haemophilus influenzae. | 22 | 6 | 320 | CHEMBL_14 | 2012-06-27 |
CHEMBL1933017 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and biological evaluation of some thiazolidinones as antimicrobial agents. | 22182927 | 10.1016/j.ejmech.2011.11.041 | nan | Patel D, Kumari P, Patel N. | 2012 | 48 | nan | 354 | 362 | PUBLICATION | A novel series of thiazolidinone derivatives namely 4-(4-dimethylamino-6-{4-[5-(4-ethylpiperazin-1-ylmethyl)-4-oxo-2-phenylthiazolidin-3-yl]-phenylamino}-[1,3,5]triazin-2-yloxy)-1-methyl-1H-quinolin-2-one have been synthesized from the key intermediate 4-[4-(4-aminophenylamino)-6-dimethylamino-[1,3,5]triazin-2-yloxy]-1-methyl-1H-quinolin-2-one (7). Condensation reaction of compound 7 with different aldehyde derivatives were performed to obtain Schiff base derivatives, which after cyclization gave thiazolidinones and finally they were reacted with N-ethylpiperazine to get target compounds. The newly synthesized compounds were evaluated for their antimicrobial activity against eight bacterial strains (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri) and four fungal strains (Aspergillus niger, Candida albicans, Aspergillus fumigatus, Aspergillus clavatus). | 20 | 12 | 456 | CHEMBL_14 | 2012-06-27 |
CHEMBL2385061 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis and carbonic anhydrase inhibitory properties of sulfamides structurally related to dopamine. | 23623256 | 10.1016/j.bmc.2013.03.077 | nan | Aksu K, Nar M, Tanc M, Vullo D, Gülçin I, Göksu S, Tümer F, Supuran CT. | 2013 | 21 | 11 | 2925 | 2931 | PUBLICATION | A series of novel sulfamides incorporating the dopamine scaffold were synthesized. Reaction of amines and tert-butyl-alcohol/benzyl alcohol in the presence of chlorosulfonyl isocyanate (CSI) afforded sulfamoyl carbamates, which were converted to the title compounds by treatment with trifluoroacetic acid or by palladium-catalyzed hydrogenolysis. Inhibition of six α-carbonic anhydrases (CAs, EC 4.2.1.1), that is, CA I, CA II, CA VA, CA IX, CA XII and CA XIV, and two β-CAs from Candida glabrata (CgCA) and Mycobacterium tuberculosis (Rv3588) with these sulfamides was investigated. All CA isozymes were inhibited in the low micromolar to nanomolar range by the dopamine sulfamide analogues. K(i)s were in the range of 0.061-1.822 μM for CA I, 1.47-2.94 nM for CA II, 2.25-3.34 μM for CA VA, 0.041-0.37 μM for CA IX, 0.021-1.52 μM for CA XII, 0.007-0.219 μM for CA XIV, 0.35-5.31 μM for CgCA and 0.465-4.29 μM for Rv3588. The synthesized sulfamides may lead to inhibitors targeting medicinally relevant CA isoforms with potential applications as antiepileptic, antiobesity antitumor agents or anti-infective. | 8 | 7 | 50 | CHEMBL_18 | 2014-03-12 |
CHEMBL1134158 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Antimycobacterial in vitro activity of cobalt(II) isonicotinoylhydrazone complexes. Part 10. | 11212096 | 10.1016/s0960-894x(00)00648-x | nan | Bottari B, Maccari R, Monforte F, Ottanà R, Rotondo E, Vigorita MG. | 2001 | 11 | 3 | 301 | 303 | PUBLICATION | Octahedral cobalt(II) complexes of isonicotinoylhydrazones, which were obtained from the primary antituberculous agent isoniazid, have been synthesised and characterised. Their antimycobacterial in vitro activity has been evaluated against Mycobacterium tuberculosis H37Rv: they exhibit MIC values ranging from < 0.1 to 0.39 microg/mL, showing them to be generally more active than previously reported analogous Cu(II) and Ni(II) complexes. | 9 | 1 | 16 | CHEMBL_1 | 2009-09-03 |
CHEMBL1914320 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | C4-alkylthiols with activity against Moraxella catarrhalis and Mycobacterium tuberculosis. | 22014754 | 10.1016/j.bmc.2011.09.030 | nan | Kostova MB, Myers CJ, Beck TN, Plotkin BJ, Green JM, Boshoff HI, Barry CE, Deschamps JR, Konaklieva MI. | 2011 | 19 | 22 | 6842 | 6852 | PUBLICATION | Antimicrobial resistance represents a global threat to healthcare. The ability to adequately treat infectious diseases is increasingly under siege due to the emergence of drug-resistant microorganisms. New approaches to drug development are especially needed to target organisms that exhibit broad antibiotic resistance due to expression of β-lactamases which is the most common mechanism by which bacteria become resistant to β-lactam antibiotics. We designed and synthesized 20 novel monocyclic β-lactams with alkyl- and aryl-thio moieties at C4, and subsequently tested these for antibacterial activity. These compounds demonstrated intrinsic activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=6) β-lactamase producing Moraxella catarrhalis clinical isolates. | 25 | 7 | 431 | CHEMBL_14 | 2012-06-27 |
CHEMBL2095176 | nan | 22 | GSK Tuberculosis Screening | GSK Tuberculosis Screening Data | nan | 10.6019/CHEMBL2095176 | nan | Ballell, L., Bates, R. H., Young, R. J., Alvarez-Gomez, D., Alvarez-Ruiz, E., Barroso, V., Blanco, D., Crespo, B., Escribano, J., Gonzalez, R., Lozano, S., Huss, S., Santos-Villarejo, A., Martin-Plaza, J. J., Mendoza, A., Rebollo-Lopez, M. J., Remuinan-Blanco, M., Lavandera, J. L., Perez-Herran, E., Gamo-Benito, F. J., Garcia-Bustos, J. F., Barros, D., Castro, J. P. and Cammack, N | nan | nan | nan | nan | nan | DATASET | As a result of a 2-million-compound anti-mycobacterial phenotypic screening campaign against Mycobacterium Bovis BCG with hit confirmation in M. Tuberculosis H37Rv, 776 hits against BCG including 177 non-cytotoxic H37Rv potent hits were identified and made available. | 776 | 4 | 1406 | CHEMBL_15 | 2013-01-23 |
CHEMBL2203181 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Microwave-assisted synthesis, molecular docking and antitubercular activity of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives. | 23122523 | 10.1016/j.bmcl.2012.10.032 | nan | Mohan SB, Ravi Kumar BV, Dinda SC, Naik D, Prabu Seenivasan S, Kumar V, Rana DN, Brahmkshatriya PS. | 2012 | 22 | 24 | 7539 | 7542 | PUBLICATION | Based on bioisosteric similarities with isoniazid, a series of 1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives has been designed. The target compounds have been synthesized by multicomponent reaction which involves one-pot organic reactions using ethylcyanoacetate, urea/thiourea and arylaldehydes in presence of ethanolic K(2)CO(3). Two methodologies, conventional and microwave-assisted, have been adopted for the synthesis. The later strategy gave high yields in less than 10 min as compared to long hours using the former approach. Molecular docking of the target compounds into the enzyme Mycobacterium tuberculosis enoyl reductase (InhA) revealed important structural information on the plausible binding interactions. Major binding interactions were found to be of dispersion type (residues Tyr158, Ile215, Met103 and Met199) and a hydrogen bond with Tyr158. Binding poses of the all the compounds were energetically favorable and showed good interactions with the active site residues. Few selected compounds were also evaluated for antitubercular activity in vitro against drug-sensitive M. tuberculosis H37Rv strain and clinically isolated S, H, R and E resistant M. tuberculosis by luciferase reporter phage (LRP) assay method. Some compounds displayed promising antimycobacterial activity comparable or less than the standard drugs isoniazid and rifampicin. | 7 | 1 | 24 | CHEMBL_16 | 2013-05-07 |
CHEMBL1156465 | The Journal of biological chemistry. | 1 | Scientific Literature | Structures of Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase provide new insights into catalysis. | 17491006 | 10.1074/jbc.m701935200 | nan | Henriksson LM, Unge T, Carlsson J, Aqvist J, Mowbray SL, Jones TA. | 2007 | 282 | 27 | 19905 | 19916 | PUBLICATION | Isopentenyl diphosphate is the precursor of various isoprenoids that are essential to all living organisms. It is produced by the mevalonate pathway in humans but by an alternate route in plants, protozoa, and many bacteria. 1-deoxy-D-xylulose-5-phosphate reductoisomerase catalyzes the second step of this non-mevalonate pathway, which involves an NADPH-dependent rearrangement and reduction of 1-deoxy-D-xylulose 5-phosphate to form 2-C-methyl-D-erythritol 4-phosphate. The use of different pathways, combined with the reported essentiality of the enzyme makes the reductoisomerase a highly promising target for drug design. Here we present several high resolution structures of the Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase, representing both wild type and mutant enzyme in various complexes with Mn(2+), NADPH, and the known inhibitor fosmidomycin. The asymmetric unit corresponds to the biological homodimer. Although crystal contacts stabilize an open active site in the B molecule, the A molecule displays a closed conformation, with some differences depending on the ligands bound. An inhibition study with fosmidomycin resulted in an estimated IC(50) value of 80 nm. The double mutant enzyme (D151N/E222Q) has lost its ability to bind the metal and, thereby, also its activity. Our structural information complemented with molecular dynamics simulations and free energy calculations provides the framework for the design of new inhibitors and gives new insights into the reaction mechanism. The conformation of fosmidomycin bound to the metal ion is different from that reported in a previously published structure and indicates that a rearrangement of the intermediate is not required during catalysis. | 1 | 2 | 2 | CHEMBL_2 | 2009-11-30 |
CHEMBL2146424 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis and structure-activity relationship of a novel class of 15-membered macrolide antibiotics known as '11a-azalides'. | 22925450 | 10.1016/j.bmc.2012.08.007 | nan | Sugimoto T, Tanikawa T, Suzuki K, Yamasaki Y. | 2012 | 20 | 19 | 5787 | 5801 | PUBLICATION | Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide scaffolds with activities against resistant pathogens is urgently needed. An efficient method for reconstructing the erythromycin A macrolactone skeleton has been established. Based on this methodology, novel 15-membered macrolides, known as '11a-azalides', with substituents at the C12, C13, or C4″ positions were synthesized and their antibacterial activities were evaluated. These derivatives showed promising antibacterial activities against erythromycin-resistant Streptococcus pneumoniae. Among them, the C4″ substituted derivatives had the most potent activity against erythromycin-resistant S. pneumoniae. | 27 | 1 | 54 | CHEMBL_16 | 2013-05-07 |
CHEMBL1142096 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Reduced susceptibility of Haemophilus influenzae to the peptide deformylase inhibitor LBM415 can result from target protein overexpression due to amplified chromosomal def gene copy number. | 17220413 | 10.1128/aac.01103-06 | nan | Dean CR, Narayan S, Richards J, Daigle DM, Esterow S, Leeds JA, Kamp H, Puyang X, Wiedmann B, Mueller D, Voshol H, van Oostrum J, Wall D, Koehn J, Dzink-Fox J, Ryder NS. | 2007 | 51 | 3 | 1004 | 1010 | PUBLICATION | Previous genetic analysis of Haemophilus influenzae revealed two mechanisms associated with decreased susceptibility to the novel peptide deformylase inhibitor LBM415: AcrAB-TolC-mediated efflux and Fmt bypass, resulting from mutations in the pump repressor gene acrR and in the fmt gene, respectively. We have isolated an additional mutant, CDS23 (LBM415 MIC, 64 microg/ml versus 4 microg/ml against the parent strain NB65044) that lacks mutations in the acrR or fmt structural genes or in the gene encoding Def, the intracellular target of LBM415. Western immunoblot analysis, two-dimensional gel electrophoresis, and tryptic digestion combined with mass spectrometric identification showed that the Def protein was highly overexpressed in the mutant strain. Consistent with this, real-time reverse transcription-PCR revealed a significant increase in def transcript titer. No mutations were found in the region upstream of def that might account for altered expression; however, pulsed-field gel electrophoresis suggested that a genetic rearrangement of the region containing def had occurred. Using a combination of PCR, sequencing, and Southern blot analyses, it was determined that the def gene had undergone copy number amplification, explaining the high level of target protein expression. Inactivation of the AcrAB-TolC efflux pump in this mutant increased susceptibility 16-fold, highlighting the role of efflux in exacerbating the overall reduced susceptibility resulting from target overexpression. | 3 | 1 | 12 | CHEMBL_1 | 2009-09-03 |
CHEMBL1955780 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors. | 22386984 | 10.1016/j.bmc.2012.02.010 | nan | Topai A, Breccia P, Minissi F, Padova A, Marini S, Cerbara I. | 2012 | 20 | 7 | 2323 | 2337 | PUBLICATION | Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl-N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents. | 34 | 7 | 97 | CHEMBL_14 | 2012-06-27 |
CHEMBL2069261 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Click-based synthesis of triazolobithiazole ΔF508-CFTR correctors for cystic fibrosis. | 22841006 | 10.1016/j.bmc.2012.06.046 | nan | Donald MB, Rodriguez KX, Shay H, Phuan PW, Verkman AS, Kurth MJ. | 2012 | 20 | 17 | 5247 | 5253 | PUBLICATION | Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1H-1,2,3-triazol-1-yl)-4,5'-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared to the benchmark bithiazole CF corrector corr-4a, improved logP values (4.5 vs 5.96). | 7 | 2 | 15 | CHEMBL_15 | 2013-01-23 |
CHEMBL2163243 | Journal of medicinal chemistry. | 1 | Scientific Literature | Metaproterenol, isoproterenol, and their bisdimethylcarbamate derivatives as human cholinesterase inhibitors. | 22817559 | 10.1021/jm300289k | nan | Bosak A, Gazić Smilović I, Sinko G, Vinković V, Kovarik Z. | 2012 | 55 | 15 | 6716 | 6723 | PUBLICATION | Metaproterenol and isoproterenol are bronchodilators that provide a structural basis for many other bronchodilators currently in use. One of these structurally related bronchodilators is terbutaline; it is administered as a prodrug, bambuterol, and is metabolized (bioconverted) into terbutaline by butyrylcholinesterase (BChE). The metabolism rate can be affected by BChE gene polymorphism in the human population and BChE stereoselectivity. The aim of our study was to investigate inhibition of human BChE and acetylcholinesterase (AChE) with metaproterenol, isoproterenol, and newly synthesized racemic bisdimethylcarbamate derivatives of metaproterenol (metacarb) and isoproterenol (isocarb) and their (R)-enantiomers to see if their bioconversion is affected by BChE inhibition in the same way as that for bambuterol. Metacarb and isocarb proved to be selective BChE inhibitors, as they progressively inhibited AChE 960 to 80 times more slowly than BChE(UU). All studied cholinesterases displayed poor affinity for metaproterenol and isoproterenol, yet BChE(UU) had an affinity about five times higher than that of AChE. | 6 | 4 | 61 | CHEMBL_16 | 2013-05-07 |
CHEMBL3046304 | Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. | 1 | Scientific Literature | Discovery of a series of novel compounds with moderate anti-avian H5N1 influenza virus activity in chick embryo | nan | 10.1007/s00044-012-0341-2 | nan | Xie Y, Huang B, Yu K, Shi F, Xu W | 2013 | 22 | 7 | 3485 | 3496 | PUBLICATION | nan | 28 | 3 | 112 | CHEMBL_19 | 2014-07-03 |
CHEMBL2203064 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides. | 23099094 | 10.1016/j.bmcl.2012.10.003 | nan | Stokes SS, Albert R, Buurman ET, Andrews B, Shapiro AB, Green OM, McKenzie AR, Otterbein LR. | 2012 | 22 | 23 | 7019 | 7023 | PUBLICATION | A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low LogD and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC(50) <0.1 μM against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with LogD -1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13. | 18 | 3 | 89 | CHEMBL_16 | 2013-05-07 |
CHEMBL2074221 | Molecular pharmacology. | 18 | TP-search Transporter Database | Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. | 12488537 | 10.1124/mol.63.1.65 | nan | Wang X, Furukawa T, Nitanda T, Okamoto M, Sugimoto Y, Akiyama S, Baba M. | 2003 | 63 | 1 | 65 | 72 | PUBLICATION | Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP- binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4+ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX 500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX 500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX 500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX 500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX 500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX 500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5'-monophosphate, in MT-4/DOX 500 cells. | 8 | 1 | 9 | CHEMBL_15 | 2013-01-23 |
CHEMBL2396578 | Journal of medicinal chemistry. | 1 | Scientific Literature | Identification, biochemical and structural evaluation of species-specific inhibitors against type I methionine aminopeptidases. | 23767698 | 10.1021/jm400395p | nan | Kishor C, Arya T, Reddi R, Chen X, Saddanapu V, Marapaka AK, Gumpena R, Ma D, Liu JO, Addlagatta A. | 2013 | 56 | 13 | 5295 | 5305 | PUBLICATION | Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity. | 38 | 1 | 153 | CHEMBL_18 | 2014-03-12 |
CHEMBL2434878 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antimycobacterial activity of analogues of the bioactive natural products sampangine and cleistopholine. | 23850570 | 10.1016/j.ejmech.2013.06.010 | nan | Claes P, Cappoen D, Mbala BM, Jacobs J, Mertens B, Mathys V, Verschaeve L, Huygen K, De Kimpe N. | 2013 | 67 | nan | 98 | 110 | PUBLICATION | Identification and investigation of novel classes and compounds for the treatment of tuberculosis remains of utmost importance in the fight against the disease. Despite many efforts, the weakly gram positive Mycobacterium tuberculosis keeps demanding its toll in human lives. For this reason a small library of substituted and unsubstituted aza analogues of cleistopholine and sampangine were synthesized in a short and straightforward manner and tested in vitro against M.tb. The compounds showed promising activity against the M.tb H37Rv strain and Minimal Inhibitory Concentrations (MIC) could be observed as low as 0.88 μM. Accompanied by moderate acute toxicity against C3A hepatocytes, the therapeutic index showed an acceptable range. Further tests confirmed the inhibition by up to 74% of intracellular growth of M.tb inside macrophages conferred by 1-hydroxybenzo[g]isoquinoline-5,10-diones. Activity of the library against other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans was confirmed. Furthermore the activity against a multi-drug-resistant MDR LAM-1 M.tb strain was tested and the MIC value situated around 1 μM. The lacking genotoxicity of a group of enamine substituted cleistopholine analogues indicates this group as a hit and encourages their use as a scaffold for further studies. | 40 | 9 | 288 | CHEMBL_18 | 2014-03-12 |
CHEMBL2429770 | Journal of medicinal chemistry. | 1 | Scientific Literature | Development of Mycobacterium tuberculosis whole cell screening hits as potential antituberculosis agents. | 23927683 | 10.1021/jm400381v | nan | Cooper CB. | 2013 | 56 | 20 | 7755 | 7760 | PUBLICATION | The global pandemic of drug sensitive tuberculosis (TB) as well as the increasing threat from various multidrug resistant forms of TB drives the quest for newer, safer, more effective TB treatment options. The general lack of success in progressing novel chemical matter from high throughput screens of Mycobacterium tuberculosis (M.tb) biochemical targets has prompted resurgence in interest and efforts in prosecuting mycobacterial phenotypic screens. Whole cell active compounds identified from such screens offer significant intrinsic advantages over biochemical screening hits, and derivatives of many of these have proven invaluable in helping to fill the current TB drug development pipeline. Modern techniques for 'de-orphaning' such screening hits (i.e., determining their specific biological mechanism of action) offer the possibility of ultimately identifying improved next-generation chemical series by screening these essential, pharmacologically validated biochemical targets as well. | 14 | 3 | 14 | CHEMBL_18 | 2014-03-12 |
CHEMBL1140643 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of 4-phenoxybenzamide adenine dinucleotide as NAD analogue with inhibitory activity against enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis. | 17560106 | 10.1016/j.bmcl.2007.05.084 | nan | Bonnac L, Gao GY, Chen L, Felczak K, Bennett EM, Xu H, Kim T, Liu N, Oh H, Tonge PJ, Pankiewicz KW. | 2007 | 17 | 16 | 4588 | 4591 | PUBLICATION | The chemical synthesis of 4-phenoxybenzamide adenine dinucleotide (3), a NAD analogue which mimics isoniazid-NAD adduct and inhibits Mycobacterium tuberculosis NAD-dependent enoyl-ACP reductase (InhA), is reported. The 4-phenoxy benzamide riboside (1) has been prepared as a key intermediate, converted into its 5'-mononucleotide (2), and coupled with AMP imidazolide to give the desired NAD analogue 3. It inhibits InhA with IC50 = 27 microM. | 3 | 1 | 3 | CHEMBL_1 | 2009-09-03 |
CHEMBL1126554 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis of novel modified dipeptide inhibitors of human collagenase: beta-mercapto carboxylic acid derivatives. | 8258825 | 10.1021/jm00077a006 | nan | Beszant B, Bird J, Gaster LM, Harper GP, Hughes I, Karran EH, Markwell RE, Miles-Williams AJ, Smith SA. | 1993 | 36 | 25 | 4030 | 4039 | PUBLICATION | The synthesis of a series of thiol-containing, modified dipeptide inhibitors (8) of human collagenase, which incorporate various carboxylic acid derivatives at the presumed P1 position, beta to the thiol group, is described. The compounds were evaluated, in vitro, for their ability to inhibit the degradation of rat skin type 1 collagen by purified human lung fibroblast collagenase, and structure-activity relationship studies are described. Optimum potency (IC50 values in the nanomolar range) was achieved by incorporating methyl (compounds 43a, 56a, and 57ab) or benzyl esters (44a) at the P1 position. Small amides were also accommodated (e.g. primary amide 47a), but in general, increasing the size of the P1 amide substituent lowered potency. PheNHMe, TrpNHMe, and Tyr(Me)NHMe substituents were found to be approximately equipotent P2'-residues. The results of testing all four diastereoisomers 56a-d of the compound with (S)-TrpNHMe at the P2' position indicated that the S,S,S diastereoisomer 56a possessed highest potency (IC50 2.5 nM) and that the second most potent diastereoisomer was 56d (IC50 12 nM) with the R,R,S configuration. It appeared that the orientation of the P1' and the thiol-bearing centers to each other is a more critical influence on potency than any absolute stereochemical requirements. It is suggested that the high potency of the beta-mercapto carboxylic acid derivatives may be a consequence of bidentate coordination of the thiol and carbonyl groups to the active-site zinc ion in the collagenase enzyme. | 24 | 1 | 31 | CHEMBL_1 | 2009-09-03 |
CHEMBL1139006 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and in vitro antibiotic activity of 16-membered 9-O-arylalkyloxime macrolides. | 16343900 | 10.1016/j.bmcl.2005.11.061 | nan | Fu H, Marquez S, Gu X, Katz L, Myles DC. | 2006 | 16 | 5 | 1259 | 1266 | PUBLICATION | A series of novel 9-O-arylalkyloxime analogs based on three different 16-membered macrolide scaffolds-5-O-mycaminosyltylonolide (OMT), tilmicosin, and 20-deoxy-20-(3,5-dimethyl-1-piperidin-1-yl)-OMT-was synthesized. In vitro antibiotic activities were assayed against Gram-positive Streptococcus pneumoniae and Staphylococcus aureus and Gram-negative Haemophilus influenzae bacterial strains. Analogs derived from OMT (3-15) showed similar or better antibacterial activities against macrolide-susceptible strains and enhanced activities against macrolide-resistant strains compared with erythromycin A, tylosin, or OMT. Similar results were observed for tilmicosin 9-O-arylalkyloxime analogs (18-24). In contrast, most of the 20-deoxy-20-(3,5-dimethyl-1-piperidin-1-yl)-OMT analogs (25-33) showed reduced antibacterial activities compared with OMT. Ribosome-binding studies were performed on compounds 12 (OMT derivative), 20 (tilmicosin derivative), and 29 [20-deoxy-20-(3,5-dimethyl-1-piperidin-1-yl)-OMT derivative]. It was found that these compounds interacted with both domain V and domain II of the Escherichia coli 23S rRNA. | 36 | 5 | 551 | CHEMBL_1 | 2009-09-03 |
CHEMBL1933046 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and antibacterial activity of a novel series of acylides active against community acquired respiratory pathogens. | 22153939 | 10.1016/j.bmcl.2011.10.101 | nan | Kumar R, Rathy S, Hajare AK, Surase YB, Dullu J, Jadhav JS, Venkataramanan R, Chakrabarti A, Pandya M, Bhateja P, Ramkumar G, Das B. | 2012 | 22 | 1 | 476 | 481 | PUBLICATION | A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains. | 71 | 4 | 368 | CHEMBL_14 | 2012-06-27 |
CHEMBL2203094 | Journal of natural products. | 1 | Scientific Literature | Ramariolides A-D, antimycobacterial butenolides isolated from the mushroom Ramaria cystidiophora. | 23205944 | 10.1021/np3006277 | nan | Centko RM, Ramón-García S, Taylor T, Patrick BO, Thompson CJ, Miao VP, Andersen RJ. | 2012 | 75 | 12 | 2178 | 2182 | PUBLICATION | Four butenolides, ramariolides A-D (1-4), have been isolated from the fruiting bodies of the coral mushroom Ramaria cystidiophora. Their structures were elucidated by analysis of 1D and 2D NMR data and a single-crystal X-ray diffraction analysis of 1, and their absolute configurations were established using Mosher's method. The major metabolite, ramariolide A (1), which contains an unusual spiro oxiranebutenolide moiety, showed in vitro antimicrobial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis. | 3 | 8 | 15 | CHEMBL_16 | 2013-05-07 |
CHEMBL2380288 | Journal of medicinal chemistry. | 1 | Scientific Literature | Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles. | 23627352 | 10.1021/jm400086g | nan | Gangjee A, Namjoshi OA, Raghavan S, Queener SF, Kisliuk RL, Cody V. | 2013 | 56 | 11 | 4422 | 4441 | PUBLICATION | Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg), and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogues. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR. | 31 | 4 | 237 | CHEMBL_18 | 2014-03-12 |
CHEMBL1137747 | European journal of medicinal chemistry. | 1 | Scientific Literature | Fullerene derivatized s-triazine analogues as antimicrobial agents. | 19062138 | 10.1016/j.ejmech.2008.10.036 | nan | Kumar A, Menon SK. | 2009 | 44 | 5 | 2178 | 2183 | PUBLICATION | A series of novel fullerene derivatives bearing s-triazine moiety have been synthesized by adopting 1,3 dipolar cycloaddition reaction of C(60) and azomethine ylides generated from the corresponding Schiff bases of 2,4,6 trisubstituted s-triazine. All the compounds synthesized were characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR and FAB-MS. The compounds were then screened for their antibacterial activity against both gram-positive (Staphylococcus aureus, Bacillus subtilis, Bacillus pumilis) and gram-negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae) bacteria by disc diffusion method. All the compounds were found to be active against these strains at very low concentration and were comparable to standard drug ciprofloxacin. | 6 | 6 | 42 | CHEMBL_2 | 2009-11-30 |
CHEMBL1777712 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening. | 21536436 | 10.1016/j.bmcl.2011.04.027 | nan | Vella P, Hussein WM, Leung EW, Clayton D, Ollis DL, Mitić N, Schenk G, McGeary RP. | 2011 | 21 | 11 | 3282 | 3285 | PUBLICATION | The emergence of metallo-β-lactamases (MBLs) capable of hydrolysing a broad spectrum of β-lactam antibiotics is particularly concerning for the future treatment of bacterial infections. This work describes the discovery of lead compounds for the development of new inhibitors using a competitive colorimetric assay based on the chromogenic cephalosporin CENTA, and a 500 compound Maybridge™ library suitable for fragment-based screening. The interactions between identified inhibitory fragments and the active site of the MBL from Klebsiella pneumoniae and Pseudomonas aeruginosa were probed by in silico docking studies. | 11 | 1 | 23 | CHEMBL_12 | 2011-11-18 |
CHEMBL1138748 | Journal of medicinal chemistry. | 1 | Scientific Literature | A prodrug approach toward the development of water soluble fluoroquinolones and structure--activity relationships of quinoline-3-carboxylic acids. | 15341485 | 10.1021/jm0497895 | nan | Baker WR, Cai S, Dimitroff M, Fang L, Huh KK, Ryckman DR, Shang X, Shawar RM, Therrien JH. | 2004 | 47 | 19 | 4693 | 4709 | PUBLICATION | A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine) at C-7 resulted in some of the most active analogues. | 50 | 4 | 255 | CHEMBL_1 | 2009-09-03 |
CHEMBL1149246 | Journal of medicinal chemistry. | 1 | Scientific Literature | Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. | 15566289 | 10.1021/jm040847w | nan | Vanheusden V, Munier-Lehmann H, Froeyen M, Busson R, Rozenski J, Herdewijn P, Van Calenbergh S. | 2004 | 47 | 25 | 6187 | 6194 | PUBLICATION | Thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for selectively blocking bacterial DNA synthesis. Hereby, we report on the discovery of a novel class of bicyclic nucleosides (10 and 11) and one dinucleoside (12), belonging to the most selective inhibitors of TMPKmt discovered so far. | 15 | 3 | 45 | CHEMBL_1 | 2009-09-03 |
CHEMBL1155034 | Journal of natural products. | 1 | Scientific Literature | Constituents of the root wood of Zanthoxylum wutaiense with antitubercular activity. | 18564877 | 10.1021/np700719e | nan | Huang HY, Ishikawa T, Peng CF, Tsai IL, Chen IS. | 2008 | 71 | 7 | 1146 | 1151 | PUBLICATION | Bioassay-guided fractionation of the root wood of Zanthoxylum wutaiense led to the isolation of 11 new compounds, wutaiensol methyl ether (1), demethoxywutaiensol methyl ether (2), methyl wutaiensate (3), methyl 7-hydroxyanodendroate (4), methyl 7-methoxyanodendroate (5), wutaifuranol (6), 7-methoxywutaifuranol (7), 7-methoxywutaifuranal (8), methyl wutaifuranate (9), methyl 7-methoxybenzofuran-5-carboxylate (10), and wutaipyranol (12), together with another 37 known compounds, of which one, 7-methoxybenzofuran-5-carboxaldehyde (11), was not previously known as a plant constituent. The structures of these isolates were identified by means of spectroscopic analysis. Five of these isolates were found to be antitubercular constituents, namely, methyl 7-methoxyanodendroate (5), 7-methoxywutaifuranal (8), wutaiensal (13), dictamnine (14), and gamma-fagarine (15), which exhibited antitubercular activity against Mycobacterium tuberculosis H37Rv, showing MIC values of 35, 35, 30, 30, and 30 microg/mL, respectively. | 9 | 1 | 9 | CHEMBL_2 | 2009-11-30 |
CHEMBL1149715 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. | 17723305 | 10.1016/j.bmc.2007.08.013 | nan | He X, Alian A, Ortiz de Montellano PR. | 2007 | 15 | 21 | 6649 | 6658 | PUBLICATION | InhA, the enoyl acyl carrier protein reductase (ENR) from Mycobacterium tuberculosis, is one of the key enzymes involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. We report here the discovery, through high-throughput screening, of a series of arylamides as a novel class of potent InhA inhibitors. These direct InhA inhibitors require no mycobacterial enzymatic activation and thus circumvent the resistance mechanism to antitubercular prodrugs such as INH and ETA that is most commonly observed in drug-resistant clinical isolates. The crystal structure of InhA complexed with one representative inhibitor reveals the binding mode of the inhibitor within the InhA active site. Further optimization through a microtiter synthesis strategy followed by in situ activity screening led to the discovery of a potent InhA inhibitor with in vitro IC(50)=90 nM, representing a 34-fold potency improvement over the lead compound. | 34 | 2 | 49 | CHEMBL_1 | 2009-09-03 |
CHEMBL1125291 | Journal of medicinal chemistry. | 1 | Scientific Literature | New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk. | 1732554 | 10.1021/jm00080a023 | nan | Sanchez JP, Bridges AJ, Bucsh R, Domagala JM, Gogliotti RD, Hagen SE, Heifetz CL, Joannides ET, Sesnie JC, Shapiro MA. | 1992 | 35 | 2 | 361 | 367 | PUBLICATION | A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones. | 23 | 11 | 530 | CHEMBL_1 | 2009-09-03 |
CHEMBL1914428 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Investigating the role of the hydroxyl groups of substrate erythrose 4-phosphate in the reaction catalysed by the first enzyme of the shikimate pathway. | 21978677 | 10.1016/j.bmcl.2011.09.017 | nan | Tran D, Pietersma AL, Schofield LR, Rost M, Jameson GB, Parker EJ. | 2011 | 21 | 22 | 6838 | 6841 | PUBLICATION | 3-Deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) synthase catalyses the first step of the shikimate pathway, which is responsible for the biosynthesis of aromatic amino acids in microorganisms and plants. This enzyme catalyses an aldol reaction between phosphoenolpyruvate and D-erythrose 4-phosphate to generate DAH7P. Both 2-deoxyerythrose 4-phosphate and 3-deoxyerythrose 4-phosphate were synthesised and tested as alternative substrates for the enzyme. Both compounds were found to be substrates for the DAH7P synthases from Escherichia coli, Pyrococcus furiosus and Mycobacterium tuberculosis, consistent with an acyclic mechanism for the enzyme for which neither C2 nor C3 hydroxyl groups are required for catalysis. The enzymes all showed greater tolerance for the loss of the C2 hydroxyl group than the C3 hydroxyl group. | 4 | 1 | 29 | CHEMBL_14 | 2012-06-27 |
CHEMBL3046679 | Journal of agricultural and food chemistry. | 1 | Scientific Literature | Design, synthesis, and biological activities of arylmethylamine substituted chlorotriazine and methylthiotriazine compounds. | 21970768 | 10.1021/jf203383s | nan | Zhao H, Liu Y, Cui Z, Beattie D, Gu Y, Wang Q. | 2011 | 59 | 21 | 11711 | 11717 | PUBLICATION | Heterocyclic rings were introduced into the core structure of s-triazine to design and synthesize a series of novel triazines containing arylmethylamino moieties. These compounds were characterized by using spectroscopic methods and elemental analysis. Their herbicidal, insecticidal, fungicidal, and antitumor activities were evaluated. Most of these compounds exhibited good herbicidal activity, especially against the dicotyledonous weeds, and compound F8 was almost at the same level as the control compound atrazine. Their structure-activity relationships were discussed. At the same time, some triazines had interesting fungicidal and insecticidal activities, of which F4 exhibited 100% efficacy against Puccinia triticina even at 20 ppm, and F5 showed Lepidopteran-specific activity in both leaf-piece and artificial diet assays. Moreover, these compounds showed antitumor activities against leukemia HL-60 cell line and lung adenocarcinoma A-549 cell line. | 13 | 24 | 270 | CHEMBL_19 | 2014-07-03 |
CHEMBL1142151 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Association of QnrB determinants and production of extended-spectrum beta-lactamases or plasmid-mediated AmpC beta-lactamases in clinical isolates of Klebsiella pneumoniae. | 17074790 | 10.1128/aac.00841-06 | nan | Pai H, Seo MR, Choi TY. | 2007 | 51 | 1 | 366 | 368 | PUBLICATION | Clinical isolates of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum beta-lactamases or plasmid-mediated AmpC beta-lactamases were screened for qnrA and qnrB genes. QnrB was present in 54 of 54 DHA-1-producing K. pneumoniae isolates and 10 of 45 SHV-12-producing ones, suggesting that the distribution of plasmids conferring resistance to extended-spectrum cephalosporins and quinolones in clinical isolates of K. pneumoniae is widespread. | 7 | 2 | 77 | CHEMBL_1 | 2009-09-03 |
CHEMBL2331356 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis. | 23294829 | 10.1016/j.bmc.2012.12.011 | nan | Gomez C, Ponien P, Serradji N, Lamouri A, Pantel A, Capton E, Jarlier V, Anquetin G, Aubry A. | 2013 | 21 | 4 | 948 | 956 | PUBLICATION | Novel 3'-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by (1)H, (13)C and (19)F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC(50)), or inducing 25% DNA cleavage by DNA gyrase (CC(25)). Compound 4 (with a methoxy in R(8) and a secondary carbamate in R(3)') and compound 5 (with a hydrogen in R(8) and an ethyl ester in R(3)') displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R(3)' substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future. | 14 | 3 | 84 | CHEMBL_17 | 2013-08-29 |
CHEMBL1145531 | European journal of medicinal chemistry. | 1 | Scientific Literature | Cyclopentanone ring-cleaved pleuromutilin derivatives. | 17156897 | 10.1016/j.ejmech.2006.07.018 | nan | Springer DM, Bunker A, Luh BY, Sorenson ME, Goodrich JT, Bronson JJ, DenBleyker K, Dougherty TJ, Fung-Tomc J. | 2007 | 42 | 1 | 109 | 113 | PUBLICATION | Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICs<or=4 microg/mL against marker strains of Streptococcus pneumoniae and Staphylococcus aureus. | 25 | 2 | 50 | CHEMBL_1 | 2009-09-03 |
CHEMBL2346657 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of novel 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents. | 23454016 | 10.1016/j.bmcl.2013.02.036 | nan | Saundane AR, Vijaykumar K, Vaijinath AV. | 2013 | 23 | 7 | 1978 | 1984 | PUBLICATION | As a part of systematic investigation of synthesis and biological activities of indole analogues linked to various heterocyclic systems, we have synthesized new compounds viz., 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitriles (2a-i), 4,5-diamino-6-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles (3a-i), 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones (4a-i), 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones (5a-i), 4-(5'-subtituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines (6a-i) and 5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones (7a-i). Antibacterial activity results revealed that, compound 6a showed promising activity versus Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 6d exhibited good activity against S. aureus, K. pneumoniae and Pseudomonas aeruginosa. Antifungal activity results indicated that, compound 4d exhibited maximum zone of inhibition against Aspergillus oryzae and Aspergillus flavus. In case of antioxidant activity, compound 4a showed promising radical scavenging activity, ferric ions (Fe(3+)) reducing antioxidant power (FRAP) and metal chelating activity. | 56 | 10 | 1386 | CHEMBL_17 | 2013-08-29 |
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