ChEMBL ID
stringlengths 13
13
| Journal
stringclasses 37
values | Source ID
stringclasses 12
values | Source Description
stringclasses 12
values | Title
stringlengths 3
383
| PubMed ID
stringlengths 3
8
| DOI
stringlengths 3
30
| Patent ID
stringclasses 9
values | Authors
stringlengths 3
1.01k
| Year
stringclasses 49
values | Volume
stringclasses 260
values | Issue
stringclasses 63
values | First Page
stringlengths 1
6
| Last Page
stringlengths 1
6
| Document Type
stringclasses 3
values | Abstract
stringlengths 3
3.44k
| Compounds
stringclasses 143
values | Targets
stringclasses 90
values | Activities
stringclasses 625
values | ChEMBL Release
stringclasses 34
values | ChEMBL Release Creation Date
stringclasses 34
values |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CHEMBL1629535 | Journal of medicinal chemistry. | 1 | Scientific Literature | Novel small molecule inhibitors of MDR Mycobacterium tuberculosis by NMR fragment screening of antigen 85C. | 21073150 | 10.1021/jm100993z | nan | Scheich C, Puetter V, Schade M. | 2010 | 53 | 23 | 8362 | 8367 | PUBLICATION | Protein target-based discovery of novel antibiotics has been largely unsuccessful despite rich genome information. Particularly in need are new antibiotics for tuberculosis, which kills 1.6 million people annually and shows a rapid increase in multiple-drug-resistant cases. By combining fragment-based drug discovery with early whole cell antibacterial screening, we discovered novel ligand-efficient inhibitors of multiple-drug resistant Mycobacterium tuberculosis (Mtb), which bind to the substrate site of the Mtb protein antigen 85C, hitherto unused in Mtb chemotherapy. | 22 | 4 | 50 | CHEMBL_11 | 2011-08-01 |
CHEMBL1275405 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Population pharmacokinetics of levofloxacin, gatifloxacin, and moxifloxacin in adults with pulmonary tuberculosis. | 18070980 | 10.1128/aac.01036-07 | nan | Peloquin CA, Hadad DJ, Molino LP, Palaci M, Boom WH, Dietze R, Johnson JL. | 2008 | 52 | 3 | 852 | 857 | PUBLICATION | The objective of this study was to determine the population pharmacokinetic parameters of levofloxacin, gatifloxacin, and moxifloxacin following multiple oral doses. Twenty-nine patients with tuberculosis at the University Hospital in Vitória, Brazil, participated. Subjects received multiple doses of one drug (levofloxacin, 1,000 mg daily, or gatifloxacin or moxifloxacin, 400 mg daily) as part of a 7-day study of early bactericidal activity. Serum samples were collected over 24 h after the fifth dose and assayed using validated high-performance liquid chromatography assays. Concentration-time data were analyzed using noncompartmental, compartmental, and population methods. The three drugs were well tolerated. Levofloxacin produced the highest maximum plasma concentrations (median, 15.55 microg/ml; gatifloxacin, 4.75 microg/ml; moxifloxacin, 6.13 microg/ml), largest volume of distribution (median, 81 liters; gatifloxacin, 79 liters; moxifloxacin, 63 liters), and longest elimination half-life (median, 7.4 h; gatifloxacin, 5.0 h; moxifloxacin, 6.5 h). A one-compartment model, with or without weight as a covariate, adequately described the data. Postmodeling simulations using median population parameter estimates closely approximated the median values from the original data. Area under the concentration-time curve/MIC ratios for free drug were high. All three quinolones showed favorable pharmacokinetic and pharmacodynamic indices, with the most favorable results in this population being seen with levofloxacin at the comparative doses used. | 3 | 3 | 16 | CHEMBL_10 | 2011-05-26 |
CHEMBL1275407 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. | 18212110 | 10.1128/aac.01388-07 | nan | Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, Rovira M, Nguyen Q, Slavin M, Chen SC, Global Scedosporium Study Group. | 2008 | 52 | 5 | 1743 | 1750 | PUBLICATION | The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with > 98% of those responding receiving > or = 28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with Scedosporium prolificans infection had significantly reduced survival times (P = 0.0259) and were more likely to die from fungal infection (P = 0.002) than were Scedosporium apiospermum-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for S. apiospermum-infected patients (54% response; MIC(50), 0.25 microg/ml) than for S. prolificans-infected patients (40% response; MIC(50), 4.0 microg/ml). Voriconazole demonstrated clinically useful activity in the treatment of both S. apiospermum and S. prolificans infections and was well tolerated. | 3 | 2 | 18 | CHEMBL_10 | 2011-05-26 |
CHEMBL1240400 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates. | 20065058 | 10.1128/aac.01197-09 | nan | Lauderdale TL, Shiau YR, Lai JF, Chen HC, King CH. | 2010 | 54 | 3 | 1338 | 1342 | PUBLICATION | The in vitro antibacterial activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, against 770 clinical isolates were investigated. Nemonoxacin (tested as its malate salt, TG-875649) showed better in vitro activity than ciprofloxacin and levofloxacin against different species of staphylococci, streptococci, and enterococci, Neisseria gonorrhoeae, and Haemophilus influenzae. The in vitro activity of TG-875649 was also comparable to or better than that of moxifloxacin against these pathogens, which included ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus and levofloxacin-resistant Streptococcus pneumoniae. | 13 | 18 | 618 | CHEMBL_10 | 2011-05-26 |
CHEMBL1153639 | European journal of medicinal chemistry. | 1 | Scientific Literature | A facile synthesis and antimycobacterial evaluation of novel spiro-pyrido-pyrrolizines and pyrrolidines. | 19524332 | 10.1016/j.ejmech.2009.05.010 | nan | Ranjith Kumar R, Perumal S, Senthilkumar P, Yogeeswari P, Sriram D. | 2009 | 44 | 9 | 3821 | 3829 | PUBLICATION | An efficient synthesis of 1-methyl-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones was achieved by the reaction of 1-methyl-4-piperidone and aromatic aldehydes in the presence of pyrrolidine under solvent-free microwave irradiation. These dipolarophiles upon cycloaddition with nitrile oxide and azomethine ylides afford stereoselectively novel spiro-isoxazolines, pyrrolizines and pyrrolidines respectively in excellent yields. The spiro compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) using agar dilution method. Among the synthesized compounds, 1-methyl-4-(2,4-dichlorophenyl)pyrrolo(spiro[2.3'']oxindole)spiro[3.3']-1'-methylpiperidin-4'-one was found to be the most active with a minimum inhibitory concentration (MIC) of 1.76 and 0.88 microM against MTB and MDR-TB respectively. | 18 | 2 | 54 | CHEMBL_3 | 2010-04-16 |
CHEMBL1275578 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Genotypic versus phenotypic characterization, with respect to beta-lactam susceptibility, of Haemophilus influenzae isolates exhibiting decreased susceptibility to beta-lactam resistance markers. | 18955529 | 10.1128/aac.00402-08 | nan | Sevillano D, Giménez MJ, Cercenado E, Cafini F, Gené A, Alou L, Marco F, Martínez-Martínez L, Coronel P, Aguilar L. | 2009 | 53 | 1 | 267 | 270 | PUBLICATION | Among 165 Spanish Haemophilus influenzae isolates with mutations in the ftsI gene (ftsI(+)) (2005 to 2007), 73% were beta-lactamase negative and 26.7% were positive. The proportion of beta-lactamase-negative isolates to beta-lactamase-positive isolates was 2:1 to 4:1 in general, versus 1:3 in pediatric hospitals. Among 44 beta-lactamase-positive strains, 8 strains produced ROB-1 (5 from the pediatric hospital). beta-Lactamase-positive ftsI(+) strains were phylogenetically closer than were beta-lactamase-negative strains. | 7 | 1 | 80 | CHEMBL_10 | 2011-05-26 |
CHEMBL1177707 | Journal of medicinal chemistry. | 1 | Scientific Literature | Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis. | 20491506 | 10.1021/jm100424m | nan | Chen L, Wilson DJ, Xu Y, Aldrich CC, Felczak K, Sham YY, Pankiewicz KW. | 2010 | 53 | 12 | 4768 | 4778 | PUBLICATION | The modular nature of nicotinamide adenine dinucleotide (NAD)-mimicking inosine monophsophate dehydrogenase (IMPDH) inhibitors has prompted us to investigate novel mycophenolic adenine dinucleotides (MAD) in which 1,2,3-triazole linkers were incorporated as isosteric replacements of the pyrophosphate linker. Synthesis and evaluation of these inhibitors led to identification of low nanomolar inhibitors of human IMPDH and more importantly the first potent inhibitor of IMPDH from Mycobacterium tuberculosis (mtIMPDH). Computational studies of these IMPDH enzymes helped rationalize the observed structure-activity relationships. Additionally, the first cloning, expression, purification and characterization of mtIMPDH is reported. | 13 | 3 | 24 | CHEMBL_8 | 2010-10-26 |
CHEMBL1649568 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Efficacy of aerosol MP-376, a levofloxacin inhalation solution, in models of mouse lung infection due to Pseudomonas aeruginosa. | 19528273 | 10.1128/aac.00268-09 | nan | Sabet M, Miller CE, Nolan TG, Senekeo-Effenberger K, Dudley MN, Griffith DC. | 2009 | 53 | 9 | 3923 | 3928 | PUBLICATION | Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa. | 3 | 2 | 22 | CHEMBL_11 | 2011-08-01 |
CHEMBL1649569 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | oqxAB encoding a multidrug efflux pump in human clinical isolates of Enterobacteriaceae. | 19528276 | 10.1128/aac.01574-08 | nan | Kim HB, Wang M, Park CH, Kim EC, Jacoby GA, Hooper DC. | 2009 | 53 | 8 | 3582 | 3584 | PUBLICATION | The genes for multidrug efflux pump OqxAB, which is active on fluoroquinolones, were found in human clinical isolates on a plasmid in Escherichia coli and on the chromosome of Klebsiella pneumoniae. IS26-like sequences flanked the plasmid-mediated oqxAB genes, suggesting that they had been mobilized as part of a composite transposon. | 2 | 3 | 50 | CHEMBL_11 | 2011-08-01 |
CHEMBL1649182 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Binding of faropenem and other beta-lactam agents to penicillin-binding proteins of pneumococci with various beta-lactam susceptibilities. | 19237649 | 10.1128/aac.01566-08 | nan | Kosowska-Shick K, McGhee P, Appelbaum PC. | 2009 | 53 | 5 | 2176 | 2180 | PUBLICATION | Faropenem demonstrated low MICs (< or = 1 microg/ml) for all penicillin-susceptible and nonsusceptible pneumococci and exhibited very strong abilities to bind to Streptococcus pneumoniae penicillin-binding proteins (PBPs), except for PBP2X. The lower faropenem affinity for PBP2X did not affect MICs for any strains tested, and only imipenem had lower MICs, with much lower binding affinities for all PBPs tested, than faropenem. | 5 | 5 | 331 | CHEMBL_11 | 2011-08-01 |
CHEMBL1154164 | Journal of medicinal chemistry. | 1 | Scientific Literature | Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors. | 19775099 | 10.1021/jm900335a | nan | Nuti E, Panelli L, Casalini F, Avramova SI, Orlandini E, Santamaria S, Nencetti S, Tuccinardi T, Martinelli A, Cercignani G, D'Amelio N, Maiocchi A, Uggeri F, Rossello A. | 2009 | 52 | 20 | 6347 | 6361 | PUBLICATION | Overexpression of macrophage elastase (MMP-12), a member of the matrix metalloproteinases family, can be linked to tissue remodeling and degradation in some inflammatory processes, such as chronic obstructive pulmonary disease (COPD), emphysema, rheumatoid arthritis (RA), and atherosclerosis. On this basis, MMP-12 can be considered an attractive target for studying selective inhibitors that are useful in the development of new therapies for COPD and other inflammatory diseases. We report herein the design, synthesis, and in vitro evaluation of a new series of compounds, possessing an arylsulfonyl scaffold, for their potential as selective inhibitors of MMP-12. The best compound in the series showed an IC50 value of 0.2 nM, with good selectivity over MMP-1 and MMP-14. A docking study was carried out on this compound in order to investigate its binding interactions with MMP-12, and NMR studies on the complex with the MMP-12 catalytic domain were able to validate the proposed binding mode. | 20 | 10 | 186 | CHEMBL_4 | 2010-05-18 |
CHEMBL1649439 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Prevalence of aac(6')-Ib-cr encoding a ciprofloxacin-modifying enzyme among Enterobacteriaceae blood isolates in Korea. | 19289526 | 10.1128/aac.01534-08 | nan | Kim ES, Jeong JY, Jun JB, Choi SH, Lee SO, Kim MN, Woo JH, Kim YS. | 2009 | 53 | 6 | 2643 | 2645 | PUBLICATION | The aac(6')-Ib gene was detected in 86 of 555 (15.5%) Enterobacteriaceae isolates. Among these 86 aac(6')-Ib-positive isolates, 19 (22.0%) were positive for aac(6')-Ib-cr: 4 of 31 (12.9%) Enterobacter spp., 7 of 13 (53.8%) Escherichia coli isolates, and 8 of 42 (19.0%) Klebsiella pneumoniae isolates. There was a strong association between aac(6')-Ib-cr and OXA-1 and CTX-M-1 group beta-lactamase genes. One aac(6')-Ib-positive K. pneumoniae isolate carried both aac(6')-Ib-cr and qnrS. | 8 | 4 | 152 | CHEMBL_11 | 2011-08-01 |
CHEMBL1152147 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Design at the atomic level: design of biaryloxazolidinones as potent orally active antibiotics. | 18947996 | 10.1016/j.bmcl.2008.10.011 | nan | Zhou J, Bhattacharjee A, Chen S, Chen Y, Duffy E, Farmer J, Goldberg J, Hanselmann R, Ippolito JA, Lou R, Orbin A, Oyelere A, Salvino J, Springer D, Tran J, Wang D, Wu Y, Johnson G. | 2008 | 18 | 23 | 6175 | 6178 | PUBLICATION | We have developed a first generation of hybrid sparsomycin-linezolid compounds into a new family of orally bioavailable biaryloxazolidinones that have activity against both linezolid-susceptible and -resistant gram-positive bacteria as well as the fastidious gram-negative bacteria Haemophilus influenzae and Moraxella catarrahalis. The convergent synthesis of these new compounds is detailed. | 11 | 6 | 117 | CHEMBL_2 | 2009-11-30 |
CHEMBL1146539 | Journal of natural products. | 1 | Scientific Literature | Homopseudopteroxazole, a new antimycobacterial diterpene alkaloid from Pseudopterogorgia elisabethae. | 12828474 | 10.1021/np030052c | nan | Rodríguez II, Rodríguez AD. | 2003 | 66 | 6 | 855 | 857 | PUBLICATION | In the course of our study to find novel antimycobacterial secondary metabolites from Caribbean gorgonian octocorals, we have isolated a new diterpene alkaloid, namely, homopseudopteroxazole (1), as a minor constituent of the hexane extract from the sea plume Pseudopterogorgia elisabethae. Its structure was deduced by interpretation of combined spectroscopic data, including extensive 1D and 2D NMR measurements, and NMR spectral comparisons with known amphilectane models. Biological screening studies indicate that homopseudopteroxazole (1) is a strong growth inhibitor of Mycobacterium tuberculosis H(37)Rv. | 3 | 1 | 6 | CHEMBL_2 | 2009-11-30 |
CHEMBL1165897 | European journal of medicinal chemistry. | 1 | Scientific Literature | Design, synthesis, characterization, and antibacterial activity of {5-chloro-2-[(3-substitutedphenyl-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanones. | 20231043 | 10.1016/j.ejmech.2010.02.021 | nan | Rai NP, Narayanaswamy VK, Govender T, Manuprasad BK, Shashikanth S, Arunachalam PN. | 2010 | 45 | 6 | 2677 | 2682 | PUBLICATION | In the present investigation, a series of novel {5-chloro-2-[(3-(substitutedphenyl)-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanones (3a-i) have been synthesized from 5-(chloromethyl)-3-substitutedphenyl-1,2,4-oxadiazole (2a-i). The newly synthesized compounds were characterized by IR, NMR (1H and 13C), mass spectral and elemental analysis. The title compounds were investigated for in-vitro qualitative (zone of inhibition) and quantitative (MIC) antibacterial activity by agar cup plate and microtitration methods, respectively. The minimum inhibitory concentration and structure activity relationships (SARs) were evaluated. Amongst the synthesized compounds in this series, {5-chloro-2-[(3-(2,5-difluoro-4-methyl-phenyl)-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanone (3d) was found to exhibit significant activity with MICs of 21.5, 22.4, 29.8 and 30.6 microg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, respectively. | 10 | 4 | 80 | CHEMBL_7 | 2010-09-29 |
CHEMBL1136024 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | CCR3 antagonists: a potential new therapy for the treatment of asthma. Discovery and structure-activity relationships. | 12067561 | 10.1016/s0960-894x(02)00206-8 | nan | Wacker DA, Santella JB, Gardner DS, Varnes JG, Estrella M, DeLucca GV, Ko SS, Tanabe K, Watson PS, Welch PK, Covington M, Stowell NC, Wadman EA, Davies P, Solomon KA, Newton RC, Trainor GL, Friedman SM, Decicco CP, Duncia JV. | 2002 | 12 | 13 | 1785 | 1789 | PUBLICATION | CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3. | 93 | 1 | 109 | CHEMBL_1 | 2009-09-03 |
CHEMBL1649221 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Novel genetic environment of the carbapenem-hydrolyzing beta-lactamase KPC-2 among Enterobacteriaceae in China. | 19620332 | 10.1128/aac.00260-09 | nan | Shen P, Wei Z, Jiang Y, Du X, Ji S, Yu Y, Li L. | 2009 | 53 | 10 | 4333 | 4338 | PUBLICATION | Thirty-nine bla(KPC)-producing isolates of the family Enterobacteriaceae with carbapenem resistance or reduced carbapenem susceptibility were obtained from inpatients from eight hospitals in six cities of three provinces in eastern China. The pulsed-field gel electrophoresis analysis of all 36 Klebsiella pneumoniae isolates revealed six major patterns. The resistant plasmids of most isolates were successfully transferred by conjugation and evaluated experimentally to be 40 to 180 kb in size. A 20.2-kb bla(KPC)-surrounding nucleotide sequence from plasmid pKP048 has been obtained and contains an integration structure of a Tn3-based transposon and partial Tn4401 segment, with the gene order Tn3-transposase, Tn3-resolvase, ISKpn8, the bla(KPC-2) gene, and the ISKpn6-like element. The chimera of several transposon-associated elements indicated a novel genetic environment of the K. pneumoniae carbapenemase beta-lactamase gene in isolates from China. | 10 | 3 | 80 | CHEMBL_11 | 2011-08-01 |
CHEMBL1212742 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Allelic exchange and mutant selection demonstrate that common clinical embCAB gene mutations only modestly increase resistance to ethambutol in Mycobacterium tuberculosis. | 19822701 | 10.1128/aac.01288-09 | nan | Safi H, Fleischmann RD, Peterson SN, Jones MB, Jarrahi B, Alland D. | 2010 | 54 | 1 | 103 | 108 | PUBLICATION | Mutations within codon 306 of the Mycobacterium tuberculosis embB gene modestly increase ethambutol (EMB) MICs. To identify other causes of EMB resistance and to identify causes of high-level resistance, we generated EMB-resistant M. tuberculosis isolates in vitro and performed allelic exchange studies of embB codon 406 (embB406) and embB497 mutations. In vitro selection produced mutations already identified clinically in embB306, embB397, embB497, embB1024, and embC13, which result in EMB MICs of 8 or 14 microg/ml, 5 microg/ml, 12 microg/ml, 3 microg/ml, and 4 microg/ml, respectively, and mutations at embB320, embB324, and embB445, which have not been identified in clinical M. tuberculosis isolates and which result in EMB MICs of 8 microg/ml, 8 microg/ml, and 2 to 8 microg/ml, respectively. To definitively identify the effect of the common clinical embB497 and embB406 mutations on EMB susceptibility, we created a series of isogenic mutants, exchanging the wild-type embB497 CAG codon in EMB-susceptible M. tuberculosis strain 210 for the embB497 CGG codon and the wild-type embB406 GGC codon for either the embB406 GCC, embB406 TGC, embB406 TCC, or embB406 GAC codon. These new mutants showed 6-fold and 3- to 3.5-fold increases in the EMB MICs, respectively. In contrast to the embB306 mutants, the isogenic embB497 and embB406 mutants did not have preferential growth in the presence of isoniazid or rifampin (rifampicin) at their MICs. These results demonstrate that individual embCAB mutations confer low to moderate increases in EMB MICs. Discrepancies between the EMB MICs of laboratory mutants and clinical M. tuberculosis strains with identical mutations suggest that clinical EMB resistance is multigenic and that high-level EMB resistance requires mutations in currently unknown loci. | 3 | 1 | 57 | CHEMBL_9 | 2011-01-20 |
CHEMBL1154639 | European journal of medicinal chemistry. | 1 | Scientific Literature | Application of Huisgen (3+2) cycloaddition reaction: synthesis of 1-(2,3-dihydrobenzofuran-2-yl-methyl [1,2,3]-triazoles and their antitubercular evaluations. | 19846238 | 10.1016/j.ejmech.2009.09.036 | nan | Tripathi RP, Yadav AK, Ajay A, Bisht SS, Chaturvedi V, Sinha SK. | 2010 | 45 | 1 | 142 | 148 | PUBLICATION | 1,4-Disubstituted-1,2,3-triazoles (3-27) have been synthesized by [3+2] cycloaddition of different 2-(azidomethyl)-dihydronaptho(benzo)furans (2a, 2b, 2c and 2d) with different alkynes. All the compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv. Compounds 2a, 7, 9, 12 and 14 exhibited antitubercular activities with MIC ranging from 12.5 to 3.12 microg/ml. | 31 | 1 | 31 | CHEMBL_4 | 2010-05-18 |
CHEMBL1135180 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and anti-influenza virus activity of 4-guanidino-7-substituted Neu5Ac2en derivatives. | 12113809 | 10.1016/s0960-894x(02)00328-1 | nan | Honda T, Masuda T, Yoshida S, Arai M, Kobayashi Y, Yamashita M. | 2002 | 12 | 15 | 1921 | 1924 | PUBLICATION | Substitution of 7-OH by small hydrophobic groups on zanamivir resulted in the retaining of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. These compounds were prepared by treatment of the corresponding 7-substituted sialic acids derived from 4-modified N-acetyl-D-mannosamine (ManNAc) using enzyme-catalyzed aldol condensation. | 12 | 2 | 47 | CHEMBL_1 | 2009-09-03 |
CHEMBL1123391 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and investigation of the beta-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol. | 2869145 | 10.1021/jm00152a003 | nan | Clark MT, Chang J, Navran SS, Huzoor-Akbar, Mukhopadhyay A, Amin H, Feller DR, Miller DD. | 1986 | 29 | 2 | 181 | 185 | PUBLICATION | The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity. | 4 | 1 | 12 | CHEMBL_1 | 2009-09-03 |
CHEMBL1144350 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and evaluation of imidazolylmethylenetetrahydronaphthalenes and imidazolylmethyleneindanes: potent inhibitors of aldosterone synthase. | 15771425 | 10.1021/jm049600p | nan | Ulmschneider S, Müller-Vieira U, Mitrenga M, Hartmann RW, Oberwinkler-Marchais S, Klein CD, Bureik M, Bernhardt R, Antes I, Lengauer T. | 2005 | 48 | 6 | 1796 | 1805 | PUBLICATION | Elevated plasma aldosterone levels play a detrimental role in certain forms of congestive heart failure and myocardial fibrosis. We proposed aldosterone synthase (CYP11B2) as a novel target for the treatment of these diseases. In this study, the synthesis and biological evaluation of substituted E- and Z-imidazolylmethylenetetrahydronaphthalenes and E- and Z-imidazolylmethyleneindanes (compounds 1a,b-9a,b) is described. The compounds were prepared by a Wittig-like reaction. They were tested for activity using bovine CYP11B and human CYP11B2 expressed in fission yeast and V79 MZh cells. Selectivity was determined toward human CYP11B1, CYP19, and CYP17. Especially in the case of CYP11B1 (steroid 11beta-hydroxylase), selectivity is a crucial issue, since sequence homology between this enzyme and the target enzyme is very high (93%). On the basis of the X-ray structure of human CYP2C9, a protein model of CYP11B2 was developed and docking experiments with the title compounds were performed. The biological results revealed highly potent inhibitors of CYP11B2 (IC(50) = 4-93 nM). The Z-isomers usually were more active than the corresponding E-isomers. Different inhibitory profiles could be observed: rather selective inhibitors of CYP11B1, dual inhibitors of both enzymes, and rather selective inhibitors of CYP11B2. The chloro derivative 8b was found to be a highly potent CYP11B2 inhibitor (IC(50) = 4 nM) showing a 5-fold selectivity for CYP11B1 (IC(50) = 20 nM). This compound could be an interesting lead for further optimization as a therapeutic agent. It also could be used as well as the CYP11B1 selective compounds as a pharmacological tool. | 18 | 5 | 108 | CHEMBL_1 | 2009-09-03 |
CHEMBL1129589 | Journal of medicinal chemistry. | 1 | Scientific Literature | Anti-inflammatory 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma. | 8960547 | 10.1021/jm9604639 | nan | Ashton MJ, Lawrence C, Karlsson JA, Stuttle KA, Newton CG, Vacher BY, Webber S, Withnall MJ. | 1996 | 39 | 25 | 4888 | 4896 | PUBLICATION | The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma. | 19 | 3 | 95 | CHEMBL_1 | 2009-09-03 |
CHEMBL1154454 | European journal of medicinal chemistry. | 1 | Scientific Literature | Tetrahydronaphthyl azole oxime ethers: the conformationally rigid analogues of oxiconazole as antibacterials. | 18313805 | 10.1016/j.ejmech.2008.01.006 | nan | Bhandari K, Srinivas N, Shiva Keshava GB, Shukla PK. | 2009 | 44 | 1 | 437 | 447 | PUBLICATION | A series of novel (Z)- and (E)-2-imidazolo-/triazolo-methyl tetrahydronaphthyl oxime ethers (7-28) were synthesized as conformationally constrained analogues of oxiconazole and evaluated for antifungal and antibacterial activities. Many of these derivatives exhibited potent antibacterial activity and surprisingly none of them was active against fungal strains. The SAR studies showed that imidazole oxime ethers were more active than the corresponding triazole oxime ethers. Imidazole derivatives 8, 11, 12, 15, 18, 19, 21 and 23 exhibited high inhibitory activity with 1.56-0.39 microg/mL MIC values against Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus. These compounds represent new structure scaffolds that can be further optimized to give new antibacterial agents with structures significantly different from those of existing classes of antibiotics. | 25 | 10 | 250 | CHEMBL_2 | 2009-11-30 |
CHEMBL1154648 | European journal of medicinal chemistry. | 1 | Scientific Literature | 1,3-Dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: synthesis and antimycobacterial evaluation of enantiomerically pure spiroisoxazolidines. | 19853329 | 10.1016/j.ejmech.2009.09.034 | nan | Kumar RS, Perumal S, Shetty KA, Yogeeswari P, Sriram D. | 2010 | 45 | 1 | 124 | 133 | PUBLICATION | A series of novel enantiomerically pure spiroisoxazolidines were synthesized regioselectively by the 1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones. These compounds have been screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among the twenty two compounds screened, (3S,4S,5R)-3,4-di(4-methylphenyl)-2-phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3e) was found to possess the maximum activity with MIC of 3.02 microM, being 2.5 times more potent than the first-line anti-TB drug ethambutol. For comparison, a series of ten enantiomerically pure spirooxazolines were also screened, among which (4R,5S)-3,4-bis(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one and (4R,5S)-4-(2-chlorophenyl)-3-(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one were found to display maximum activity with MIC of 3.25 microM. | 36 | 1 | 37 | CHEMBL_4 | 2010-05-18 |
CHEMBL1136112 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Novel inhibitors of procollagen C-proteinase. Part 2: glutamic acid hydroxamates. | 12824039 | 10.1016/s0960-894x(03)00402-5 | nan | Robinson LA, Wilson DM, Delaet NG, Bradley EK, Dankwardt SM, Campbell JA, Martin RL, Van Wart HE, Walker KA, Sullivan RW. | 2003 | 13 | 14 | 2381 | 2384 | PUBLICATION | Glutamic acid derived hydroxamates were identified as potent and selective inhibitors of procollagen C-proteinase, an essential enzyme for the processing of procollagens to fibrillar collagens. Such compounds have potential therapeutic application in the treatment of fibrosis. | 44 | 3 | 56 | CHEMBL_1 | 2009-09-03 |
CHEMBL1629558 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Effect of electrical current on the activities of antimicrobial agents against Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis biofilms. | 18725436 | 10.1128/aac.00237-08 | nan | del Pozo JL, Rouse MS, Mandrekar JN, Sampedro MF, Steckelberg JM, Patel R. | 2009 | 53 | 1 | 35 | 40 | PUBLICATION | Bacterial biofilms are resistant to conventional antimicrobial agents. Prior in vitro studies have shown that electrical current (EC) enhances the activities of aminoglycosides, quinolones, and oxytetracycline against Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus epidermidis, Escherichia coli, and Streptococcus gordonii. This phenomenon, known as the bioelectric effect, has been only partially defined. The purpose of this work was to study the in vitro bioelectric effect on the activities of 11 antimicrobial agents representing a variety of different classes against P. aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and S. epidermidis. An eight-channel current generator/controller and eight chambers delivering a continuous flow of fresh medium with or without antimicrobial agents and/or EC to biofilm-coated coupons were used. No significant decreases in the numbers of log(10) CFU/cm(2) were seen after exposure to antimicrobial agents alone, with the exception of a 4.57-log-unit reduction for S. epidermidis and trimethoprim-sulfamethoxazole. We detected a statistically significant bioelectric effect when vancomycin plus 2,000 microamperes EC were used against MRSA biofilms (P = 0.04) and when daptomycin and erythromycin were used in combination with 200 or 2,000 microamperes EC against S. epidermidis biofilms (P = 0.02 and 0.0004, respectively). The results of these experiments indicate that the enhancement of the activity of antimicrobial agents against biofilm organisms by EC is not a generalizable phenomenon across microorganisms and antimicrobial agents. | 10 | 3 | 57 | CHEMBL_11 | 2011-08-01 |
CHEMBL1629597 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro evaluation of the antimicrobial activity of ceftaroline against cephalosporin-resistant isolates of Streptococcus pneumoniae. | 19015339 | 10.1128/aac.01324-08 | nan | McGee L, Biek D, Ge Y, Klugman M, du Plessis M, Smith AM, Beall B, Whitney CG, Klugman KP. | 2009 | 53 | 2 | 552 | 556 | PUBLICATION | Increasing pneumococcal resistance to extended-spectrum cephalosporins warrants the search for novel agents with activity against such resistant strains. Ceftaroline, a parenteral cephalosporin currently in phase 3 clinical development, has demonstrated potent in vitro activity against resistant gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae. In this study, the activity of ceftaroline was evaluated against highly cefotaxime-resistant isolates of pneumococci from the Active Bacterial Core surveillance program of the Centers for Disease Control and Prevention and against laboratory-derived cephalosporin-resistant mutants of S. pneumoniae. The MICs of ceftaroline and comparators were determined by broth microdilution. In total, 120 U.S. isolates of cefotaxime-resistant (MIC > or = 4 microg/ml) S. pneumoniae were tested along with 18 laboratory-derived R6 strains with known penicillin-binding protein (PBP) mutations. Clinical isolates were characterized by multilocus sequence typing, and the DNAs of selected isolates were sequenced to identify mutations affecting pbp genes. Ceftaroline (MIC(90) = 0.5 microg/ml) had greater in vitro activity than penicillin, cefotaxime, or ceftriaxone (MIC(90) = 8 microg/ml for all comparators) against the set of highly cephalosporin-resistant clinical isolates of S. pneumoniae. Ceftaroline was also more active against the defined R6 PBP mutant strains, which suggests that ceftaroline can overcome common mechanisms of PBP-mediated cephalosporin resistance. These data indicate that ceftaroline has significant potency against S. pneumoniae strains resistant to existing parenteral cephalosporins and support its continued development for the treatment of infections caused by resistant S. pneumoniae strains. | 6 | 1 | 118 | CHEMBL_11 | 2011-08-01 |
CHEMBL1795235 | Journal of medicinal chemistry. | 1 | Scientific Literature | Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents. | 21534606 | 10.1021/jm200010x | nan | Hossion AM, Zamami Y, Kandahary RK, Tsuchiya T, Ogawa W, Iwado A, Sasaki K. | 2011 | 54 | 11 | 3686 | 3703 | PUBLICATION | A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6''-acylgalactoside, and quercetin 2'',6''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 μg/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure-activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent. | 32 | 8 | 443 | CHEMBL_13 | 2012-02-21 |
CHEMBL1817667 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antimicrobial properties of some new thiazolyl coumarin derivatives. | 21712145 | 10.1016/j.ejmech.2011.05.044 | nan | Arshad A, Osman H, Bagley MC, Lam CK, Mohamad S, Zahariluddin AS. | 2011 | 46 | 9 | 3788 | 3794 | PUBLICATION | Two novel series of hydrazinyl thiazolyl coumarin derivatives have been synthesized and fully characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectral data. The structures of some compounds were further confirmed by X-ray crystallography. All of these derivatives, 10a-d and 15a-h, were screened in vitro for antimicrobial activity against various bacteria species including Mycobacterium tuberculosis and Candida albicans. The compounds 10c, 10d and 15e exhibited very good activities against all of the tested microbial strains. | 16 | 5 | 66 | CHEMBL_13 | 2012-02-21 |
CHEMBL1131006 | Journal of medicinal chemistry. | 1 | Scientific Literature | Antimycobacterial activity of substituted isosteres of pyridine- and pyrazinecarboxylic acids. | 9632376 | 10.1021/jm9708745 | nan | Wächter GA, Davis MC, Martin AR, Franzblau SG. | 1998 | 41 | 13 | 2436 | 2438 | PUBLICATION | Pyrazines and pyridines substituted with alkylated tetrazoles, esterified vinylogous carboxylic acids, and ketosulfides were synthesized as precursors of antimycobacterial agents which, after penetration of the mycobacterial cell wall, could be biotransformed by esterases or peroxidase-catalases. The expected products are tetrazoles, a vinylogous carboxylic acid, and CH-acidic ketosulfoxides, isosteres of pyrazinoic and nicotinic acids, which should inhibit mycobacterial growth when released inside the bacterial cell. The growth inhibitory activity of the synthesized compounds against the H37Rv strain of Mycobacterium tuberculosis was determined to assess the viability of this concept. It was shown that all of the compounds designed as lipophilic precursors were more active than the unmodified polar isosteres of pyrazinoic and nicotinic acids. | 21 | 1 | 21 | CHEMBL_1 | 2009-09-03 |
CHEMBL1130782 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Syntheses and evaluation of benzodiazaborine compounds against M. tuberculosis H37Rv in vitro. | 9871552 | 10.1016/s0960-894x(98)00126-7 | nan | Davis MC, Franzblau SG, Martin AR. | 1998 | 8 | 7 | 843 | 846 | PUBLICATION | The synthesis of six benzo[e]diazaborine compounds and thier in vitro evaluation against M. tuberculosis H37Rv is described. The compounds 1,2-dihydro-1-hydroxy-2-phenyl-2,4,1-benzo[e]diazaborin-3(4H)-one, 4, and 1,2-dihydro-1-hydroxy-2-(3-pyridyl)-2,4,1-benzo[e]diazaborin-3(4H) - thione, (5), showed the greatest inhibitory activity. | 8 | 2 | 17 | CHEMBL_1 | 2009-09-03 |
CHEMBL1145067 | Journal of medicinal chemistry. | 1 | Scientific Literature | 3'-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. | 12930144 | 10.1021/jm021108n | nan | Vanheusden V, Munier-Lehmann H, Froeyen M, Dugué L, Heyerick A, De Keukeleire D, Pochet S, Busson R, Herdewijn P, Van Calenbergh S. | 2003 | 46 | 18 | 3811 | 3821 | PUBLICATION | Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for blocking the bacterial DNA synthesis. In an attempt to find high-affinity inhibitors of TMPKmt, a cavity in the enzyme at the 3'-position was explored via the introduction of various substituents at the 3'-position of the thymidine monophosphate (dTMP) scaffold. Various 3'-C-branched chain substituted nucleotides in the 2'-deoxyribo (3-6) and ribo series (7, 8) were synthesized from one key intermediate (23). 2'-Deoxy analogues proved to be potent inhibitors of TMPKmt: 3'-CH(2)NH(2) (4), 3'-CH(2)N(3) (3), and 3'-CH(2)F (5) nucleotides exhibit the highest affinities within this series, with K(i) values of 10.5, 12, and 15 microM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the 3'-position. Ribo analogues experience a significant affinity decrease, which is probably due to steric hindrance of Tyr103 in close vicinity of the 2'-position. Although the 5'-O-phosphorylated compounds have somewhat higher affinities for the enzyme, the parent nucleosides generally exhibit affinities for TMPKmt in the same order of magnitude and display a superior selectivity profile versus human TMPK. This series of inhibitors holds promise for the development of a new class of antituberculosis agents. | 19 | 3 | 55 | CHEMBL_1 | 2009-09-03 |
CHEMBL1153421 | Journal of medicinal chemistry. | 1 | Scientific Literature | Molecular cloning, characterization, and inhibition studies of the Rv1284 beta-carbonic anhydrase from Mycobacterium tuberculosis with sulfonamides and a sulfamate. | 19317447 | 10.1021/jm9000488 | nan | Minakuchi T, Nishimori I, Vullo D, Scozzafava A, Supuran CT. | 2009 | 52 | 8 | 2226 | 2232 | PUBLICATION | The beta-carbonic anhydrase (CA, EC 4.2.1.1) encoded by the gene Rv1284 (mtCA 1) of Mycobacterium tuberculosis shows appreciable catalytic activity for CO(2) hydration, with a k(cat) of 3.9 x 10(5) s(-1) and a k(cat)/K(m) of 3.7 x 10(7) M(-1) s(-1). A panel of 36 sulfonamides and one sulfamate, some of which are used clinically, were assayed for their effect on mtCA 1 catalytic activity. Most sulfonamides exhibited K(I) values in the range of 1-10 microM, but several derivatives, including sulfanilyl-sulfonamides acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide, and the sulfamate topiramate, exhibited submicromolar inhibition (K(I) values of 0.481-0.905 microM). The best inhibitors were 3-bromosulfanilamide and indisulam (K(I) values of 97-186 nM). This study demonstrates that mtCA 1 can be inhibited by sulfonamides and sulfamates and thus has potential for developing antimycobacterial agents with an alternate mechanism of action. This is an important finding to explore further, as many strains exhibit multidrug resistance and extensive multidrug resistance to existing therapeutics. | 37 | 7 | 115 | CHEMBL_2 | 2009-11-30 |
CHEMBL1148958 | Journal of natural products. | 1 | Scientific Literature | Antibacterial activity of naphthoquinones and triterpenoids from Euclea natalensis root bark. | 15568795 | 10.1021/np030465d | nan | Weigenand O, Hussein AA, Lall N, Meyer JJ. | 2004 | 67 | 11 | 1936 | 1938 | PUBLICATION | Phytochemical studies of an ethanolic extract of Euclea natalensis root bark afforded two new compounds, octahydroeuclein (1) and 20(29)-lupene-3 beta-isoferulate (2), in addition to three known compounds, shinanolone (3), lupeol, and betulin. The chemical structures of 1 and 2 were determined by spectroscopic means. Shinanolone (3) showed inhibitory activity against Gram-positive bacterial strains and a drug-sensitive strain of Mycobacterium tuberculosis at a concentration of 0.1 mg/mL. | 6 | 12 | 20 | CHEMBL_2 | 2009-11-30 |
CHEMBL1151468 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Selection of SHV extended-spectrum-beta-lactamase-dependent cefotaxime and ceftazidime resistance in Klebsiella pneumoniae requires a plasmid-borne blaSHV gene. | 17999968 | 10.1128/aac.00359-07 | nan | Hammond DS, Harris T, Bell J, Turnidge J, Giffard PM. | 2008 | 52 | 2 | 441 | 445 | PUBLICATION | In Klebsiella pneumoniae, it is common for plasmid-located and chromosome-located bla(SHV) copies to coexist within single cells. The plasmid-borne genes are mainly derived from two separate IS26-mediated mobilizations of bla(SHV). The objective of this study was to test the hypothesis that the presence of a non-extended-spectrum beta-lactamase (non-ESBL) encoding plasmid-borne form of bla(SHV) facilitates the cefotaxime (CTX)-mediated selection of ESBL-expressing mutants, even when there is a chromosomal copy of the same gene. Twenty-one diverse ESBL-negative, bla(TEM)-negative K. pneumoniae clinical isolates were tested for the IS26 insertions characteristic of the two mobilization events. The isolates were then tested for their ability to be selected for ESBL-mediated CTX resistance by serial subculturing with a doubling of the CTX concentration at every subculture. Fourteen isolates possessed neither of the IS26 insertions. None of these became ESBL positive, and all died during the course of the experiment, despite possessing chromosomal bla(SHV) copies. The other isolates all became ESBL positive and grew abundantly up to a CTX concentration of 128 microg/ml. Similar results were obtained with ceftazidime. ESBL expression was associated with the appearance of the expected G-->A mutation at position 1 of codon 238 and also with bla(SHV) copy number amplification. It was concluded that plasmid-borne bla(SHV) greatly facilitates the selection of ESBL expression, even when the same gene is on the chromosome, and that gene dosage effects are likely to contribute to this phenomenon. | 2 | 1 | 25 | CHEMBL_3 | 2010-04-16 |
CHEMBL1629613 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Klebsiella pneumoniae OmpA confers resistance to antimicrobial peptides. | 19015361 | 10.1128/aac.00657-08 | nan | Llobet E, March C, Giménez P, Bengoechea JA. | 2009 | 53 | 1 | 298 | 302 | PUBLICATION | A Klebsiella pneumoniae ompA mutant was more susceptible to antimicrobial peptides (APs) than the wild type. Susceptibility did not result from surface changes other than the absence of OmpA. Our data suggest that OmpA is implicated in the activation of yet-unknown systems dedicated to ameliorating AP cytotoxicity. | 7 | 2 | 35 | CHEMBL_11 | 2011-08-01 |
CHEMBL1795313 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antimicrobial activities of hexahydroimidazo[1,5-a]pyridinium bromides with varying benzyl substituents. | 21543140 | 10.1016/j.ejmech.2011.04.012 | nan | Türkmen H, Ceyhan N, Ulkü Karabay Yavaşoğlu N, Ozdemir G, Cetinkaya B. | 2011 | 46 | 7 | 2895 | 2900 | PUBLICATION | Variously substituted benzyl bromides were employed to quaternize hexahydrobenzylimidazo[1,5-a]pyridine (A) and the resulting bromides (1-11) were evaluated for their in vitro antimicrobial activity against 10 pathogenic microorganisms: Staphylococcus aureus, Staphylococcus epidermidis, Bacillus cereus, Micrococcus luteus, Proteus vulgaris, Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia, Candida albicans and Candida krusei. Antimicrobial activities were surprisingly high (MIC: 0.78-400 μg/mL) and the sensitivity of the salts tested has been found to depend strongly both on the benzyl substituents and the microorganisms used. However, the correlation observed between antimicrobial activity and calculated partition coefficient (ClogP) was poor. Acute toxicity assessment of these salts showed LD(50) of 757-2000 mg/kg, after oral administration in mice in 24h. | 15 | 11 | 139 | CHEMBL_13 | 2012-02-21 |
CHEMBL1208753 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Peptide deformylase inhibitors with retro-amide scaffold: synthesis and structure-activity relationships. | 20615695 | 10.1016/j.bmcl.2010.06.088 | nan | Lee SK, Choi KH, Lee SJ, Suh SW, Kim BM, Lee BJ. | 2010 | 20 | 15 | 4317 | 4319 | PUBLICATION | Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins. Thus inhibition of PDF activity is considered to be one of the most effective antibiotic strategies. Reported herein are the synthesis and structure-activity relationship studies of retro-amide inhibitors based on actinonin, a naturally occurring PDF inhibitor. Analysis of the structure-activity relationships led to the discovery of 7a, which exhibits potent enzyme inhibition and antibacterial activity against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. | 25 | 4 | 100 | CHEMBL_9 | 2011-01-20 |
CHEMBL1177803 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | In vitro antituberculosis activities of the constituents isolated from Haloxylon salicornicum. | 20542692 | 10.1016/j.bmcl.2010.05.061 | nan | Bibi N, Tanoli SA, Farheen S, Afza N, Siddiqi S, Zhang Y, Kazmi SU, Malik A. | 2010 | 20 | 14 | 4173 | 4176 | PUBLICATION | In vitro antituberculosis activities of fractions and pure compounds (1-20) including seven triterpenes, two alkaloids, two cycloheximide derivatives, two coumarins six sterol derivatives and a long chain alcohol, respectively, isolated from Haloxylon salicornicum were determined against Mycobacterium tuberculosis H37Rv. Actively growing cultures were tested by rapid colorimetric method while the stationary phase cultures were tested by drug exposure methods for bactericidal activity. The MIC values were found to be 50 microg/ml for compounds 15, 19 and 20 where as rest of the compounds invariably showed MIC value of 100 microg/ml against the logarithmic phase culture. These were compare to Isoniazid as a control drug. The compounds exhibited no activity against the stationary phase culture of M. tuberculosis H37Rv up to 200 microg/ml. Further studies are required to investigate the in vivo efficacies and activities of the compounds in combination with antimicrobials that are already being used for TB therapy. | 21 | 1 | 42 | CHEMBL_8 | 2010-10-26 |
CHEMBL1122718 | Journal of medicinal chemistry. | 1 | Scientific Literature | Benzylamines: synthesis and evaluation of antimycobacterial properties. | 6433022 | 10.1021/jm00375a005 | nan | Meindl WR, von Angerer E, Schönenberger H, Ruckdeschel G. | 1984 | 27 | 9 | 1111 | 1118 | PUBLICATION | The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (19, MIC 10.2 micrograms/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 micrograms/mL), and N-butyl-3,5-difluorobenzylamine (103, MIC 6.4 micrograms/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combinations of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra. | 118 | 5 | 172 | CHEMBL_1 | 2009-09-03 |
CHEMBL1156172 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Substituted hydrazinecarbothioamide as potent antitubercular agents: synthesis and quantitative structure-activity relationship (QSAR). | 20304645 | 10.1016/j.bmcl.2010.02.081 | nan | Singh S, Mandal PK, Singh N, Misra AK, Singh S, Chaturvedi V, Sinha S, Saxena AK. | 2010 | 20 | 8 | 2597 | 2600 | PUBLICATION | A series of novel substituted hydrazinecarbothioamides was synthesized and evaluated for anti-TB activity. Three most active compounds viz. 1, 6 and 12 were found to exhibit minimum inhibitory concentration (MIC) of 0.4 microg/mL, whereas four compounds viz. 3, 5, 10 and 11 showed comparatively lesser activity with MIC value of 0.8 microg/mL against Mycobacterium tuberculosis strain. A highly significant QSAR equation explaining 81.8% variance is described. | 24 | 1 | 39 | CHEMBL_6 | 2010-08-27 |
CHEMBL1221309 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of novel tetrahydroisoquinoline bronchodilators. | 20678935 | 10.1016/j.bmcl.2010.07.057 | nan | Dalence-Guzmán MF, Toftered J, Oltner VT, Wensbo D, Johansson MH. | 2010 | 20 | 17 | 4999 | 5003 | PUBLICATION | The synthesis and bronchorelaxing effects of a series of novel tetrahydroisoquinoline amides are described. The compounds were evaluated for their ability to relax LTD4 contracted isolated human small airways ex-vivo. Several compounds demonstrated highly efficacious bronchorelaxing properties. Cinnamide 71 was selected for further studies and constitutes a promising candidate as a novel bronchorelaxing agent for the treatment of pulmonary disorders. | 25 | 2 | 52 | CHEMBL_9 | 2011-01-20 |
CHEMBL1828532 | European journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antitubercular evaluation of novel dibenzo[b,d]furan and 9-methyl-9H-carbazole derived hexahydro-2H-pyrano[3,2-c]quinolines via Povarov reaction. | 21723649 | 10.1016/j.ejmech.2011.06.014 | nan | Kantevari S, Yempala T, Surineni G, Sridhar B, Yogeeswari P, Sriram D. | 2011 | 46 | 10 | 4827 | 4833 | PUBLICATION | A series of novel hexahydro-2H-pyrano[3,2-c]quinoline analogues derived from dibenzo[b,d]furan and 9-methyl-9H-carbazole has been synthesized in very good yields through SnCl(2)·2H(2)O catalyzed one-pot Povarov reaction (imino-Diels-Alder reaction). The imines generated in situ from dibenzo[b,d]furan-2-carbaldehyde or 9-methyl-9H-carbazole-3-carbaldehyde and aromatic amines, were reacted with 3,4-dihydro-2H-pyran in a diasteroselective manner in acetonitrile at RT. These synthesized isomeric pyranoquinoline analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 23 compounds screened, 5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 4f, 5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 5f and 9-fluoro-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-hexa hydro-2H-pyrano[3,2-c]quinoline 7f (MIC 3.13 μg/mL) were resulted as most active antitubercular agents. | 26 | 2 | 49 | CHEMBL_13 | 2012-02-21 |
CHEMBL1125541 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antiviral evaluation of N-carboxamidine-substituted analogues of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride. | 1507208 | 10.1021/jm00095a020 | nan | Gabrielsen B, Phelan MJ, Barthel-Rosa L, See C, Huggins JW, Kefauver DF, Monath TP, Ussery MA, Chmurny GN, Schubert EM. | 1992 | 35 | 17 | 3231 | 3238 | PUBLICATION | Ten, hitherto unreported, analogues of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (2a, ribamidine) and methyl carboximidate 5 have been synthesized. These include the N-cyano (2b), N-alkyl (2c-e), N-amino acid (2f-h), N,N'-disubstituted (6, 7a,b), and the N-methylated carboxamide (1f) analogues of ribavirin. In addition, a new facile synthesis of carboxamidine 2a was also developed. All compounds were evaluated for biological activity against the following RNA viruses: Punta Toro (PT) and sandfly fever (SF) viruses (bunyaviruses); Japanese encephalitis (JE), yellow fever (YF), and dengue-4 viruses (flaviviruses); parainfluenza type 3 (PIV3), respiratory syncytial virus (RSV), and measles viruses (paramyxoviruses); influenza A and influenza B viruses (orthomyxoviruses); Venezuelan equine encephalomyelitis virus (VEE, alphavirus); human immunodeficiency virus type-1 (HIV-1, lentivirus); the DNA-containing vaccinia (VV) virus (poxvirus); and adeno type 5 (Ad5) viruses. All of the compounds except for 2b and 7a,b exhibited activity against the bunyaviruses such as that observed with 2a; however, higher IC50 values were generally observed. Glycine analogue 2f showed activity in PT-virus-infected mice in terms of increased survivors and decreased markers of viral pathogenicity. Carboxamidine 2a, carboximidate 5, and dimethyl amidine 6 exhibited activity against dengue type-4 virus. Monomethyl amidine 2c demonstrated activity against RSV, PIV3, and, to a lesser extent, influenza A and B. Activity of 2c generally required higher IC50 values than unsubstituted 2a. The latter exhibited hitherto unreported activity against RSV; therapeutic indices for 2a against RSV and PIV3 were greater than 64 and greater than 21. No substantial in vitro activity was observed for any of the compounds tested against Ad5, measles, JE, YF, VEE, or HIV-1. In addition, evidence is presented which argues in favor of a distinct antiviral mechanism of action for carboxamidines, e.g. 6, in contrast to a role as a carboxamide precursor. | 13 | 6 | 101 | CHEMBL_1 | 2009-09-03 |
CHEMBL1138535 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia. | 17709460 | 10.1128/aac.00006-07 | nan | Lodise TP, Kwa A, Cosler L, Gupta R, Smith RP. | 2007 | 51 | 11 | 3977 | 3982 | PUBLICATION | Data comparing the treatment outcomes of the two most frequently recommended empirical antibiotic regimens for community-acquired pneumonia (CAP)--combination therapy with an extended-spectrum beta-lactam and a macrolide (BL+M) or fluoroquinolone (F) monotherapy--for patients with severe CAP are sparse. The purpose of this study was to compare empirical BL+M combination therapy with F monotherapy for Veterans Affairs (VA) patients with severe CAP. This retrospective study included patients with CAP who received empirical therapy with BL+M or F between October 1999 and May 2003 in the Upstate New York VA Network. Outcome measures were 14-day mortality, 30-day mortality, and length of hospital stay (LOS). Severe CAP was defined as a class V pneumonia severity index (PSI). During the study period, 261 patients received BL+M and 254 received F. Disease severity was similar for the two treatment groups at admission, and the presence of tachycardia was the only difference noted. For PSI class V patients, there were lower 14-day and 30-day mortality rates with BL+M than with F (14-day rates, 8.2% versus 26.8% [P = 0.02]; 30-day rates, 18.4% versus 36.6% [P = 0.05]). No differences in mortality between treatment groups were noted for the lower PSI classes. The overall median LOS was significantly longer for the BL+M combination group than for the F monotherapy group (6.0 days versus 5.0 days, respectively [P = 0.01]), but no difference in LOS was noted among PSI class V patients. Our study showed that improved outcomes may be realized with BL+M in cases of severe CAP. A randomized clinical study is warranted based on these results. | 1 | 1 | 8 | CHEMBL_2 | 2009-11-30 |
CHEMBL1135078 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Syntheses of novel antimycobacterial combinatorial libraries of structurally diverse substituted pyrimidines by three-component solid-phase reactions. | 11844696 | 10.1016/s0960-894x(01)00829-0 | nan | Kumar A, Sinha S, Chauhan PM. | 2002 | 12 | 4 | 667 | 669 | PUBLICATION | A new pyrimidine based scaffold has been developed by three-component solid-phase syntheses. The utility of scaffolds was demonstrated by synthesizing libraries of 80 substituted pyrimidines (a-p), (a-p), 14(a-p), 15(a-p), 16(a-p). Among 80 compounds screened, six compounds, 12i, 13c, 14d, 14e, 14o, and 15d showed in vitro activity against Mycobacterium tuberculosis (MABA) at a concentration of 50 and 25 microg/mL | 80 | 1 | 80 | CHEMBL_1 | 2009-09-03 |
CHEMBL1135682 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. | 12459027 | 10.1021/jm020310n | nan | Seitz LE, Suling WJ, Reynolds RC. | 2002 | 45 | 25 | 5604 | 5606 | PUBLICATION | A series of pyrazine and quinoxaline derivatives have been synthesized, and their activity against M. tuberculosis (Mtb) and Mycobacterium avium (MAC) are reported. The 4-acetoxybenzyl ester of pyrazinoic acid and 4'-acetoxybenzyl 2-quinoxalinecarboxylate showed excellent activity against Mtb (MIC ranges of less than 1-6.25 microg/mL) but only modest activity against MAC (MICs of 4-32 microg/mL). | 21 | 2 | 77 | CHEMBL_1 | 2009-09-03 |
CHEMBL1687777 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Membrane efflux and influx modulate both multidrug resistance and virulence of Klebsiella pneumoniae in a Caenorhabditis elegans model. | 20679507 | 10.1128/aac.01607-09 | nan | Bialek S, Lavigne JP, Chevalier J, Marcon E, Leflon-Guibout V, Davin A, Moreau R, Pagès JM, Nicolas-Chanoine MH. | 2010 | 54 | 10 | 4373 | 4378 | PUBLICATION | Cross-resistance to cefoxitin (FOX), chloramphenicol (CMP), and quinolones (nalidixic acid [NAL]) related to a putative efflux system overexpression has recently been reported for Klebsiella pneumoniae. The potential impact of this multidrug resistance (MDR) on the virulence of K. pneumoniae was evaluated in the Caenorhabditis elegans model. For 2 of the 3 MDR clinical isolates studied, a significant increase in acrB transcription was found in comparison with their antibiotic-susceptible revertants. ATCC 138821 and MDR, revertant, and derivative strains with altered porin expression were studied. Strains proved or suspected to overexpress an efflux system were significantly more virulent than the ATCC and revertant strains (time to kill 50% of nematodes [LT(50)] in days: 3.4 to 3.8 ± 0.2 versus 4.1 to 4.4 ± 0.3, P < 0.001). Inversely, strains with altered porin expression were significantly less virulent, independently of the expression level of efflux system (LT(50) = 5.4 to 5.6 ± 0.2, P < 0.001). Altered porin expression did not change MICs of CMP and NAL but did those of FOX (4 to 16× MIC) and ertapenem (16 to 64× MIC). The strains with a normally or an overexpressed efflux system that received the β-lactamase CTX-M-15 became more widely resistant without modification of their virulence potential, suggesting that balance between resistance and virulence is dependent on the type of resistance mechanisms. In conclusion, this study shows that the expression of both efflux systems and porins is a key factor not only for antibiotic resistance but also virulence potential in K. pneumoniae. | 8 | 1 | 136 | CHEMBL_11 | 2011-08-01 |
CHEMBL1131707 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Methionyl adenylate analogues as inhibitors of methionyl-tRNA synthetase. | 10360737 | 10.1016/s0960-894x(99)00206-1 | nan | Lee J, Kang SU, Kang MK, Chun MW, Jo YJ, Kwak JH, Kim S. | 1999 | 9 | 10 | 1365 | 1370 | PUBLICATION | Four stable analogues of methionyl adenylate (3-6) were designed as inhibitors of methionyl-tRNA synthetase and synthesized from 2',3'-isopropylideneadenosine. They strongly inhibited aminoacylation activity of methionyl-tRNA synthetases isolated from Escherichia coli, Mycobacterium tuberculosis, Saccharomyces cerevisiae and human. Among the microorganisms tested, however, these chemicals showed the growth inhibition effect only on E. coli. | 5 | 8 | 40 | CHEMBL_1 | 2009-09-03 |
CHEMBL1130250 | Journal of medicinal chemistry. | 1 | Scientific Literature | NAcSDKP analogues resistant to angiotensin-converting enzyme. | 9397177 | 10.1021/jm9701132 | nan | Gaudron S, Adeline MT, Potier P, Thierry J. | 1997 | 40 | 24 | 3963 | 3968 | PUBLICATION | Two series of analogues of the tetrapeptide NAcSDKP, an inhibitor of hematopoietic stem cell proliferation, were prepared, and their enzymatic stability toward rabbit lung angiotensin-converting enzyme (ACE) was evaluated as well as their capacity to inhibit NAcSDKP hydrolysis by this enzyme. In the first series, each of the peptide bonds has been successively replaced by an aminomethylene bond. In the second one, the C-terminus of the peptide has been modified by decarboxylation or amidation. The results reported here indicate that all of these molecules but one have good stability toward the enzyme but none of the compounds is able to inhibit NAcSDKP hydrolysis by ACE. | 8 | 1 | 26 | CHEMBL_1 | 2009-09-03 |
CHEMBL1158325 | Journal of natural products. | 1 | Scientific Literature | Norditerpenoids and diterpenoids from Salvia multicaulis with antituberculous activity. | 9428161 | 10.1021/np9700681 | nan | Ulubelen A, Topcu G, Johansson CB. | 1997 | 60 | 12 | 1275 | 1280 | PUBLICATION | From the roots of Salvia multicaulis, four new aromatic norditerpenoids, multicaulin (1), 12-demethylmulticauline (2), multiorthoquinone (3), and 12-demetylmultiorthoquinone (4), two new abietane diterpenoids, 12-methyl-5-dethydrohorminone (5) and 12-methyl-5-dehydroacetylhorminone (6), as well as a new pimarane diterpenoid, salvipimarone (7), were isolated. Also obtained in this investigation were the known compounds alpha-amyrin, hinokione, horminone, lupeol, manool, 1-oxoferruginol, 18-oxoferruginol, pisiferal, and sempervirol. The structures of compounds 1-7 were established by 1D and 2D NMR techniques and by chemical methods. The antituberculous activity of 1-7 was tested against Mycobacterium tuberculosis strain H37Rv, and all compounds were found to be significantly active, with 2 and 4-6 being the most potent substances. Six of these novel compounds were evaluated against a number of additional bacterial cultures. | 14 | 8 | 71 | CHEMBL_2 | 2009-11-30 |
CHEMBL1155777 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Increased survival after gemfibrozil treatment of severe mouse influenza. | 17562808 | 10.1128/aac.00219-07 | nan | Budd A, Alleva L, Alsharifi M, Koskinen A, Smythe V, Müllbacher A, Wood J, Clark I. | 2007 | 51 | 8 | 2965 | 2968 | PUBLICATION | Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n = 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n = 46) (P = 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain. | 1 | 2 | 21 | CHEMBL_2 | 2009-11-30 |
CHEMBL1134378 | Journal of medicinal chemistry. | 1 | Scientific Literature | Comparative binding energy (COMBINE) analysis of influenza neuraminidase-inhibitor complexes. | 11300878 | 10.1021/jm001070j | nan | Wang T, Wade RC. | 2001 | 44 | 6 | 961 | 971 | PUBLICATION | Neuraminidase is a surface glycoprotein of influenza viruses that cleaves terminal sialic acids from carbohydrates. It is critical for viral release from infected cells and facilitates viral spread in the respiratory tract. The catalytic active site of neuraminidase is highly conserved in all type A and B influenza viruses, making it an excellent target for antiinfluenza drug design. Indeed, neuraminidase inhibitors have recently become available in the clinic for the treatment of influenza. Here, we describe the use of 3D structures of neuraminidase-inhibitor complexes to derive quantitative structure-activity relationships (QSARs) to aid understanding of the mechanism of inhibition and the discovery of new inhibitors. Crystal structures of neuraminidase-inhibitor complexes were used alongside modeled complexes to derive QSAR models by COMparative BINding Energy (COMBINE) analysis (Ortiz, A. R.; Pisabarro, M. T.; Gago, F.; Wade, R. C. J. Med. Chem. 1995, 38, 2681-2691). The neuraminidase proteins studied include type A subtypes N2 and N9 (which have ca. 50% sequence identity) and an active site mutant of the N9 subtype. The inhibitors include sialic acid and benzoic acid analogues with diverse frameworks and substitution groups. By considering the contributions of the protein residues and a key water molecule to the electrostatic and van der Waals intermolecular interaction energies, a predictive and robust QSAR model for binding to type A neuraminidase was obtained. In this QSAR model, 12 protein residues and 1 bound water molecule are highlighted as particularly important for inhibitory activity. This QSAR model provides guidelines for structural modification of current inhibitors and the design of novel inhibitors in order to optimize inhibitory activity. | 29 | 1 | 45 | CHEMBL_1 | 2009-09-03 |
CHEMBL1641439 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | The effect of 5-substitution on the electrochemical behavior and antitubercular activity of PA-824. | 21168331 | 10.1016/j.bmcl.2010.11.093 | nan | Bollo S, Núñez-Vergara LJ, Kang S, Zhang L, Boshoff HI, Barry CE, Squella JA, Dowd CS. | 2011 | 21 | 2 | 812 | 817 | PUBLICATION | Nitroimidazole PA-824 is part of an exciting new class of compounds currently undergoing clinical evaluation as novel TB therapeutics. The recently elucidated mechanism of action of PA-824 involves reduction of the nitroimidazole ring and subsequent nitric oxide release. The importance of this compound and its unique activity prompted us to explore how substitution of the nitroimidazole ring would affect electrochemical reduction and antitubercular activity. We prepared analogs of PA-824 with bromo, chloro, cyano, and amino substituents in the 5-position of the aromatic ring. We found that substitution of the imidazole ring greatly influences reduction and the stability of the corresponding nitro radical anion. Further, the antitubercular activities of the bromo and chloro analogs may indicate that an alternate nitroreductase pathway within Mycobacterium tuberculosis exists. | 5 | 1 | 20 | CHEMBL_11 | 2011-08-01 |
CHEMBL1152380 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | The synthesis and biological evaluation of a novel series of C7 non-basic substituted fluoroquinolones as antibacterial agents. | 19539467 | 10.1016/j.bmcl.2009.06.006 | nan | Huang X, Chen D, Wu N, Zhang A, Jia Z, Li X. | 2009 | 19 | 15 | 4130 | 4133 | PUBLICATION | A series of non-basic building blocks was synthesized and introduced to the C7 position of the quinolone nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid to afford the corresponding fluoroquinolones in 46-85% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. The sulfur-containing quinolone, 7-(2-thia-5-azabicyclo[2.2.1]heptan-5-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid exhibited a superior antibacterial activity against quinolone-susceptible and multidrug-resistant strains in comparison with the clinically used fluoroquinolones ciprofloxacin and vancomycin, especially to the Streptococcus pneumonia and multidrug-resistant S. pneumonia clinical isolates. | 16 | 6 | 150 | CHEMBL_3 | 2010-04-16 |
CHEMBL1122482 | Journal of medicinal chemistry. | 1 | Scientific Literature | Optical resolution, absolute configuration, and activity of the enantiomers of proxyphylline. | 6620311 | 10.1021/jm00364a029 | nan | Selvig K, Ruud-Christensen M, Aasen AJ. | 1983 | 26 | 10 | 1514 | 1518 | PUBLICATION | The enantiomers of proxyphylline have been separated via their corresponding camphanates. Synthesis of (+)-proxyphylline from theophylline and (S)-propylene oxide derived from (S)-lactic acid established the absolute configuration of the (+) and (-) isomer as S and R, respectively. The activity of the enantiomers as cyclic nucleotide phosphodiesterase inhibitors was tested in human lung tissue homogenate. No differences were found either between the two enantiomers or between the enantiomers and racemic proxyphylline. | 3 | 4 | 12 | CHEMBL_1 | 2009-09-03 |
CHEMBL1123123 | Journal of medicinal chemistry. | 1 | Scientific Literature | Orally absorbable cephalosporin antibiotics. 2. Structure-activity studies of bicyclic glycine derivatives of 7-aminodeacetoxycephalosporanic acid. | 3877809 | 10.1021/jm00150a023 | nan | Kukolja S, Draheim SE, Graves BJ, Hunden DC, Pfeil JL, Cooper RD, Ott JL, Counter FT. | 1985 | 28 | 12 | 1896 | 1903 | PUBLICATION | Three positional analogues (4-, 5-, and 7-) of benzothienylglycine and (N-acetylindolinyl)-5-glycine were prepared and coupled to 7-aminodeacetoxycephalosporanic acid (7-ADCA) to give the cephalosporins 17a-c. In addition two isomeric (2,3-b and 3,2-b) thienothiopheneglycines were synthesized and coupled to 7-ADCA to yield cephalosporins 30d and 30e. In vitro testing of these new cephalosporins indicates good activity against Gram-positive bacteria. Against Streptococcus pneumoniae infections compound 25 displayed better mouse protection (both orally and subcutaneously) than cephalexin. | 8 | 7 | 92 | CHEMBL_1 | 2009-09-03 |
CHEMBL1153054 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Functionalized 3-amino-imidazo[1,2-a]pyridines: a novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors. | 19560924 | 10.1016/j.bmcl.2009.06.045 | nan | Odell LR, Nilsson MT, Gising J, Lagerlund O, Muthas D, Nordqvist A, Karlén A, Larhed M. | 2009 | 19 | 16 | 4790 | 4793 | PUBLICATION | 3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC(50)=0.38+/-0.02 microM). This compound was significantly more potent than the known inhibitors, l-methionine-SR-sulfoximine and phosphinothricin. | 33 | 1 | 33 | CHEMBL_3 | 2010-04-16 |
CHEMBL1671689 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Activity of ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States. | 20308374 | 10.1128/aac.01797-09 | nan | Jacobs MR, Good CE, Windau AR, Bajaksouzian S, Biek D, Critchley IA, Sader HS, Jones RN. | 2010 | 54 | 6 | 2716 | 2719 | PUBLICATION | The in vitro activity of ceftaroline against 891 pneumococci collected in 2008 from 22 centers in the United States was investigated. Ceftaroline was the most potent agent tested, with the MICs being <0.008 to 0.5 microg/ml and the MIC(90)s being <0.008 to 0.25 microg/ml against 11 prevailing serotypes. The overall rates of susceptibility were as follows: penicillin G, 86.2%; ceftriaxone, 90.7%; cefuroxime, 70.1%; erythromycin, 61.6%; clindamycin, 79.2%; levofloxacin, 99.4%; and vancomycin, 100%. Serotype 19A isolates were the least susceptible. These results support the use of ceftaroline for the treatment of pneumococcal infections, including those caused by pneumococci resistant to other agents. | 13 | 1 | 504 | CHEMBL_11 | 2011-08-01 |
CHEMBL1153431 | Journal of medicinal chemistry. | 1 | Scientific Literature | Potent inhibitors of pro-inflammatory cytokine production produced by a marine-derived bacterium. | 19323483 | 10.1021/jm801110j | nan | Strangman WK, Kwon HC, Broide D, Jensen PR, Fenical W. | 2009 | 52 | 8 | 2317 | 2327 | PUBLICATION | Cytokines produced through the antigen presenting cell (APC)-T-cell interaction play a key role in the activation of the allergic asthmatic response. Evaluating small molecules that inhibit the production of these pro-inflammatory proteins is therefore important for the discovery of novel chemical structures with potential antiasthma activity. We adapted a mouse splenocyte cytokine assay to screen a library of 2,500 marine microbial extracts for their ability to inhibit T(H)2 cytokine release and identified potent activity in a marine-derived strain CNQ431, identified as a Streptomyces species. Bioactivity guided fractionation of the organic extract of this strain led to the isolation of ten new 9-membered bis-lactones, splenocins A-J (1-10). The new compounds display potent biological activities, comparable to that of the corticosteroid dexamethasone, with IC(50) values from 2 to 50 nM in the splenocyte cytokine assay. This study provides the foundation for the optimization of these potent anti-inflammatory compounds for development in the treatment of asthma. | 11 | 2 | 39 | CHEMBL_2 | 2009-11-30 |
CHEMBL1158114 | Journal of natural products. | 1 | Scientific Literature | Acetylated flavanone glycosides from the rhizomes of Cyclosorus acuminatus. | 17125239 | 10.1021/np060334n | nan | Fang W, Ruan J, Wang Z, Zhao Z, Zou J, Zhou D, Cai Y. | 2006 | 69 | 11 | 1641 | 1644 | PUBLICATION | Six new flavanone glycosides (1-6) were isolated from the methanol extract of the rhizomes of Cyclosorus acuminatus, together with the parent flavanone glycoside 2a. Their structures were established on the basis of spectroscopic and chemical methods. All compounds showed moderate activity against Streptococcus pneumoniae and Haemophilus influenzae. | 9 | 4 | 36 | CHEMBL_2 | 2009-11-30 |
CHEMBL1146783 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Conformationally restricted analogs of deoxynegamycin. | 15149653 | 10.1016/j.bmcl.2004.04.036 | nan | Raju B, Anandan S, Gu S, Herradura P, O'Dowd H, Kim B, Gomez M, Hackbarth C, Wu C, Wang W, Yuan Z, White R, Trias J, Patel DV. | 2004 | 14 | 12 | 3103 | 3107 | PUBLICATION | Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules. | 19 | 7 | 173 | CHEMBL_1 | 2009-09-03 |
CHEMBL1128640 | Journal of medicinal chemistry. | 1 | Scientific Literature | Thiopyranol[2,3,4-c,d]indoles as inhibitors of 5-lipoxygenase, 5-lipoxygenase-activating protein, and leukotriene C4 synthase. | 7473582 | 10.1021/jm00022a020 | nan | Hutchinson JH, Charleson S, Evans JF, Falgueyret JP, Hoogsteen K, Jones TR, Kargman S, Macdonald D, McFarlane CS, Nicholson DW. | 1995 | 38 | 22 | 4538 | 4547 | PUBLICATION | The attachment of an arylacetic or benzoic acid moiety to the thiopyrano[2,3,4-c,d]indole nucleus results in compounds which are highly potent and selective 5-lipoxygenase (5-LO) inhibitors. These compounds are structurally simpler than previous compounds of similar potency in that they contain a single chiral center. From the data presented, 2-[[1-(3-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]- 4, 5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]-phenylacetic acid, 14b, was shown to inhibit 5-hydroperoxyeicosatetraenoic acid (5-HPETE) production by human 5-LO (IC50 of 18 nM). The acid 14b is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or human leukocyte leukotriene A4 (LTA4) hydrolase (IC50 > 20 microM). In addition, 14b was inactive in a 5-lipoxygenase-activating protein (FLAP) binding assay at 10 microM. In vivo studies showed that 14b is bioavailable in rat and functionally active in the hyperreactive rat model of antigen-induced dyspnea (74% inhibition at 0.5 mk/kg po; 2 h pretreatment). In the conscious squirrel monkey model of asthma, 14b showed excellent functional activity at 0.1 mg/kg against antigen-induced bronchoconstriction (94% inhibition of the increase in RL and 100% inhibition in the decrease in Cdyn; n = 4). Resolution of this compound gave (-)-14b, the most potent enantiomer (IC50 = 10 nM in the human 5-LO assay), which was shown to possess the S configuration at the chiral center by X-ray crystallographic analysis of an intermediate. Subsequent studies on the aryl thiopyrano[2,3,4-c,d]indole series of inhibitors led to the discovery of potent dual inhibitors of both FLAP and 5-LO, the most potent of which is 2-[[1-(4-chlorobenzyl)-4-methyl-6-(quinolin-2-ylmethoxy)-4, 5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 19. Acid 19 has an IC50 of 100 nM for the inhibition of 5-HPETE production by human 5-LO and is active in a FLAP binding assay with an IC50 of 32 nM. Furthermore, thiopyrano[2,3,4-c,d]indoles such as 1 and 14b are capable of inhibiting the LTC4 synthase reaction in a dose dependent manner (IC50s of 11 and 16 microM, respectively, compared to that of LTC2 at 1.2 microM) in contrast to other, structurally distinct 5-LO inhibitors. It has also been observed that the thiopyrano[2,3,4-c,d]indole class of compounds strongly promotes the translocation of 5-LO from the cytosol to a membrane fraction in the presence or absence of the ionophore A23187.(ABSTRACT TRUNCATED AT 400 WORDS) | 21 | 4 | 48 | CHEMBL_1 | 2009-09-03 |
CHEMBL1133709 | Journal of medicinal chemistry. | 1 | Scientific Literature | Acyclic analogues of deoxyadenosine 3',5'-bisphosphates as P2Y(1) receptor antagonists. | 10691699 | 10.1021/jm9905211 | nan | Kim YC, Gallo-Rodriguez C, Jang SY, Nandanan E, Adams M, Harden TK, Boyer JL, Jacobson KA. | 2000 | 43 | 4 | 746 | 755 | PUBLICATION | P2Y(1) receptors are activated by ADP and occur on endothelial cells, smooth muscle, epithelial cells, lungs, pancreas, platelets, and in the central nervous system. With the aid of molecular modeling, we have designed nucleotide analogues that act as selective antagonists at this subtype. The present study has tested the hypothesis that acyclic modifications of the ribose ring, proven highly successful for nucleoside antiviral agents such as gancyclovir, are generalizable to P2Y receptor ligands. Specifically, the binding site of the P2Y(1) receptor was found to be sufficiently accommodating to allow the substitution of the ribose group with acyclic aliphatic and aromatic chains attached to the 9-position of adenine. Three groups of adenine derivatives having diverse side-chain structures, each containing two symmetrical phosphate or phosphonate groups, were prepared. Biological activity was demonstrated by the ability of the acyclic derivatives to act as agonists or antagonists in the stimulation of phospholipase C in turkey erythrocyte membranes. An acyclic N(6)-methyladenine derivative, 2-[2-(6-methylamino-purin-9-yl)-ethyl]-propane-1, 3-bisoxy(diammoniumphosphate) (10), containing an isopentyl bisphosphate moiety, was a full antagonist at the P2Y(1) receptor with an IC(50) value of 1.60 micro¿. The corresponding 2-Cl derivative (11) was even more potent with an IC(50) value of 0.84 microM. Homologation of the ethylene group at the 9-position to 3-5 methylene units or inclusion of cis- or trans-olefinic groups greatly reduced antagonist potency at the P2Y(1) receptor. Analogues containing a diethanolamine amide group and an aryl di(methylphosphonate) were both less potent than 10 as antagonists, with IC(50) values of 14 and 16 microM, respectively, and no agonist activity was observed for these analogues. Thus, the ribose moiety is clearly not essential for recognition by the turkey P2Y(1) receptor, although a cyclic structure appears to be important for receptor activation, and the acyclic approach to the design of P2 receptor antagonists is valid. | 16 | 3 | 53 | CHEMBL_1 | 2009-09-03 |
CHEMBL1154403 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Serotypes, Clones, and Mechanisms of Resistance of Erythromycin-Resistant Streptococcus pneumoniae Isolates Collected in Spain. | 17606677 | 10.1128/aac.00157-07 | nan | Calatayud L, Ardanuy C, Cercenado E, Fenoll A, Bouza E, Pallares R, Martín R, Liñares J. | 2007 | 51 | 9 | 3240 | 3246 | PUBLICATION | The aim of this study was to analyze the distributions of antibiotic susceptibility patterns, serotypes, phenotypes, genotypes, and macrolide resistance genes among 125 nonduplicated erythromycin-resistant Streptococcus pneumoniae clinical isolates collected in a Spanish point prevalence study. The prevalence of resistance to macrolides in this study was 34.7%. Multiresistance (to three or more antimicrobials) was observed in 81.6% of these strains. Among 15 antimicrobials studied, cefotaxime, moxifloxacin, telithromycin, and quinupristin-dalfopristin were the most active drugs. The most frequent serotypes of erythromycin-resistant isolates were 19F (25%), 19A (17%), 6B (12%), 14 (10%), and 23F (10%). Of the 125 strains, 109 (87.2%) showed the MLS(B) phenotype [103 had the erm(B) gene and 6 had both erm(B) and mef(E) genes]. Sixteen (12.8%) strains showed the M phenotype [14 with mef(E) and 2 with mef(A)]. All isolates were tested by PCR for the presence of the int, xis, tnpR, and tnpA genes associated with conjugative transposons (Tn916 family and Tn917). Positive detection of erm(B), tet(M), int, and xis genes related to the Tn916 family was found in 77.1% of MLS(B) phenotype strains. In 16 strains, only the tndX, erm(B), and tet(M) genes were detected, suggesting the presence of Tn1116, a transposon recently described for Streptococcus pyogenes. Five clones, namely, Sweden(15A)-25, clone(19F) ST87, Spain(23F)-1, Spain(6B)-2, and clone(19A) ST276, accounted for half of the MLS(B) strains. In conclusion, the majority of erythromycin-resistant pneumococci isolated in Spain had the MLS(B) phenotype, belonged to multiresistant international clones, and carried the erm(B), tet(M), xis, and int genes, suggesting the spread of transposons of the Tn916 family. | 11 | 1 | 76 | CHEMBL_2 | 2009-11-30 |
CHEMBL1150325 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Synthesis of methyl 5-S-alkyl-5-thio-D-arabinofuranosides and evaluation of their antimycobacterial activity. | 18450455 | 10.1016/j.bmc.2008.03.062 | nan | Sanki AK, Boucau J, Srivastava P, Adams SS, Ronning DR, Sucheck SJ. | 2008 | 16 | 10 | 5672 | 5682 | PUBLICATION | The emergence of drug resistant tuberculosis necessitates a search for new antimycobacterial compounds. The antigen 85 (ag85) complex is a family of mycolyl transferases involved in the synthesis of trehalose-6,6'-dimycolate and the mycolated hexasaccharide motif found at the terminus of the arabinogalactan in mycobacterium. Enzymes involved in the synthesis of cell wall structures like these are potential targets for the development of new antiinfectives. To potentially inhibit the ag85 complex, methyl 5-S-alkyl-5-thio-arabinofuranoside analogues were designed based on docking studies with ag85C derived from Mycobacterium tuberculosis. The target arabinofuranosides were then synthesized and the antibacterial activity evaluated against Mycobacterium smegmatis ATCC 14468. Two of the compounds, 5-S-octyl-5-thio-alpha-d-arabinofuranoside (8) and 5-S-octyl-5-thio-beta-d-arabinofuranoside (11), showed MICs of 256 and 512microg/mL, respectively. Attempts to directly evaluate acyltransferase inhibitory activity of the arabinofuranosides against ag85C are also described. In conclusion, a new class of antimycobacterial arabinofuranosides has been discovered. | 7 | 4 | 39 | CHEMBL_2 | 2009-11-30 |
CHEMBL1140096 | Journal of medicinal chemistry. | 1 | Scientific Literature | Discovery of novel nitrobenzothiazole inhibitors for Mycobacterium tuberculosis ATP phosphoribosyl transferase (HisG) through virtual screening. | 18778048 | 10.1021/jm800328v | nan | Cho Y, Ioerger TR, Sacchettini JC. | 2008 | 51 | 19 | 5984 | 5992 | PUBLICATION | HisG is an ATP-phosphoribosyl transferase (ATPPRTase) that catalyzes the first step in the biosynthetic pathway for histidine. Among the enzymes in this pathway, only HisG represents a potential drug target for tuberculosis. Only a few inhibitors with limited potency for HisG are currently known. To discover more potent and diverse inhibitors, virtual screening was performed. The crystal structure of M. tuberculosis HisG has been solved and reveals a large, solvent-exposed active site with subsites for ATP and PRPP substrates. Two docking algorithms, GOLD and FLEXX, were used to screen two large libraries, Chembridge and NCI, containing over 500000 compounds combined. An initial subset of top-ranked compounds were selected and assayed, and seven were found to have enzyme inhibition activity at micromolar concentrations. Several of the hits contained a nitrobenzothiazole fragment, which was predicted to dock into the monophosphate-binding loop, and this binding mode was confirmed by crystallographic evidence. A secondary screen was performed to identify compounds with similar structures. Several of these also exhibited micromolar inhibition. Furthermore, two of the compounds showed bacteriocidal activity in a whole-cell assay against Mycobacterium smegmatis. | 14 | 3 | 35 | CHEMBL_2 | 2009-11-30 |
CHEMBL1135555 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | A prenylated flavonol, sophoflavescenol: a potent and selective inhibitor of cGMP phosphodiesterase 5. | 12161123 | 10.1016/s0960-894x(02)00401-8 | nan | Shin HJ, Kim HJ, Kwak JH, Chun HO, Kim JH, Park H, Kim DH, Lee YS. | 2002 | 12 | 17 | 2313 | 2316 | PUBLICATION | During the search for naturally occurring cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitors, it was found that the extracts from Sophora flavescens exhibit potent inhibitory activity against cGMP PDE5 prepared from rat diaphragm. Therefore, the inhibitory activities of five flavonoids, kushenol H (1), kushenol K (2), kurarinol (3), sophoflavescenol (4) and kuraridine (5), isolated from S. flavescens were measured against cGMP PDE5 to identify potent cGMP PDE5 inhibitory constituents. Among tested compounds, sophoflavescenol (4), a C-8 prenylated flavonol, showed the most potent inhibitory activity (IC(50)=0.013 microM) against cGMP PDE5 with 31.5- and 196.2-fold selectivity over PDE3 and PDE4, respectively. Kinetic analysis revealed that sophoflavescenol was a mixed inhibitor of PDE5 with a K(i) value of 0.005 microM. | 8 | 3 | 29 | CHEMBL_1 | 2009-09-03 |
CHEMBL1132155 | Journal of medicinal chemistry. | 1 | Scientific Literature | Endothelin antagonists: substituted mesitylcarboxamides with high potency and selectivity for ET(A) receptors. | 10579813 | 10.1021/jm9900063 | nan | Wu C, Decker ER, Blok N, Bui H, Chen Q, Raju B, Bourgoyne AR, Knowles V, Biediger RJ, Market RV, Lin S, Dupré B, Kogan TP, Holland GW, Brock TA, Dixon RA. | 1999 | 42 | 22 | 4485 | 4499 | PUBLICATION | We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. #3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation 1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ET(A) selectivity by approximately 10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has approximately 10-fold higher ET(A) binding affinity than 1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity. | 46 | 4 | 147 | CHEMBL_1 | 2009-09-03 |
CHEMBL1135342 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and evaluation of thymidine-5'-O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase. | 12217356 | 10.1016/s0960-894x(02)00551-6 | nan | Vanheusden V, Munier-Lehmann H, Pochet S, Herdewijn P, Van Calenbergh S. | 2002 | 12 | 19 | 2695 | 2698 | PUBLICATION | A number of 2'- and 3'-modified thymidine 5'-O-monophosphate analogues were synthesized as potential leads for new anti-mycobacterial drugs. Evaluation of their affinity for Mycobacterium tuberculosis thymidine monophosphate kinase showed that a 2'-halogeno substituent and a 3'-azido function are the most favorable leads for further development of potent inhibitors of this enzyme. | 13 | 1 | 20 | CHEMBL_1 | 2009-09-03 |
CHEMBL1157188 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Structure-activity relationship of truncated analogs of caprazamycins as potential anti-tuberculosis agents. | 18375127 | 10.1016/j.bmc.2008.03.020 | nan | Hirano S, Ichikawa S, Matsuda A. | 2008 | 16 | 9 | 5123 | 5133 | PUBLICATION | Systematic structure-activity relationship studies of caprazamycin (CPZ) analogs, including the aminoribose-truncated 5 and the uridine-truncated 6, have been carried out. Both 5 and 6 were synthesized efficiently via diazepanone ring construction by intramolecular reductive alkylation of aminoaldehyde derivatives. The antibacterial activity of a range of analogs, including 5 and 6, against Mycobacteriumosis was evaluated, and it was found that the uridine, the aminoribose, and the fatty acyl side chains are crucial for antibacterial activity. This study would be a guide for designing novel anti-tuberculosis agents based on the 6'-N-alkyl-5'-beta-O-aminoribosyl-glycyluridine class of antibiotics including the CPZs. | 6 | 2 | 7 | CHEMBL_2 | 2009-11-30 |
CHEMBL1123859 | Journal of medicinal chemistry. | 1 | Scientific Literature | Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists. | 3806607 | 10.1021/jm00384a017 | nan | Musser JH, Chakraborty UR, Sciortino S, Gordon RJ, Khandwala A, Neiss ES, Pruss TP, Van Inwegen R, Weinryb I, Coutts SM. | 1987 | 30 | 1 | 96 | 104 | PUBLICATION | A series of new substituted arylmethyl phenyl ethers has been prepared. These compounds were tested as inhibitors of 5-lipoxygenase (5-LO) in rat neutrophils, in vitro antagonists of leukotriene-induced contraction of guinea pig (GP) lung parenchymal strips, and inhibitors of slow reacting substance of anaphylaxis (SRS-A) mediated bronchospasm in the GP in vivo. Most representatives of this new class of potential antiallergic/antiinflammatory agents showed potent inhibition of 5-LO activity in rat PMNs. The most potent compound, 2-[[3-(1-hydroxyhexyl)phenoxy]-methyl]quinoline (33), had an I50 of 0.12 microM in the rat PMN 5-LO assay and an I50 of 3.6 microM in the leukotriene-induced contraction of GP lung parenchymal strips, and it also showed 91% inhibition of SRS-A-mediated bronchospasm in the GP in vivo at 10 mg/kg, administered intraduodenally. Some of the compounds in this series were also leukotriene antagonists in vitro, and several of them showed in vivo activity against SRS-A-mediated bronchospasm in the GP. | 58 | 2 | 110 | CHEMBL_1 | 2009-09-03 |
CHEMBL1158341 | European journal of medicinal chemistry. | 1 | Scientific Literature | A macrolactone from benzo[a]phenazine with potent activity against Mycobacterium tuberculosis. | 18662840 | 10.1016/j.ejmech.2008.06.014 | nan | Silva RS, Pinto Mdo C, Goulart MO, de Souza Filho JD, Neves I, Lourenço MC, Pinto AV. | 2009 | 44 | 5 | 2334 | 2337 | PUBLICATION | We report here an alternative to the MCPBA or ozonolysis-based oxidation methods of quinoxaline-featuring compounds prepared from beta-lapachones. The use of peracetic acid allowed a simple preparation of the corresponding macrolactones by cleavage of the ring system. These lactones were evaluated for their antimycobacterial potential and compound 4 turned out to have an MIC of 0.62 microg per mL on Mycocabteriumtuberculosis H37Rv. These results justify further research into its value as a potential lead for an original treatment of tuberculosis. | 6 | 1 | 11 | CHEMBL_3 | 2010-04-16 |
CHEMBL1159328 | Journal of natural products. | 1 | Scientific Literature | Cyclotheonamide E4 and E5, new potent tryptase inhibitors from an Ircinia species of sponge. | 11908961 | 10.1021/np010304e | nan | Murakami Y, Takei M, Shindo K, Kitazume C, Tanaka J, Higa T, Fukamachi H. | 2002 | 65 | 3 | 259 | 261 | PUBLICATION | Tryptase is a protease released from mast cells and is believed to contribute to the inflammatory process in allergic diseases including asthma. In the course of screening to find tryptase inhibitors, we isolated two new tryptase inhibitors, cyclotheonamide E4 (3) and E5 (4), from a marine sponge of the genus Ircinia. The structures of these molecules were determined by interpretation of 1H and 13C NMR spectra, and they were shown to be closely related to the previously reported cyclotheonamides E (1), E2, and E3 (2). These molecules contain two unusual amino acids, vinylogous tyrosine and alpha-ketohomoarginine, which are involved in strong activities against serine proteases. Cyclotheonamide E4 showed potent inhibitory activity against human tryptase (IC50 5.1 nM). Therefore, cyclotheonamide E4 may be useful as a therapeutic agent in the treatment of allergic diseases including asthma. | 3 | 2 | 12 | CHEMBL_2 | 2009-11-30 |
CHEMBL1121997 | Journal of medicinal chemistry. | 1 | Scientific Literature | 2-beta-D-Ribofuranosylthiazole-4-carboxamide, a novel potential antitumor agent for lung tumors and metastases. | 7057413 | 10.1021/jm00344a002 | nan | Robins RK, Srivastava PC, Narayanan VL, Plowman J, Paull KD. | 1982 | 25 | 2 | 107 | 108 | PUBLICATION | nan | 2 | 1 | 90 | CHEMBL_1 | 2009-09-03 |
CHEMBL1149191 | Journal of medicinal chemistry. | 1 | Scientific Literature | Novel pyridazino[4,3-b]indoles with dual inhibitory activity against Mycobacterium tuberculosis and monoamine oxidase. | 15189042 | 10.1021/jm030479g | nan | Velezheva VS, Brennan PJ, Marshakov VY, Gusev DV, Lisichkina IN, Peregudov AS, Tchernousova LN, Smirnova TG, Andreevskaya SN, Medvedev AE. | 2004 | 47 | 13 | 3455 | 3461 | PUBLICATION | Tuberculosis is one of the most common infectious diseases known to man. About 37% of the world's population (about 1.86 billion people) are infected with Mycobacterium tuberculosis. According to the World Health Organization, every year approximately 8 million people develop active tuberculosis and almost 2 million of those die from the disease. The incidence of multidrug-resistant tuberculosis (MDR-TB) is increasing. The present drug regimen for treating tuberculosis has been in existence for 30 years. New drugs that will shorten total treatment duration, improve the treatment of MDR-TB, and address latent tuberculosis are the most urgent need of tuberculosis control programs. A new series of synthetic 3-amino-4-arylpyridazino[4,3-b]indoles (pyridazinoindoles) were identified as inhibitors of Mycobacterium tuberculosis. The design, synthesis, and antimycobacterial activity of these compounds are described. While the most active compounds are still not comparable to the front-line drugs rifampicin and isoniazid, they do show promise. Most of the pyridazinoindoles with appreciable antituberculosis activity also inhibit monoamine oxidase, suggestive of a novel inhibitory effect on mycobacterial redox reactions. | 36 | 3 | 146 | CHEMBL_1 | 2009-09-03 |
CHEMBL1275454 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Assessment of Aspergillus fumigatus burden in pulmonary tissue of guinea pigs by quantitative PCR, galactomannan enzyme immunoassay, and quantitative culture. | 18474582 | 10.1128/aac.00276-08 | nan | Vallor AC, Kirkpatrick WR, Najvar LK, Bocanegra R, Kinney MC, Fothergill AW, Herrera ML, Wickes BL, Graybill JR, Patterson TF. | 2008 | 52 | 7 | 2593 | 2598 | PUBLICATION | Early diagnosis of invasive pulmonary aspergillosis is problematic in some patient groups due to the lack of rapid, sensitive, specific, and reliable diagnostic tests. Fungal burden and therapeutic efficacy were assessed by survival, quantitative culture (CFU counts), galactomannan enzyme immunoassay (GM-EIA), and quantitative PCR (qPCR) in a new guinea pig model of invasive pulmonary aspergillosis using an aerosol challenge. At 1 day postinfection, qPCR determined that the pulmonary fungal burden was 2 log(10) higher than that determined by CFU counting and increased significantly (P < 0.03) over time. In contrast, the tissue burden assessed by CFU counting did not rise over the course of the study. Therapy with the antifungal drug voriconazole produced statistically significant decreases in pulmonary fungal burden, as detected by CFU counting (P < 0.02), qPCR, and GM-EIA (both P < 0.0002). Daily assessment of the progression of fungal infection in serum was performed by qPCR and GM-EIA. GM-EIA demonstrated a statistically significant reduction in the fungal load on days 6 and 7 in voriconazole-treated animals compared to time-matched controls (P < 0.02). Confirmation of fungal tissue burden by two or more methods should provide a more precise account of the burden, allowing improved assessment of diagnostic and therapeutic strategies in invasive pulmonary aspergillosis. | 1 | 1 | 5 | CHEMBL_10 | 2011-05-26 |
CHEMBL1133887 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Anti-influenza virus activities of 2-alkoxyimino-n-(2-isoxazolin-3-ylmethyl)acetamides. | 11454466 | 10.1016/s0960-894x(01)00362-6 | nan | Kai H, Matsumoto H, Hattori N, Takase A, Fujiwara T, Sugimoto H. | 2001 | 11 | 15 | 1997 | 2000 | PUBLICATION | A series of 2-alkoxyimino-N-(2-isoxazolin-3-ylmethyl)acetamides and related compounds were synthesized and their antiviral activities against human influenza A virus were assessed. Studies of the structure-activity relationships revealed the strongest antiviral activity when position-5 of the isoxazoline ring was substituted with a tert-butyl group. When the alkoxyimino moiety was substituted with a methyl, ethyl, isopropyl or allyl group, good antiviral activity was obtained. Among the geometrical isomers at the oxime moiety, the E-isomers were more active than the Z-isomers. Among the compounds examined, (E)-2-allyloxyimino-2-cyano-N-(5-tert-butyl-2-isoxazolin-3-ylmethyl)acetamide (1j) was the most active inhibitor with an EC(50) of 3 microg/mL in vitro. | 25 | 1 | 50 | CHEMBL_1 | 2009-09-03 |
CHEMBL1129525 | Journal of medicinal chemistry. | 1 | Scientific Literature | Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations. | 8632434 | 10.1021/jm950760y | nan | Piper JR, Johnson CA, Krauth CA, Carter RL, Hosmer CA, Queener SF, Borotz SE, Pfefferkorn ER. | 1996 | 39 | 6 | 1271 | 1280 | PUBLICATION | 2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl groups attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3),CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 microM) with 14 compounds below 0.1 microM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 microM). As inhibitors of T gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 microM) and trimetrexate (0.010 microM), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 microM) and trimetrexate (0.042 microM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 microM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)2-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia. | 66 | 6 | 393 | CHEMBL_1 | 2009-09-03 |
CHEMBL1287784 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | A facile 1,3-dipolar cycloaddition of azomethine ylides to 2-arylidene-1,3-indanediones: synthesis of dispiro-oxindolylpyrrolothiazoles and their antimycobacterial evaluation. | 21071220 | 10.1016/j.bmcl.2010.10.080 | nan | Maheswari SU, Balamurugan K, Perumal S, Yogeeswari P, Sriram D. | 2010 | 20 | 24 | 7278 | 7282 | PUBLICATION | A facile 1,3-dipolar cycloaddition of azomethine ylide generated in situ from the reaction of 1,3-thiazolane-4-carboxylic acid and isatin to 2-arylidene-1,3-indanediones furnished novel dispiro-oxindolylpyrrolothiazoles regio- and stereo-selectively in moderate to good yields (60-92%). In vitro antitubercular screening of 27 compounds against Mycobacterium tuberculosis H37Rv (MTB) disclosed that spiro[5.3']-5'-nitrooxindolespiro-[6.3″]-1H-inden-1″,3″(2H)-dione-7-(4-bromophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole has the maximum potency with a minimum inhibitory concentration (MIC) of 1.4 μM against MTB, being 3.4 and 5.4 times more potent than ciprofloxacin and ethambutol, respectively. | 32 | 1 | 32 | CHEMBL_10 | 2011-05-26 |
CHEMBL1155354 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Carbonic anhydrase inhibitors. Inhibition of the Rv1284 and Rv3273 beta-carbonic anhydrases from Mycobacterium tuberculosis with diazenylbenzenesulfonamides. | 19651511 | 10.1016/j.bmcl.2009.07.088 | nan | Maresca A, Carta F, Vullo D, Scozzafava A, Supuran CT. | 2009 | 19 | 17 | 4929 | 4932 | PUBLICATION | A series of diazenylbenzenesulfonamides obtained from sulfanilamide or metanilamide by diazotization followed by coupling with phenols or amines, was tested for the inhibition of the beta-carbonic anhydrases (CAs, EC 4.2.1.1) encoded by the genes Rv1284 and Rv3273 of Mycobacterium tuberculosis. Several low micromolar inhibitors of the two enzymes were detected, with prontosil being the best inhibitor (K(I)s of 126-148nM). Inhibition of pathogenic beta-CAs may lead to the development of antiinfectives with a new mechanism of action, devoid of resistance problems encountered with classical antibiotics. | 22 | 3 | 62 | CHEMBL_4 | 2010-05-18 |
CHEMBL1152134 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. | 18930396 | 10.1016/j.bmcl.2008.09.105 | nan | Chiaradia LD, Mascarello A, Purificação M, Vernal J, Cordeiro MN, Zenteno ME, Villarino A, Nunes RJ, Yunes RA, Terenzi H. | 2008 | 18 | 23 | 6227 | 6230 | PUBLICATION | In the search for lead compounds for new drugs for tuberculosis, the activity of 38 synthetic chalcones were assayed for their potential inhibitory action towards a protein tyrosine phosphatase from Mycobacterium tuberculosis--PtpA. The compounds were obtained by aldolic condensation between aldehydes and acetophenones, under basic conditions. Five compounds presented moderate or good activity. The structure-activity analysis reveals that the predominant factor for the activity is the molecule planarity/hydrophobicity and the nature of the substituents. | 37 | 1 | 42 | CHEMBL_2 | 2009-11-30 |
CHEMBL1157363 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. | 17485499 | 10.1128/aac.01458-06 | nan | Ngo SC, Zimhony O, Chung WJ, Sayahi H, Jacobs WR, Welch JT. | 2007 | 51 | 7 | 2430 | 2435 | PUBLICATION | An analog of pyrazinamide (PZA), 5-chloropyrazinamide (5-Cl-PZA), has previously been shown to inhibit mycobacterial fatty acid synthase I (FASI). FASI has been purified from a recombinant strain of M. smegmatis (M. smegmatis Deltafas1 attB::M. tuberculosis fas1). Following purification, FASI activity and inhibition were assessed spectrophotometrically by monitoring NADPH oxidation. The observed inhibition was both concentration and structure dependent, being affected by both substitution at the 5 position of the pyrazine nucleus and the nature of the ester or N-alkyl group. Under the conditions studied, both 5-Cl-PZA and PZA exhibited concentration and substrate dependence consistent with competitive inhibition of FASI with K(i)s of 55 to 59 microM and 2,567 to 2,627 microM, respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. This assay showed that FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs. | 15 | 2 | 33 | CHEMBL_2 | 2009-11-30 |
CHEMBL1649263 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | In vitro activity of a new quinoline derivative, ER-2, against clinical isolates of Mycoplasma pneumoniae and Mycoplasma hominis. | 19738013 | 10.1128/aac.00746-09 | nan | Rao SS, Raghunathan R, Ekambaram R, Raghunathan M. | 2009 | 53 | 12 | 5317 | 5318 | PUBLICATION | nan | 10 | 2 | 51 | CHEMBL_11 | 2011-08-01 |
CHEMBL1153799 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis of sialic acid derivatives having a C=C double bond substituted at the C-5 position and their glycopolymers. | 19631531 | 10.1016/j.bmcl.2009.07.034 | nan | Suzuki K, Sakamoto J, Koyama T, Yingsakmongkon S, Suzuki Y, Hatano K, Terunuma D, Matsuoka K. | 2009 | 19 | 17 | 5105 | 5108 | PUBLICATION | Glycomonomers of sialic acid in which the acetamide group at C-5 was converted into two kinds of C=C double bond substituents were prepared and the fully protected glycomonomers were directly polymerized before deprotection steps. Radical polymerization with acrylamide in DMF in the presence of ammonium persulfate and N,N,N',N'-tetramethylethylenediamine proceeded smoothly and gave corresponding sialopolymers. Interestingly glycomonomers had hemagglutination inhibitory activities not only for H1N1 but also for H3N2 of human influenza virus strains. | 2 | 2 | 6 | CHEMBL_6 | 2010-08-27 |
CHEMBL1131489 | Journal of medicinal chemistry. | 1 | Scientific Literature | Dihydropyrancarboxamides related to zanamivir: a new series of inhibitors of influenza virus sialidases. 2. Crystallographic and molecular modeling study of complexes of 4-amino-4H-pyran-6-carboxamides and sialidase from influenza virus types A and B. | 9526556 | 10.1021/jm9703754 | nan | Taylor NR, Cleasby A, Singh O, Skarzynski T, Wonacott AJ, Smith PW, Sollis SL, Howes PD, Cherry PC, Bethell R, Colman P, Varghese J. | 1998 | 41 | 6 | 798 | 807 | PUBLICATION | The first paper in this series (see previous article) described structure-activity studies of carboxamide analogues of zanamivir binding to influenza virus sialidase types A and B and showed that inhibitory activity of these compounds was much greater against influenza A enzyme. To understand the large differences in affinities, a number of protein-ligand complexes have been investigated using crystallography and molecular dynamics. The crystallographic studies show that the binding of ligands containing tertiary amide groups is accompanied by the formation of an intramolecular planar salt bridge between two amino acid residues in the active site of the enzyme. It is proposed that the unexpected strong binding of these inhibitors is a result of the burial of hydrophobic surface area and salt-bridge formation in an environment of low dielectric. In sialidase from type A virus, binding of the carboxamide moeity and salt-bridge formation have only a minor effect on the positions of the surrounding residues, whereas in type B enzyme, significant distortion of the protein is observed. The results suggest that the decreased affinity in enzyme from influenza B is directly correlated with the small changes that occur in the amino acid residue interactions accompanying ligand binding. Molecular dynamics calculations have shown that the tendency for salt-bridge formation is greater in influenza A sialidase than influenza B sialidase and that this tendency is a useful descriptor for the prediction of inhibitor potency. | 9 | 2 | 18 | CHEMBL_1 | 2009-09-03 |
CHEMBL1124611 | Journal of medicinal chemistry. | 1 | Scientific Literature | Synthesis and antitubercular activity of N-(2-naphthyl)glycine hydrazide analogues. | 2509708 | 10.1021/jm00131a002 | nan | Ramamurthy B, Bhatt MV. | 1989 | 32 | 11 | 2421 | 2426 | PUBLICATION | N-(2-Naphthyl)glycine hydrazide analogues were synthesized and tested for possible in vitro antitubercular activity. N-(2-Naphthyl)alanine hydrazide (3), N-methyl-N-(2-naphthyl)glycine hydrazide (5), N-(6-methoxy-2-naphthyl)glycine hydrazide (7), and 3-(2-naphthylamino)butyric acid hydrazide (23) showed potent inhibitory action against Mycobacterium tuberculosis H37Rv in Youman's medium at concentrations ranging from 0.5 to 10.0 micrograms/mL. These compounds showed significant inhibitory action against isonicotinic acid hydrazide and streptomycin-resistant strains of M. tuberculosis. N-(6-Quinolyl)glycine hydrazide (18) and 3-(2-quinolylamino)butyric acid hydrazide (24), which are bioisosteres of compounds 1 and 23, showed loss of antitubercular activity at low concentrations. | 14 | 1 | 58 | CHEMBL_1 | 2009-09-03 |
CHEMBL1156416 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Influence of high mutation rates on the mechanisms and dynamics of in vitro and in vivo resistance development to single or combined antipseudomonal agents. | 17470655 | 10.1128/aac.00174-07 | nan | Plasencia V, Borrell N, Maciá MD, Moya B, Pérez JL, Oliver A. | 2007 | 51 | 7 | 2574 | 2581 | PUBLICATION | We studied the mechanisms and dynamics of the development of resistance to ceftazidime (CAZ) alone or combined with tobramycin (TOB) or ciprofloxacin (CIP) in vitro and in vivo (using a mouse model of lung infection with human antibiotic regimens). Pseudomonas aeruginosa strain PAO1 and its hypermutable derivative PAODeltamutS were used, and the results were compared with those previously obtained with CIP, TOB, and CIP plus TOB (CIP-TOB) under the same conditions. An important (200-fold) amplification of the number of resistant mutant cells was documented for PAODeltamutS-infected mice that were under CAZ treatment compared to the number for mice that received placebo, whereas the median number of resistant mutant cells was below the detection limits for mice infected by PAO1. These results were intermediate between the high amplification with CIP (50,000-fold) and the low amplification with TOB (10-fold). All CAZ-resistant single mutant cells selected in vitro or in vivo hyperproduced AmpC. On the other hand, the three combinations studied were found to be highly effective in the prevention of in vivo resistance development in mice infected with PAODeltamutS, although the highest therapeutic efficacy (in terms of mortality and total bacterial load reduction) compared to those of the individual regimens was obtained with CIP-TOB and the lowest was with CAZ-CIP. Nevertheless, mutant cells that were resistant to the three combinations tested were readily selected in vitro for PAODeltamutS (mutation rates from 1.2 x 10(-9) to 5.8 x 10(-11)) but not for PAO1, highlighting the potential risk for antimicrobial resistance development associated with the presence of hypermutable strains, even when combined therapy was used. All five independent CAZ-TOB-resistant PAODeltamutS double mutants studied presented the same resistance mechanism (AmpC hyperproduction plus an aminoglycoside resistance mechanism not related to MexXY), whereas four different combinations of resistance mechanisms were documented for the five CAZ-CIP-resistant double mutants. | 9 | 3 | 52 | CHEMBL_2 | 2009-11-30 |
CHEMBL1156807 | Journal of medicinal chemistry. | 1 | Scientific Literature | Catalysis and inhibition of Mycobacterium tuberculosis methionine aminopeptidase. | 20038112 | 10.1021/jm901624n | nan | Lu JP, Chai SC, Ye QZ. | 2010 | 53 | 3 | 1329 | 1337 | PUBLICATION | Methionine aminopeptidase (MetAP) carries out an important cotranslational N-terminal methionine excision of nascent proteins and represents a potential target to develop antibacterial and antitubercular drugs. We cloned one of the two MetAPs in Mycobacterium tuberculosis (MtMetAP1c from the mapB gene) and purified it to homogeneity as an apoenzyme. Its activity required a divalent metal ion, and Co(II), Ni(II), Mn(II), and Fe(II) were among activators of the enzyme. Co(II) and Fe(II) had the tightest binding, while Ni(II) was the most efficient cofactor for the catalysis. MtMetAP1c was also functional in E. coli cells because a plasmid-expressed MtMetAP1c complemented the essential function of MetAP in E. coli and supported the cell growth. A set of potent MtMetAP1c inhibitors were identified, and they showed high selectivity toward the Fe(II)-form, the Mn(II)-form, or the Co(II) and Ni(II) forms of the enzyme, respectively. These metalloform selective inhibitors were used to assign the metalloform of the cellular MtMetAP1c. The fact that only the Fe(II)-form selective inhibitors inhibited the cellular MtMetAP1c activity and inhibited the MtMetAP1c-complemented cell growth suggests that Fe(II) is the native metal used by MtMetAP1c in an E. coli cellular environment. Finally, X-ray structures of MtMetAP1c in complex with three metalloform-selective inhibitors were analyzed, which showed different binding modes and different interactions with metal ions and active site residues. | 8 | 1 | 48 | CHEMBL_4 | 2010-05-18 |
CHEMBL1125455 | Journal of medicinal chemistry. | 1 | Scientific Literature | Novel anthraquinone inhibitors of human leukocyte elastase and cathepsin G. | 1578486 | 10.1021/jm00087a014 | nan | Zembower DE, Kam CM, Powers JC, Zalkow LH. | 1992 | 35 | 9 | 1597 | 1605 | PUBLICATION | A large series of variously substituted anthraquinones has been synthesized and assayed for inhibitory capacity against human leukocyte elastase (HLE) and cathepsin G (CatG), two serine proteinases implicated in diseases characterized by the abnormal degradation of connective tissue, such as pulmonary emphysema and rheumatoid arthritis. It was found that 2-alkyl-1,8-dihydroxyanthraquinone analogues are competitive inhibitors of HLE with IC50 values ranging from 4 to 10 microM, and also inhibit CatG with IC50 values ranging from 25 to 55 microM. Consequently, analogues containing the 2-alkyl-1-hydroxy-8-methoxyanthraquinone substitution pattern inhibit HLE to the same magnitude as for the compounds above, but show very little inhibition of CatG. Anthraquinones containing long, hydrophobic n-butyl carbonate moieties in the 1- and 8-positions in conjunction with a third hydrophobic substituent in the 2- or 3-position are highly selective for HLE, with Ki values in the range of 10(-7) M. All of the inhibitors described are completely reversible, with no evidence of acyl-enzyme formation detected. | 52 | 4 | 153 | CHEMBL_1 | 2009-09-03 |
CHEMBL1147602 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | DNA binding ligands targeting drug-resistant Gram-positive bacteria. Part 1: Internal benzimidazole derivatives. | 14980676 | 10.1016/j.bmcl.2003.12.042 | nan | Bürli RW, McMinn D, Kaizerman JA, Hu W, Ge Y, Pack Q, Jiang V, Gross M, Garcia M, Tanaka R, Moser HE. | 2004 | 14 | 5 | 1253 | 1257 | PUBLICATION | Novel DNA minor-groove binding ligands with a promising antibacterial profile are described. Apart from excellent in vitro potency against multiple Gram-positive bacterial strains such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-intermediate Streptococcus pneumoniae (PISP), a small subset of compounds was active against Gram-negative bacteria such as Escherichia coli (E. coli). | 13 | 9 | 93 | CHEMBL_1 | 2009-09-03 |
CHEMBL1158387 | European journal of medicinal chemistry. | 1 | Scientific Literature | Regioselective synthetic approaches towards 1,2,8,9-tetraazadispiro[4.1.4.2]trideca-2,9-dien-6-ones of potential antimicrobial properties. | 19211175 | 10.1016/j.ejmech.2009.01.008 | nan | Girgis AS, Barsoum FF, Samir A. | 2009 | 44 | 6 | 2447 | 2451 | PUBLICATION | Reaction of 2,5-bis(arylmethylidene)cyclopentanones 1a-d with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a,b) in 1:2 molar ratio proceeds in a high regioselective manner affording monocycloadducts 3 and dicycloadducts in the form of two isomers 4, 5. Single crystal X-ray diffraction studies of the isolated crystalline form of 3c support the established structure and indicate that the formed product is 7E, 4S, 5R. Antimicrobial activity screening of the synthesized compounds 3-5, utilizing a variety of gram-positive (Staphylococcus aureus, Enterococcus fecalis and Streptococcus agalactiae), gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae and Proteus vulgaris) and yeast (Candida albicans), exhibited that all the prepared analogues acquire promising activities against both gram-positive and gram-negative bacteria especially compounds 3b, 4a (antimicrobial active agents against gram-positive bacteria) and 3c (antimicrobial active agent against gram-negative bacteria). | 12 | 7 | 84 | CHEMBL_3 | 2010-04-16 |
CHEMBL1687813 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Mutually exclusive genotypes for pyrazinamide and 5-chloropyrazinamide resistance reveal a potential resistance-proofing strategy. | 20876380 | 10.1128/aac.00529-10 | nan | Baughn AD, Deng J, Vilchèze C, Riestra A, Welch JT, Jacobs WR, Zimhony O. | 2010 | 54 | 12 | 5323 | 5328 | PUBLICATION | The pyrazinamide (PZA) analog 5-chloropyrazinamide (5-Cl PZA) is active against mycobacterial species, including PZA-resistant strains of Mycobacterium tuberculosis. In M. smegmatis, overexpression of the type 1 fatty acid synthase (FAS I) confers resistance to 5-Cl PZA, a potent FAS I inhibitor. Since M. tuberculosis and M. bovis cannot tolerate FAS I overexpression, 5-Cl PZA resistance mutations have yet to be described for tubercle bacilli. In an attempt to identify other factors that govern the activity of 5-Cl PZA, we selected for 5-Cl PZA-resistant isolates from a library of transposon-mutagenized M. smegmatis isolates. Here, we report that increased expression of the M. smegmatis pyrazinamidase PzaA confers resistance to 5-Cl PZA and susceptibility to PZA in M. smegmatis, M. tuberculosis, and M. bovis. In contrast, while ectopic overexpression of the M. tuberculosis pyrazinamidase PncA increases PZA susceptibility, this amidase does not mediate resistance to 5-Cl PZA. We conclude that PncA-independent turnover of 5-Cl PZA represents a potential mechanism of resistance to this compound for M. tuberculosis, which will likely translate into enhanced PZA susceptibility. Thus, countersusceptibility can be manipulated as a resistance-proofing strategy for PZA-based compounds when these agents are used simultaneously. | 3 | 9 | 78 | CHEMBL_11 | 2011-08-01 |
CHEMBL1130482 | Bioorganic & medicinal chemistry letters. | 1 | Scientific Literature | Synthesis and activity of C2-substituted analogs of influenza neuraminidase inhibitor GS 4071 | nan | 10.1016/S0960-894X(97)00331-4 | nan | Zhang L, Williams MA, Mendel DB, Escarpe PA, Kim CU | 1997 | 7 | 14 | 1847 | 1850 | PUBLICATION | nan | 4 | 1 | 4 | CHEMBL_1 | 2009-09-03 |
CHEMBL1152948 | Bioorganic & medicinal chemistry. | 1 | Scientific Literature | Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations. | 19467603 | 10.1016/j.bmc.2009.04.055 | nan | Zampieri D, Mamolo MG, Laurini E, Fermeglia M, Posocco P, Pricl S, Banfi E, Scialino G, Vio L. | 2009 | 17 | 13 | 4693 | 4707 | PUBLICATION | 3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H(37)Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14alpha-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values. | 35 | 1 | 37 | CHEMBL_3 | 2010-04-16 |
CHEMBL1154173 | European journal of medicinal chemistry. | 1 | Scientific Literature | L-proline-catalysed facile green protocol for the synthesis and antimycobacterial evaluation of [1,4]-thiazines. | 19781824 | 10.1016/j.ejmech.2009.09.001 | nan | Indumathi S, Perumal S, Banerjee D, Yogeeswari P, Sriram D. | 2009 | 44 | 12 | 4978 | 4984 | PUBLICATION | A series of ethyl 6-(4-chlorobenzoyl)-1,1-dioxo-3,5-diaryl-1,4-thiazinane-2-carboxylates was prepared in good yields (72-90%) from the reaction of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate, substituted aromatic aldehydes and amines in presence of green catalyst, L-proline. These compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) using agar dilution method. Ethyl 6-(4-chlorobenzoyl)-3,5-di(4-nitrophenyl)-1,1-dioxo-1,4-thiazinane-2-carboxylate was found to be the most promising compound (MIC: 0.68 microM) active against MTB and MDR-TB. | 31 | 2 | 93 | CHEMBL_4 | 2010-05-18 |
CHEMBL1129595 | Journal of medicinal chemistry. | 1 | Scientific Literature | Potent 6-desfluoro-8-methylquinolones as new lead compounds in antibacterial chemotherapy. | 8960555 | 10.1021/jm960414w | nan | Cecchetti V, Fravolini A, Palumbo M, Sissi C, Tabarrini O, Terni P, Xin T. | 1996 | 39 | 25 | 4952 | 4957 | PUBLICATION | In a furtherance of our SAR study on the C-6 position of quinolone antibacterials, a series of 6-desfluoro-8-methylquinolones were synthesized and evaluated for their in vitro antimicrobial activity. As a result of this study, compounds with strong activity against Gram-positive bacteria, including ciprofloxacin-resistant and methicillin-resistant Staphylococcus aureus, were identified. The best Gram-positive antibacterial activity was exhibited by piperidinyl derivative 6c, which was 17 times more potent than ciprofloxacin and displayed extremely high activity against Streptococcus pneumoniae with an MIC value of <0.016 microg/mL. Thus, we have shown that substituent combinations in the quinolone ring, excluding the C-6 fluorine atom, might produce powerful antibacterial agents. | 22 | 14 | 448 | CHEMBL_1 | 2009-09-03 |
CHEMBL1671681 | Antimicrobial agents and chemotherapy. | 1 | Scientific Literature | Distribution of serotypes, genotypes, and resistance determinants among macrolide-resistant Streptococcus pneumoniae isolates. | 20065057 | 10.1128/aac.01268-09 | nan | Xu X, Cai L, Xiao M, Kong F, Oftadeh S, Zhou F, Gilbert GL. | 2010 | 54 | 3 | 1152 | 1159 | PUBLICATION | Macrolide resistance in Streptococcus pneumoniae has emerged as an important clinical problem worldwide over the past decade. The aim of this study was to analyze the phenotypes (serotype and antibiotic susceptibility), genotypes (multilocus sequence type [MLST] and antibiotic resistance gene/transposon profiles) among the 31% (102/328) of invasive isolates from children in New South Wales, Australia, in 2005 that were resistant to erythromycin. Three serotypes--19F (47 isolates [46%]), 14 (27 isolates [26%]), and 6B (12 isolates [12%])--accounted for 86 (84%) of these 102 isolates. Seventy four (73%) isolates had the macrolide-lincosamide-streptogramin B (MLS(B)) resistance phenotype and carried Tn916 transposons (most commonly Tn6002); of these, 73 (99%) contained the erythromycin ribosomal methylase gene [erm(B)], 34 (47%) also carried the macrolide efflux gene [mef(E)], and 41 (55%) belonged to serotype 19F. Of 28 (27%) isolates with the M phenotype, 22 (79%) carried mef(A), including 16 (57%) belonging to serotype 14, and only six (19%) carried Tn916 transposons. Most (84%) isolates which contained mef also contained one of the msr(A) homologues, mel or msr(D); 38 of 40 (95%) isolates with mef(E) (on mega) carried mel, and of 28 (39%) isolates with mef(A), 10 (39%) carried mel and another 11(39%) carried msr(D), on Tn1207.1. Two predominant macrolide-resistant S. pneumoniae clonal clusters (CCs) were identified in this population. CC-271 contained 44% of isolates, most of which belonged to serotype 19F, had the MLS(B) phenotype, were multidrug resistant, and carried transposons of the Tn916 family; CC-15 contained 23% of isolates, most of which were serotype 14, had the M phenotype, and carried mef(A) on Tn1207.1. Erythromycin resistance among S. pneumoniae isolates in New South Wales is mainly due to the dissemination of multidrug-resistant S. pneumoniae strains or horizontal spread of the Tn916 family of transposons. | 14 | 1 | 70 | CHEMBL_11 | 2011-08-01 |
CHEMBL1156774 | Journal of medicinal chemistry. | 1 | Scientific Literature | Design of O-acetylserine sulfhydrylase inhibitors by mimicking nature. | 19928859 | 10.1021/jm901325e | nan | Salsi E, Bayden AS, Spyrakis F, Amadasi A, Campanini B, Bettati S, Dodatko T, Cozzini P, Kellogg GE, Cook PF, Roderick SL, Mozzarelli A. | 2010 | 53 | 1 | 345 | 356 | PUBLICATION | The inhibition of cysteine biosynthesis in prokaryotes and protozoa has been proposed to be relevant for the development of antibiotics. Haemophilus influenzae O-acetylserine sulfhydrylase (OASS), catalyzing l-cysteine formation, is inhibited by the insertion of the C-terminal pentapeptide (MNLNI) of serine acetyltransferase into the active site. Four-hundred MNXXI pentapeptides were generated in silico, docked into OASS active site using GOLD, and scored with HINT. The terminal P5 Ile accounts for about 50% of the binding energy. Glu or Asp at position P4 and, to a lesser extent, at position P3 also significantly contribute to the binding interaction. The predicted affinity of 14 selected pentapeptides correlated well with the experimentally determined dissociation constants. The X-ray structure of three high affinity pentapeptide-OASS complexes were compared with the docked poses. These results, combined with a GRID analysis of the active site, allowed us to define a pharmacophoric scaffold for the design of peptidomimetic inhibitors. | 14 | 1 | 28 | CHEMBL_4 | 2010-05-18 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.