1-Substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their isosteric analogs: A new class of selective antitubercular agents active against drug-susceptible and multidrug-resistant mycobacteria
Language English Country France Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24927053
DOI
10.1016/j.ejmech.2014.05.069
PII: S0223-5234(14)00501-7
Knihovny.cz E-resources
- Keywords
- Antituberculosis drug, Mycobacterium, Selectivity, Structure–activity relationships, Tetrazole, Tuberculosis,
- MeSH
- Antitubercular Agents chemical synthesis chemistry pharmacology MeSH
- Hep G2 Cells MeSH
- HeLa Cells MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Drug Resistance, Multiple, Bacterial drug effects MeSH
- Molecular Structure MeSH
- Mycobacterium tuberculosis drug effects MeSH
- Tumor Cells, Cultured MeSH
- Nitrobenzenes chemical synthesis chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Triazoles chemical synthesis chemistry pharmacology MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antitubercular Agents MeSH
- Nitrobenzenes MeSH
- Antineoplastic Agents MeSH
- Triazoles MeSH
In this work, a new class of highly potent antituberculosis agents, 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their oxa and selanyl analogs, is described. The minimal inhibitory concentration (MIC) values reached 1 μM (0.36-0.44 μg/mL) against Mycobacterium tuberculosis CNCTC My 331/88 and 0.25-1 μM against six multidrug-resistant clinically isolated strains of M. tuberculosis. The antimycobacterial effects of these compounds were highly specific because they were ineffective against all eight bacterial strains and eight fungal strains studied. Furthermore, these compounds exhibited low in vitro toxicity in four mammalian cell lines (IC50 > 30 μM). We also examined the structure-activity relationships of the compounds, particularly the effects on antimycobacterial activity of the number and position of the nitro groups, the linker between tetrazole and benzyl moieties, and the tetrazole itself. Relatively high variability of substituent R(1) on the tetrazole in the absence of negative effects on antimycobacterial activity allows further structural optimization with respect to toxicity and the ADME properties of the 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles lead compounds.
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