Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Antitubercular Agents chemical synthesis pharmacology toxicity MeSH
- Bacteria drug effects MeSH
- Cell Line MeSH
- Fungi drug effects MeSH
- Latent Tuberculosis drug therapy microbiology MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Microsomes metabolism MeSH
- Drug Resistance, Multiple, Bacterial MeSH
- Mutagens toxicity MeSH
- Mycobacterium tuberculosis drug effects MeSH
- Oxazoles chemical synthesis pharmacology MeSH
- Primary Cell Culture MeSH
- Drug Design MeSH
- Rifampin pharmacology MeSH
- Thiadiazoles chemical synthesis pharmacology MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antitubercular Agents MeSH
- Mutagens MeSH
- Oxazoles MeSH
- Rifampin MeSH
- Thiadiazoles MeSH
Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.
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