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.
- MeSH
- antituberkulotika chemická syntéza farmakologie toxicita MeSH
- Bacteria účinky léků MeSH
- buněčné linie MeSH
- houby účinky léků MeSH
- latentní tuberkulóza farmakoterapie mikrobiologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mikrozomy metabolismus MeSH
- mnohočetná bakteriální léková rezistence MeSH
- mutageny toxicita MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- oxazoly chemická syntéza farmakologie MeSH
- primární buněčná kultura MeSH
- racionální návrh léčiv MeSH
- rifampin farmakologie MeSH
- thiadiazoly chemická syntéza farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
