Journal of Medicinal Chemistry p. 2362 - 2380 (2016)
Update date:2022-08-15
Topics:
Karabanovich, Galina
Zemanová, Júlia
Smutny, Tomá?
Székely, Rita
?arkan, Michal
Centárová, Ivana
Vocat, Anthony
Pávková, Ivona
?onka, Patrik
Něme?ek, Jan
Stola?íková, Ji?ina
Vejsová, Marcela
Vávrová, Kate?ina
Klime?ová, Věra
Hrabálek, Alexandr
Pávek, Petr
Cole, Stewart T.
Miku?ová, Katarína
Roh, Jaroslav
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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