Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis
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- 作者：Galina Karabanovich ; Júlia Zemanová ; Tomáš Smutný ; Rita Székely ; Michal Šarkan ; Ivana Centárová ; Anthony Vocat ; Ivona Pávková ; Patrik Čonka ; Jan Němeček ; Jiřina Stolaříková ; Marcela Vejsová ; Kateřina Vávrová ; Věra Klimešová ; Alexandr Hrabálek ; Petr Pávek ; Stewart T. Cole ; Katarína Mikušová ; Jaroslav Roh
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：March 24, 2016
- 年：2016
- 卷：59
- 期：6
- 页码：2362-2380
- 全文大小：613K
- ISSN：1520-4804
文摘
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.