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J Med Chem. 2016 Mar 24;59(6):2362-80. doi: 10.1021/acs.jmedchem.5b00608. Epub 2016 Mar 15.

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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Faculty of Pharmacy in Hradec Králové, Charles University in Prague , Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
Faculty of Natural Sciences, Department of Biochemistry, Comenius University in Bratislava , Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia.
Ecole Polytechnique Fédérale de Lausanne, Global Health Institute , CH-1015 Lausanne, Switzerland.
Faculty of Military Health Sciences, Department of Molecular Pathology and Biology, University of Defence , Třebešská 1575, 50005 Hradec Králové, Czech Republic.
Department of Bacteriology and Mycology, Regional Institute of Public Health , Partyzánské náměstí 7, 70200 Ostrava, Czech Republic.


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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