Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis

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.