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

Abstract

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.

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

“…Furthermore, studies were performed which attempted to characterize the possible target of the compounds. In vitro studies suggested that compounds ( 1 ) and ( 2 ) could act inhibiting the synthesis of nucleic acids [13]. The same research group has reported a new series of 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as promising antitubercular agents.…”

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

“…Structure activity relationship studies demonstrated that the 3,5 dinitro phenyl fragment to be the crucial in conferring anti-mycobacterial activity. [138][139][140] Any changes in position of the dinitro group led to the loss or several fold decrease of anti-TB activity. An AMES test indicated these nitro group-containing compounds have no mutagenic activity.…”

Synthesis and Antioxidant Activity of Bis (Aroyl/Arylsulfonyl Ethenesulfonylmethylazolyl)Pyridines

“…Among five membered heterocyclic compounds, azoles such as oxadiazoles, thiadiazoles, and triazoles are an indispensable class of heterocyclic family to display diverse pharmaceutical as well as biological applications . 1,3,4‐Oxadiazole and their derivatives presents antioxidant antimicrobial and anticonvulsant properties.…”