Synthesis, antituberculosis activity and QSAR study of some novel 2-(nitroaryl)-5-(nitrobenzylsulfinyl and sulfonyl)-1,3,4-thiadiazole derivatives

Abstract

Background and the purpose of the study: In continuation of our research program for new antitubercular agents, some hybrid compounds containing a 5-nitrohetrocyle and 1,3,4-thiadiazole ring havae been synthesized and their antituberculosis activity have been evaluated. QSAR studies were subsequently used to find the structural requirements for activity of this series of compounds.

Methods: 2-(nitroaryl)-5-(nitrobenzylsulfinyl and sulfonyl)-1,3,4-thiadiazole derivatives, have been synthesized and evaluated against Mycobacterium tuberculosis H37Rv (ATCC27294) in BACTEC 12B medium using a broth micro dilution assay. The minimum inhibitory concentration (MIC) was determined for compounds that demonstrated ≥ 90% growth inhibition in the primary screening. A QSAR study was performed on percentage of inhibition of the corresponding compounds using multiple linear regressions. The predictive ability of the obtained model was verified by cross-validation and chance correlation. The final model showed that the calculated and predicted activities are in good agreement with their observed antituberculosis activities (R (cross-validation) = 0.87).

Results and major conclusion: Results of the biological assay showed that three compounds (8c, 9a, 10b) were antimycobacterial agents showing MIC value of 6.25 µg.ml-1.It was also concluded that all three active compounds belong to nitroimidazoles and sulfonyl compound 9a, was the most active analogue. The results of QSAR study demonstrated that electronic distribution is among the most important determining factors for activity in this series of compounds.