Additional synthesis on thiophene-containing trisubstituted methanes (TRSMs) as inhibitors of M. tuberculosis and 3D-QSAR studies

Abstract

We earlier reported thiophene-containing trisubstituted methanes (TRSMs) as novel cores carrying anti-tubercular activity, and identified S006-830 as the phenotypic lead with potent bactericidal activity against single- and multi-drug resistant clinical isolates of Mycobacterium tuberculosis (M. tb). In this work, we carried out additional synthesis of several TRSMs. The reaction scheme essentially followed the Grignard reaction and Friedel–Crafts alkylation, followed by insertion of a dialkylaminoethyl chain. We also performed microbiological evaluations including in vitro screening against the virulent strain M. tb H37Rv, cytotoxicity assessment in the Vero C-1008 cell line, and 3D-QSAR studies with comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). CoMFA and CoMSIA models yielded good statistical results in terms of q² and r² values, suggesting the validity of the models. It was concluded that a para-substituted benzene ring with bulkier electron-donating groups and aminoalkyl chains are required for higher inhibitory capacity against M. tuberculosis. We believe that these insights will rationally guide the design of newer, optimal, TRSMs.

Keywords:

• Mycobacterium tuberculosis
• trisubstituted methanes
• 3D-QSAR
• CoMFA
• CoMSIA
• anti-tuberculosis
• M. Tb H37Rv

Acknowledgements

TS thanks project fellowship (BSC 0104), SK thanks ICMR for a fellowship, PS thanks CSIR, SI thanks project fellowship (HCP0001P) and PM thanks TATA-CSIR-OSDD for fellowships. This manuscript bears CDRI communication number 9355.