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

• Published in: SAR and QSAR in environmental research Vol. 27; no. 11; pp. 883 - 909
• Main Authors: Singh, P., Saha, T., Mishra, P., Parai, M. K., Ireddy, S., Lavanya Kumar M., S., Krishna, S., Kumar, S. K., Chaturvedi, V., Sinha, S., Siddiqi, M. I., Panda, G.
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 01.11.2016
• Subjects: 3D-QSAR; anti-tuberculosis; CoMFA; CoMSIA; M. Tb H37Rv; Mycobacterium tuberculosis; trisubstituted methanes
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2016.1243575

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 q 2 and r 2 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.