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. 911 - 937
• 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: England 01.11.2016
• Subjects: Animals; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cercopithecus aethiops; Drug Design; Drug Resistance, Multiple, Bacterial; Methane - analogs & derivatives; Methane - chemical synthesis; Methane - chemistry; Methane - pharmacology; Microbial Sensitivity Tests; Mycobacterium tuberculosis - drug effects; Quantitative Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Tuberculosis - drug therapy; Vero Cells; anti-tuberculosis; trisubstituted methanes; M. Tb H37Rv; Mycobacterium tuberculosis; 3D-QSAR; CoMFA; CoMSIA
• ISSN: 1029-046X

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 and r 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.