Abstract

3D-QSAR DRIVEN DESIGN, SYNTHESIS AND EVALUATION OF NOVEL BIPHENYL DERIVATIVES OF BENZIMIDAZOLE (PA-824 ANALOGUES) AS ANTI-TUBERCULAR AGENTS

Sazid Ali* and Shailendra Sharma

Abstract

A series of novel biphenyl derivatives of benzimidazole (PA-824 analogues) as anti-tubercular agents was synthesised, characterised and evaluated for their anti-mycobacterial activity, by using an in silico design and 3D-QSAR-driven approach. Initially, we developed SAR rules and 3D-QSAR models using literature data for targeted design of new biphenyl derivatives of PA-824 analogues with anti-TB activity. Using these models, we prioritized 12 compounds for synthesis and biological evaluation. As a result compound 6c & 6d were 2.5 and 2 fold more active against M. tuberculosis when compared to the standard drug RMP (MICs of 0.04 and 0.05 μg mL-1 respectively) while compound 6e & 6f having 3-fluoro-4-methoxy and 3-fluoro-4-trifluoromethoxy groups at ring B were found to be equally potent to standard drug RMP (MICs of 0.09 and 0.12 μg mL-1 respectively).

Keywords: 3D-QSAR, Mycobacterium tuberculosis, tuberculosis, drug design, benzimidazole, PA-824.