3D QSAR-based design and liquid phase combinatorial synthesis of 1,2-disubstituted benzimidazole-5-carboxylic acid and 3-substituted-5 H -benzimidazo[1,2- d ][1,4]benzodiazepin-6(7 H )-one derivatives as anti-mycobacterial agents

Tuberculosis (TB) is one of the world's deadliest infectious diseases, caused by ( ). In the present study, a 3D QSAR study was performed for the design of novel substituted benzimidazole derivatives as anti-mycobacterial agents. The anti-tubercular activity of the designed compounds was predicted using the generated 3D QSAR models. The designed compounds which showed better activity were synthesized as 1,2-disubstituted benzimidazole-5-carboxylic acid derivatives (series 1) and 3-substituted-5 -benzimidazo[1,2- ][1,4]benzodiazepin-6(7 )-one derivatives (series 2) using the liquid phase combinatorial approach using a soluble polymer assisted support (PEG5000). The compounds were characterized by H-NMR, C-NMR, FTIR and mass spectrometry. HPLC analysis was carried out to evaluate the purity of the compounds. We observed that the synthesised compounds inhibited the growth of intracellular H Rv in a bactericidal manner. The most active compound displayed an MIC value of 0.0975 μM against the H Rv strain in liquid cultures. The lead compound was also able to inhibit the growth of intracellular mycobacteria in THP-1 macrophages.