Synthesis and QSAR Studies of Benzimidazole Analogues for Antitubercular Activity

Abstract

Filamenting temperature-sensitive mutant (FtsZ) is an essential bacterial cell division protein and highly promising therapeutic target especially for the discovery of novel antitubercular agents. The present study described molecular docking study, synthesis, structure elucidations, in vitro antitubercular activity, cytotoxicity assay, intracellular and extracellular macrophage assay, anticancer activity and FtsZ target confirmation study of all the targeted synthesized (R)-2-(4'- chlorophenyl)-3-(4'-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2-c]pyrimidin-4-ol derivatives and 3-amino-3-(3,4-dimethoxyphenyl)-2-(p-tolyl)-1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-c] pyrimidin-4-ol derivatives. These benzimidazole derivatives were designed, synthesized and docked on the FtsZ protein crystal structure (PDB Id: 1RLU, resolution 2.08 Å) through rational drug design. We have synthesized and evaluated series of cyclic substituted benzimidazole derivatives in good yields. Compound 7m and 7o showed potent in vitro antitubercular activity 0.012 μg/mL and 0.020 μg/mL against M. tb H37Rv. All the synthesized compounds showed very low in vitro cytotoxicity against VERO cells. Compound 7m and 7o have passed intracellular and extracellular tuberculosis infected macrophage assay. In addition, compound 7d, 7i, 7n, 8h and 8k expressed potent anticancer activity against A549, MDA-MB- 231, KB and KB-VIN human tumor cell lines respectively. Most of the synthesized compounds were found to be good FtsZ inhibitor. The potency, selectivity and low cytotoxicity of benzimidazole derivatives make them valid leads for improved antitubercular and anticancer drug developments.