Novel drug targets for Mycobacterium tuberculosis: 2-heterostyrylbenzimidazoles as inhibitors of cell wall protein synthesis.

BACKGROUND: Multi drug-resistant and mycobacterial infections are a major public health challenge, leading to high mortality and socioeconomic burdens through worldwide. Novel therapeutics are necessary to treat the drug resistant strains, since no new chemical entities are emerged in the last four decades for the treatment of TB. FINDINGS: A series of novel 2-heterostyrylbenzimidazole derivatives were synthesised by cyclisation of (3,4-diaminophenyl)(phenyl)methanone, cinnamic acid using glycerol in high yield. The molecular structures of target compounds (5a-5n) were confirmed by (1)H and (13)C NMR spectroscopy and mass spectrometry. Newly synthesized compounds were screened for anti-tubercular activity and the MIC was determined against Mycobacterium tuberculosis H(37)Rv by broth microdilution method using Lowenstein Jensen medium (LJ). These compounds docked into the active site of "Crystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid" (PDB code, 3IVX). Auto dock 4.2 software was used for docking studies. RESULTS: 5d, 5e, 5f, 5g, 5i, and 5l show better activity and the most active inhibitor of tuberculosis 5f showed a promising inhibition of M. tuberculosis with MIC value of 16 μg/mL. The molecules functionalized with electron-donating groups (Cl, O, S, etc.) on different aromatic aldehydes (5a-5n) were found to be more active in inhibiting M. tuberculosis. CONCLUSIONS: On the basis of docking studies, 5f has shown good affinity for the enzyme. Comparison was made with the binding energies of the standard drugs amoxicillin (-34.28 kcal/mol) and ciprofloxacin (-28.20 kcal/mol). Among all the designed compounds, the compound 5f shows highest binding energy with two amino acid interactions Lys160, Val187 (-9.80 kcal/mol).