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

Mohana Rao Anguru,Shravan Kumar Gunda,Ashok Kumar Taduri,Malathi Jojula,Rama Devi Bhoomireddy

doi:10.1186/s13065-017-0295-z

Abstract

BackgroundMulti 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.FindingsA 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 1H and 13C NMR spectroscopy and mass spectrometry. Newly synthesized compounds were screened for anti-tubercular activity and the MIC was determined against Mycobacterium tuberculosis H37Rv 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.Results5d, 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.ConclusionsOn 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).

Highlights

Multi drug-resistant and mycobacterial infections are a major public health challenge, leading to high mortality and socioeconomic burdens through worldwide
Comparison was made with the binding energies of the standard drugs amoxicillin (−34.28 kcal/mol) and ciprofloxacin (−28.20 kcal/mol)
In an attempt to look for better bioactive heterocyclic compounds containing nitrogen hetero atom, our consideration curved in the direction of benzimidazole derivatives, as these compounds exhibit a wide spectrum of biological activities including antituberculous activity [7]

Summary

Introduction

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. In an attempt to look for better bioactive heterocyclic compounds containing nitrogen hetero atom (since most of antituberculosis compounds are based on either pyridine or pyrazines), our consideration curved in the direction of benzimidazole derivatives, as these compounds exhibit a wide spectrum of biological activities including antituberculous activity [7]. This nucleus is a constituent of vitamin-B12 and many currently existing medications [8]. Almost all benzimidazoles with different heterocyclic substituents led to essential modification in their physico-chemical, metabolic and pharmacokinetic properties [9]

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Conclusion