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

ABSTRACT: 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 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. 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 ?g/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).

SUBMITTER: Anguru MR

PROVIDER: S-EPMC5524660 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Anguru Mohana Rao MR Taduri Ashok Kumar AK Bhoomireddy Rama Devi RD Jojula Malathi M Gunda Shravan Kumar SK

Chemistry Central journal 20170724 1

<h4>Background</h4>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.<h4>Findings</h4>A series of novel 2-heterostyrylbenzimidazole derivatives were synthesised by cyclisation of (3,4-diaminophenyl)(phenyl)methanone, cinnamic acid ...[more]

PMID: 29086847

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Project description:BACKGROUND: Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis, killing ~1.7 million people annually. The remarkable capacity of this pathogen to escape the host immune system for decades and then to cause active tuberculosis disease, makes M.tb a successful pathogen. Currently available anti-mycobacterial therapy has poor compliance due to requirement of prolonged treatment resulting in accelerated emergence of drug resistant strains. Hence, there is an urgent need to identify new chemical entities with novel mechanism of action and potent activity against the drug resistant strains. RESULTS: This study describes novel computational models developed for predicting inhibitors against both replicative and non-replicative phase of drug-tolerant M.tb under carbon starvation stage. These models were trained on highly diverse dataset of 2135 compounds using four classes of binary fingerprint namely PubChem, MACCS, EState, SubStructure. We achieved the best performance Matthews correlation coefficient (MCC) of 0.45 using the model based on MACCS fingerprints for replicative phase inhibitor dataset. In case of non-replicative phase, Hybrid model based on PubChem, MACCS, EState, SubStructure fingerprints performed better with maximum MCC value of 0.28. In this study, we have shown that molecular weight, polar surface area and rotatable bond count of inhibitors (replicating and non-replicating phase) are significantly different from non-inhibitors. The fragment analysis suggests that substructures like hetero_N_nonbasic, heterocyclic, carboxylic_ester, and hetero_N_basic_no_H are predominant in replicating phase inhibitors while hetero_O, ketone, secondary_mixed_amine are preferred in the non-replicative phase inhibitors. It was observed that nitro, alkyne, and enamine are important for the molecules inhibiting bacilli residing in both the phases. In this study, we introduced a new algorithm based on Matthews correlation coefficient called MCCA for feature selection and found that this algorithm is better or comparable to frequency based approach. CONCLUSION: In this study, we have developed computational models to predict phase specific inhibitors against drug resistant strains of M.tb grown under carbon starvation. Based on simple molecular properties, we have derived some rules, which would be useful in robust identification of tuberculosis inhibitors. Based on these observations, we have developed a webserver for predicting inhibitors against drug tolerant M.tb H37Rv available at http://crdd.osdd.net/oscadd/mdri/.

Dataset Information

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

Publications

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

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