Pharmacophore mapping, molecular docking, chemical synthesis of some novel pyrrolyl benzamide derivatives and evaluation of their inhibitory activity against enoyl-ACP reductase (InhA) and Mycobacterium tuberculosis

• Published in: Bioorganic chemistry Vol. 81; pp. 440 - 453
• Main Authors: Joshi, Shrinivas D., Dixit, Sheshagiri R., Basha, Jeelan, Kulkarni, V.H., Aminabhavi, Tejraj M., Nadagouda, Mallikarjuna N., Lherbet, Christian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2018; Elsevier
• Subjects: A549 Cells; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Benzamides - chemistry; Benzamides - pharmacology; Catalytic Domain - drug effects; Chemical Sciences; Drug Design; Enoyl-ACP reductase; GALAHAD; Humans; InhA; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis - chemistry; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - metabolism; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - chemistry; Oxidoreductases - metabolism; Pyrroles; Tuberculosis; Enoyl-ACP reductase; Tuberculosis; InhA; Pyrroles; GALAHAD
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.08.035

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•A series of pyrrolyl benzamide derivatives have been designed and synthesized.•Compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral analysis.•Compounds were evaluated antitubercular activity against Mycobacterium tuberculosis H37Rv and MDR-TB.•All the compounds exhibited good antimicrobial activities.
In an effort to produce new lead antimycobacterial compounds, herein we have reported the synthesis of a sequence of new pyrrolyl benzamide derivatives. The new chemical entities were screened to target enoyl-ACP reductase enzyme, which is one of the key enzymes of M. tuberculosis that are involved in type II fatty acid biosynthetic pathway. Compound 3q exhibited H-bonding interactions with Tyr158, Thr196 and co-factor NAD+ that binds the active site of InhA. All the pyrrolyl benzamide compounds were evaluated as inhibitors of M. tuberculosis H37Rv as well as inhibitors of InhA. Among them, few representative compounds were tested for mammalian cell toxicity on the human lung cancer cell-line (A549) and MV cell line that presented no cytotoxicity. Five of these compounds exhibited a good activity against InhA.