Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA |
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Authors: | Mahamadhanif S Shaikh Ashish M Kanhed Balakumar Chandrasekaran Mahesh B Palkar Nikhil Agrawal Christian Lherbet Girish A Hampannavar Rajshekhar Karpoormath |
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Institution: | 1. Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (UKZN), Westville, Durban 4001, South Africa;2. Laboratoire SPCMIB, UMR CNRS 5068, Université Paul Sabatier-Toulouse III, 118 route de Narbonne, 31062 Toulouse Cedex 9, France;3. ITAV‐USR3505, CNRS, Université Paul Sabatier-Toulouse III, Toulouse, France |
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Abstract: | InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H37Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 µM concentration and IC50 of 2.82 µM against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe. |
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Keywords: | Corresponding author Tuberculosis InhA inhibitor Carbazole Hybridization GLIDE Molecular dynamics |
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