Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA

• Published in: Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (16), p.2338-2344
• Main Authors: Shaikh, Mahamadhanif S., Kanhed, Ashish M., Chandrasekaran, Balakumar, Palkar, Mahesh B., Agrawal, Nikhil, Lherbet, Christian, Hampannavar, Girish A., Karpoormath, Rajshekhar
• Format: Article
• Language: English
• Subjects: Carbazole; Chemical Sciences; GLIDE; Hybridization; InhA inhibitor; Molecular dynamics; Tuberculosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.06.015

Synthesis, spectral studies antimycobacterial, InhA enzyme inhibition and cytotoxicity evaluation of novel carbazole hybrid compounds are described. [Display omitted] •Novel N-methyl carbazole tethered rhodanines were synthesized and characterized.•All of them were evaluated against Mtb virulent cell line and InhA enzyme inhibition.•9e displayed promising inhibition at IC50 2.82 µM against InhA.•Cytotoxicity data suggested that the compounds are safe.•Molecular docking and molecular dynamics supported the in vitro results. 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.