Indole-2-carboxamides as New Anti-Mycobacterial Agents: Design, Synthesis, Biological Evaluation and Molecular Modeling against mmpL3

摘要

Tuberculosis (TB), an airborne disease caused by Mycobacterium tuberculosis, has infected millions of people and been responsible for their deaths. Toward the anti-TB endeavor, the synthesis of total twenty-four indole-2-carboxamide derivatives as potent anti-TB agents have been carried out using CDI-mediated amidation. The biological evaluation against H(37)Rv revealed compounds 5d, 5e and 5u with MICs in the range of 3.125-12.5 mu g/mL using MABA assay. Further, compound 5u was tested against RAW 264.7 cell by MTT assay and showed 32 % growth inhibitions. The structure activity relationship of the indole-2-carboxamides has been established for antimycobacterial activity. The physicochemical properties and ADMET parameters of the 5d, 5e and 5u using pKCSM and SwissADME revealed their suitability as promising drug candidates. Molecular docking studies using AutoDock Vina revealed binding of 5u with the catalytic site of mmpL3 (PDB ID: 6AJG). The MD simulations of the most active compound 5u using GROMACS 2020.1 revealed its stability at the protein active site. Further optimization of indole-2-carboxamies may reveal the potentiation of identified anti-mycobacterial drug candidates.