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 H37Rv revealed compounds 5d, 5e and 5u with MICs in the range of 3.125‐12.5 μg/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.
The anilinopyridine derivatives were designed, synthesized and evaluated against Mycobacterium tuberculosis H37Rv. The detail SAR study was carried out using various analogues including positional isomers. The screening data revealed that the free −NH2 on pyridine ring is crucial for antitubercular activity. The current study identified three promising leads 16 e, 16 i and 16 o with MIC 3.1, 3.1 and 1.2 μM, respectively. Important to note that the compound 16 o showed excellent selectivity index of 135.58 when its antitubercular activity was compared with the inhibition of CHO−K1 cells. The other notable compounds were 16 b, 16 d, 16 e, 16 f, 16 g, 16 h, 16 i, 16 l and 16 q which exhibited anti‐TB activity with MIC ≤25 μM. Interestingly, compounds 16 e, 16 i and 16 o did not show inhibition of bacterial pathogen panel indicating the selectivity of this class of compounds towards Mtb. Furthermore, physico‐chemical and ADMET properties of the synthesized derivatives were studied. The compounds fulfill the criteria of Lipinski's rule of five for drug‐likeness.
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