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Development of coumarin-benzimidazole conjugates via Pd/Cu-catalyzed coupling for mycobacterial inhibition supported by molecular docking, ADME prediction, and molecular dynamics simulations
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DOI：10.1007/s11164-026-06081-1.png)
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Abstract
En 中文
The development of multifunctional heterocyclic hybrid frameworks has emerged as a promising strategy for discovering new therapeutic agents with enhanced biological profiles. Here, we report the synthesis of novel coumarin-benzimidazole hybrid molecules 6a-o using an efficient Sonogashira cross-coupling approach catalyzed by a Pd(0)/CuI catalytic system. The bimetallic system efficiently facilitated C(sp2)–C(sp) bond formation under mild reaction conditions, affording desired derivatives in higher yields up to 88%, also maintaining broad compatibility with electron-donating and electron-withdrawing groups. All synthesized compounds were screened against Mycobacterium tuberculosis H37Rv and cytotoxicity against the VERO cell line. Among all the synthesized compounds, 6b, 6c, 6k, 6m, and 6n showed the most potent antimycobacterial activity at 1.6 µg/mL, with low cytotoxicity and a high selectivity index (SI > 62.5), comparable to the standard drugs Isoniazid and Ethambutol. Moreover, in-silico ADME analysis revealed that all the synthesized scaffolds possess acceptable lipophilicity, favorable oral absorption, and suitable blood–brain barrier permeability. Molecular docking against enoyl-ACP reductase demonstrated strong binding affinities, particularly for scaffolds consisting of methyl (6b), fluoro (6d), and trifluoromethyl (6o) functional groups, which showed interactions comparable to Isoniazid. Post-docking MM-GBSA binding free energy calculations were performed to validate the ligand–protein interactions further. The most active compounds showed favorable ΔGbind values, demonstrating good correlation with docking results and in vitro antimycobacterial activity. Molecular dynamics simulations further confirmed the stability of the docked complex through sustained protein–ligand interactions and low structural fluctuations, corroborating the predicted binding mode.
Keywords:
Antimycobacterial activity
Benzimidazole
Coumarin
C(sp2)–C(sp) bond formation
Sonogashira cross-coupling
In-silico ADME studies
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