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<p>In this study, coumarin-3-carboxamide derivatives were designed and evaluated through a comprehensive in silico and in vitro combined approaches to identify cholinesterase inhibitors. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA analyses revealed strong binding affinities and stable interactions within key catalytic regions of AChE and BChE, with AChE-<b>CM4</b> (ΔG<sub>bind</sub> = −60.27 ± 5.88&#xa0;kcal/mol) and BChE-<b>CM5</b> (ΔG<sub>bind</sub> = −54.95 ± 6.90&#xa0;kcal/mol) emerging as the most promising complexes. ADME predictions indicated generally favorable pharmacokinetic profiles for the compounds; however, the predicted blood-brain barrier permeability levels were low to moderate. In vitro enzyme inhibition studies validated the computational results, showing that <b>CM4</b> (IC<sub>50</sub> = 19.04 ± 1.67 nM) and <b>CM8</b> (IC<sub>50</sub> = 17.73 ± 0.66 nM) exhibited significantly greater AChE inhibition than donepezil (IC<sub>50</sub> = 27.27 ± 1.22 nM; <i>p</i> &lt; 0.001), with <b>CM3</b> (IC<sub>50</sub> = 24.84 ± 1.99 nM) comparable to donepezil, while all derivatives (<b>CM1-CM9</b>) significantly outperformed tacrine against BChE (<i>p</i> &lt; 0.001). Moreover, <b>CM6</b> and <b>CM9</b> inhibited colony formation in brain, breast, and colon cancer cell lines at concentrations below 5 µM. As a result, the alignment of computational and biological data highlights these coumarin-3-carboxamides as compelling lead candidates with both neuroprotective and anticancer potential for further pharmacological development.</p> Graphical abstract <p></p>

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Design, synthesis, biological evaluation, and in silico analysis of novel coumarin carboxamides as acetylcholinesterase and butyrylcholinesterase inhibitors and anticancer agents

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Kadircan Ural,
  • Bulent Ozpolat,
  • Ferah Comert Onder

摘要

In this study, coumarin-3-carboxamide derivatives were designed and evaluated through a comprehensive in silico and in vitro combined approaches to identify cholinesterase inhibitors. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA analyses revealed strong binding affinities and stable interactions within key catalytic regions of AChE and BChE, with AChE-CM4 (ΔGbind = −60.27 ± 5.88 kcal/mol) and BChE-CM5 (ΔGbind = −54.95 ± 6.90 kcal/mol) emerging as the most promising complexes. ADME predictions indicated generally favorable pharmacokinetic profiles for the compounds; however, the predicted blood-brain barrier permeability levels were low to moderate. In vitro enzyme inhibition studies validated the computational results, showing that CM4 (IC50 = 19.04 ± 1.67 nM) and CM8 (IC50 = 17.73 ± 0.66 nM) exhibited significantly greater AChE inhibition than donepezil (IC50 = 27.27 ± 1.22 nM; p < 0.001), with CM3 (IC50 = 24.84 ± 1.99 nM) comparable to donepezil, while all derivatives (CM1-CM9) significantly outperformed tacrine against BChE (p < 0.001). Moreover, CM6 and CM9 inhibited colony formation in brain, breast, and colon cancer cell lines at concentrations below 5 µM. As a result, the alignment of computational and biological data highlights these coumarin-3-carboxamides as compelling lead candidates with both neuroprotective and anticancer potential for further pharmacological development.

Graphical abstract