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<p>Alzheimer’s disease is a complex neurodegenerative disorder characterized by cognitive decline and memory loss, with acetylcholinesterase and monoacylglycerol lipase being two key enzymes involved in its pathogenesis. In this study, a series of carbamoyl flavonoid derivatives were synthesized and evaluated as potential dual inhibitors of acetylcholinesterase and monoacylglycerol lipase. Among them, compound B3 (a baicalein derivative) exhibited the most potent dual inhibition, with IC<sub>50</sub> values of 67.95 µM for acetylcholinesterase and 61.28 µM for monoacylglycerol lipase. Molecular docking and molecular dynamics simulations confirmed the strong binding affinity and stability of B3 within the active sites of both enzymes. The MM-GBSA binding free energy analysis revealed ΔG<sub>bind</sub> values of –31.58 ± 2.24 kcal/mol for acetylcholinesterase and –41.24 ± 2.42 kcal/mol for monoacylglycerol lipase, indicating favorable interactions through hydrogen bonding, <i>π</i>-stacking interactions, and hydrophobic contacts. These findings suggest that carbamoyl flavonoid derivatives, particularly B3, hold promise as multifunctional inhibitors, providing a novel and effective strategy for the treatment of Alzheimer’s disease.</p><p></p>

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Carbamoyl flavonoids as dual inhibitors of acetylcholinesterase and monoacylglycerol lipase: synthesis, in vitro evaluation, and computational studies

  • 期刊论文

  • 发表日期：

    2025年5月14日

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  • The-Huan Tran,
  • Thai-Son Tran,
  • Minh-Hieu Nguyen,
  • Thi-Trang Pham,
  • Thanh-Tan Mai,
  • Thanh-Dao Tran

摘要

Alzheimer’s disease is a complex neurodegenerative disorder characterized by cognitive decline and memory loss, with acetylcholinesterase and monoacylglycerol lipase being two key enzymes involved in its pathogenesis. In this study, a series of carbamoyl flavonoid derivatives were synthesized and evaluated as potential dual inhibitors of acetylcholinesterase and monoacylglycerol lipase. Among them, compound B3 (a baicalein derivative) exhibited the most potent dual inhibition, with IC50 values of 67.95 µM for acetylcholinesterase and 61.28 µM for monoacylglycerol lipase. Molecular docking and molecular dynamics simulations confirmed the strong binding affinity and stability of B3 within the active sites of both enzymes. The MM-GBSA binding free energy analysis revealed ΔGbind values of –31.58 ± 2.24 kcal/mol for acetylcholinesterase and –41.24 ± 2.42 kcal/mol for monoacylglycerol lipase, indicating favorable interactions through hydrogen bonding, π-stacking interactions, and hydrophobic contacts. These findings suggest that carbamoyl flavonoid derivatives, particularly B3, hold promise as multifunctional inhibitors, providing a novel and effective strategy for the treatment of Alzheimer’s disease.