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<p>Cholinergic neuron damage and oxidative stress are prominent hypotheses explaining the pathogenesis of Alzheimer’s disease (AD). In this study, dual-acting compounds combining carbamate and diazepine structures were designed to function as both butyrylcholinesterase (BChE) inhibitors and antioxidants. Selective inhibition of BChE, particularly during the late stages of AD when its activity increases, was targeted. Introducing different diazepine derivatives (<b>14</b>, <b>15</b> and <b>16</b>) provided insights into inhibitor basicity and enzyme-binding affinity. Among the synthesized compounds, heptyl carbamate (<b>6b</b>) demonstrated an IC<sub>50</sub> value of 32 ± 25 nM for BChE, with 96.5% purity confirmed by HPLC. Post-carbamoylation, the released compounds <b>15</b> and <b>16</b> exhibited antioxidant activities (70.2–85.3%) at 0.0136–0.1088 mM, comparable to ascorbic acid and α-tocopherol. The prepared carbamates demonstrated selectivity for BChE over acetylcholinesterase (AChE). Docking studies corroborated biological data, revealing compound <b>6b</b> as the most potent. These findings highlight the therapeutic potential of these dual-acting compounds in addressing the multifaceted pathology of AD.</p><p></p>

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Novel diazepine-carbamate derivatives as dual-acting butyrylcholinesterase inhibitors and antioxidants for Alzheimer’s disease

  • 期刊论文

  • 发表日期：

    2025年10月11日

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  • Nafisah Al-Rifai,
  • Rayanah Amro,
  • Jalal A. Zahra,
  • Fouad Darras,
  • Mutasem O. Taha

摘要

Cholinergic neuron damage and oxidative stress are prominent hypotheses explaining the pathogenesis of Alzheimer’s disease (AD). In this study, dual-acting compounds combining carbamate and diazepine structures were designed to function as both butyrylcholinesterase (BChE) inhibitors and antioxidants. Selective inhibition of BChE, particularly during the late stages of AD when its activity increases, was targeted. Introducing different diazepine derivatives (14, 15 and 16) provided insights into inhibitor basicity and enzyme-binding affinity. Among the synthesized compounds, heptyl carbamate (6b) demonstrated an IC50 value of 32 ± 25 nM for BChE, with 96.5% purity confirmed by HPLC. Post-carbamoylation, the released compounds 15 and 16 exhibited antioxidant activities (70.2–85.3%) at 0.0136–0.1088 mM, comparable to ascorbic acid and α-tocopherol. The prepared carbamates demonstrated selectivity for BChE over acetylcholinesterase (AChE). Docking studies corroborated biological data, revealing compound 6b as the most potent. These findings highlight the therapeutic potential of these dual-acting compounds in addressing the multifaceted pathology of AD.