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<p>The present study describes the design, synthesis, and evaluation of novel tricyclic tetrahydropyridothienopyrimidinone (THPTP) derivatives as dual AChE/MAO-B inhibitors. Building on our previous hit <b>A03</b>, an additional benzyl substituent was added to improve interactions with the peripheral anionic site of AChE and enhance MAO-B binding. The derivatives showed increased inhibitory activities, with compound <b>A03-12</b> exhibiting significant potency (<i>hu</i>AChE: IC<sub>50</sub> = 0.14&#xa0;µM, <i>hu</i>MAO-B: IC<sub>50</sub> = 0.52&#xa0;µM). Kinetic studies and molecular simulations revealed distinct binding interactions, supporting its mixed-type AChE inhibition and competitive MAO-B inhibition. Compound <b>A03-12</b> also demonstrated high metabolic stability, better pharmacokinetic parameters, favorable blood–brain barrier permeability, and low cytotoxicity (CC<sub>50</sub> &gt; 100&#xa0;µM). These results offer a promising chemical template, especially compound <b>A03-12</b>, as a potential lead for designing new anti-AD drugs.</p>

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Molecular docking-based design of novel tricyclic tetrahydropyridothienopyrimidinone derivatives as AChE/MAO-B dual inhibitors

  • 期刊论文

  • 发表日期：

    2025年9月20日

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  • Juan Zhang,
  • Yue Li,
  • Jia-Dong Shao,
  • Guo Wei,
  • Nai-Yu Zhang,
  • Kong-Kai Zhu,
  • Kai-Ming Wang,
  • Cheng-Shi Jiang,
  • Jia-Hong Wang

摘要

The present study describes the design, synthesis, and evaluation of novel tricyclic tetrahydropyridothienopyrimidinone (THPTP) derivatives as dual AChE/MAO-B inhibitors. Building on our previous hit A03, an additional benzyl substituent was added to improve interactions with the peripheral anionic site of AChE and enhance MAO-B binding. The derivatives showed increased inhibitory activities, with compound A03-12 exhibiting significant potency (huAChE: IC50 = 0.14 µM, huMAO-B: IC50 = 0.52 µM). Kinetic studies and molecular simulations revealed distinct binding interactions, supporting its mixed-type AChE inhibition and competitive MAO-B inhibition. Compound A03-12 also demonstrated high metabolic stability, better pharmacokinetic parameters, favorable blood–brain barrier permeability, and low cytotoxicity (CC50 > 100 µM). These results offer a promising chemical template, especially compound A03-12, as a potential lead for designing new anti-AD drugs.