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

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-09-20 DOI:10.1007/s11030-025-11354-9

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

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Abstract

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.

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新型三环四氢吡啶噻吩嘧啶衍生物作为AChE/MAO-B双抑制剂的分子对接设计。

本研究描述了新型三环四氢吡啶多噻吩嘧啶酮（THPTP）衍生物作为AChE/MAO-B双抑制剂的设计、合成和评价。在我们之前的研究结果A03的基础上，添加了一个额外的苄基取代基来改善与AChE外周阴离子位点的相互作用，并增强MAO-B的结合。其中化合物A03-12的抑菌活性显著（huAChE: IC50 = 0.14µM, huMAO-B: IC50 = 0.52µM）。动力学研究和分子模拟显示了不同的结合相互作用，支持其混合型AChE抑制和竞争性MAO-B抑制。化合物A03-12还具有较高的代谢稳定性、较好的药代动力学参数、良好的血脑屏障通透性和较低的细胞毒性（CC50 bb0 100µM）。这些结果为设计新的抗阿尔茨海默病药物提供了一个有前景的化学模板，特别是化合物A03-12。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;