El Fadili Mohamed, Ez-Zoubi Amine, Aloui Mourad, Mujwar Somdutt, Abuelizz Hatem A, Elhalaoui Menana, Amin Adnan
LIMAS Laboratory, Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, Morocco.
Laboratory of Applied Organic Chemistry, Faculty of Sciences and Techniques, Sidi Mohamed Ben Abdellah University, Route d'Imouzzer, Fez, Morocco.
Front Chem. 2025 May 22;13:1614462. doi: 10.3389/fchem.2025.1614462. eCollection 2025.
Being a complex neurodegenerative disease with many clinical features, Alzheimer's disease calls for multiple-targeted drugs to treat several aspects of its progression in the human body. The present study sheds light on evaluating and designing novel pyrazole and benzofuran-based derivatives as potent acetylcholinesterase (AChE) inhibitors with improved antioxidant features to manage Alzheimer's disease.
Various molecular interaction fields, specifically steric, electrostatic, hydrophobic, acceptor, and donor fields of hydrogen bonds, were examined using 3D-QSAR models to predict inhibitory activity against the AChE enzyme, which was successfully validated through both external and internal assessments.
Consequently, the CoMFA and CoMSIA/ SEHDA models led to the design of the candidate compound C27** as one of the most potent acetylcholinesterase inhibitors while building on the most active molecule (C7). Both C27** and C7 revealed their significant chemical reactivity after their optimization with B3LYP 6-31G (d, p) using the density functional theory (DFT), in addition to large similarities to the candidate drugs with desired pharmacokinetic and physicochemical features and good levels of molecular stability towards the crystal structure of human acetylcholinesterase protein (PDB ID of 4EY7).
阿尔茨海默病作为一种具有多种临床特征的复杂神经退行性疾病，需要多靶点药物来治疗其在人体进展过程中的多个方面。本研究旨在评估和设计新型吡唑和苯并呋喃基衍生物，作为具有增强抗氧化特性的有效乙酰胆碱酯酶（AChE）抑制剂，以治疗阿尔茨海默病。
使用3D-QSAR模型研究了各种分子相互作用场，特别是氢键的空间、静电、疏水、受体和供体场，以预测对AChE酶的抑制活性，并通过外部和内部评估成功验证。
因此，比较分子场分析（CoMFA）和比较分子相似性指数分析/表面静电势氢键供体分析（CoMSIA/SEHDA）模型在最具活性的分子（C7）基础上设计出候选化合物C27**，它是最有效的乙酰胆碱酯酶抑制剂之一。除了与具有所需药代动力学和物理化学特征且对人乙酰胆碱酯酶蛋白晶体结构（PDB ID为4EY7）具有良好分子稳定性水平的候选药物有很大相似性外，C27**和C7在用密度泛函理论（DFT）通过B3LYP 6-31G（d, p）进行优化后，还显示出显著的化学反应性。
