Hasan Aso Hameed, Abdulrahman Faruq Azeez, Obaidullah Ahmad J, Alotaibi Hadil Faris, Alanazi Mohammed M, Noamaan Mahmoud A, Murugesan Sankaranarayanan, Amran Syazwani Itri, Bhat Ajmal R, Jamalis Joazaizulfazli
Department of Chemistry, Faculty of Science, University Teknologi Malaysia, Johor Bahru 81310, Johor, Malaysia.
Department of Chemistry, College of Science, University of Garmian, Kalar 46021, Kurdistan Region, Iraq.
Pharmaceuticals (Basel). 2023 Jul 6;16(7):971. doi: 10.3390/ph16070971.
To discover anti-acetylcholinesterase agents for the treatment of Alzheimer's disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC values ranged from 87.84 to 515.59 μg/mL; hybrids and with IC values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, and , with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems' trajectories at 100 ns. These results revealed that the complex system of compound acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes.
为发现用于治疗阿尔茨海默病（AD）的抗乙酰胆碱酯酶药物，合理设计并成功合成了一系列新型席夫碱 - 香豆素杂化物，并通过傅里叶变换红外光谱（FTIR）、核磁共振（NMR）和高分辨率质谱（HRMS）分析对其进行了结构表征。评估了这些杂化物对乙酰胆碱酯酶（AChE）的潜在抑制作用。它们均表现出对AChE的优异抑制活性。IC值范围为87.84至515.59μg/mL；IC值分别为0.232±0.011和0.190±0.004μM的杂化物 和 显示出作为乙酰胆碱酯酶抑制剂（AChEIs）的最强活性。参比药物加兰他敏的IC值为1.142±0.027μM。在wB97XD/6 - 311++G(d,p)水平计算了包括化学势（μ）、化学硬度（η）、亲电性（ω）、凝聚福井函数和双描述符在内的反应性描述符，以确定所设计化合物的反应性变化。对所研究化合物的自然电荷模式进行深入研究，从而深入了解这些化合物与AChE生物受体之间的重要相互作用中心。利用高质量信息和可视化手段确定了这些衍生物中最活性位点的分子静电表面势（MESP）。进行分子对接分析以预测结合位点和结合能。构效关系研究表明，所提出的化合物具有良好的口服生物利用度性质。为探索配体 - 受体复合物的稳定性和动态行为，对两种最佳对接衍生物 和 与AChE（4EY7）受体进行了100 ns的分子动力学模拟（MDS）。使用从系统轨迹100 ns时获取的快照进行了一种常用的确定自由结合能（MM/GBSA）的方法。这些结果表明，化合物 的复合系统获得了相对更稳定的构象，并且比化合物 的复合系统和加兰他敏药物表现出更好的描述符，表明其作为有效抑制药物的潜力。结合自由能分析表明，13d - 4EY7复合物与AChE受体相比，与其他复合物具有更高的稳定性。
