Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, Egypt.
Drug Dev Res. 2023 Aug;84(5):937-961. doi: 10.1002/ddr.22064. Epub 2023 Apr 17.
A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All the newly synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and the most active compounds were tested for their butyrylcholinesterase (BuChE) inhibitory activity. Moreover, all the synthesized compounds were evaluated for their inhibitory effects against Aβ aggregation and antioxidant activity using the oxygen radical absorbance capacity method. Compounds 4b, 6b, and 8b displayed the most prominent AChE inhibitory action comparable to donepezil. Compound 6b showed the greatest AChE inhibitory action (IC = 0.07 ± 0.003 µM) and the most potent BuChE inhibitory action (IC = 0.059 ± 0.004 µM). Furthermore, the three compounds exhibited significant antioxidant activity. Compounds 6b and 8b exerted more inhibitory action on Aβ aggregation than donepezil. The cytotoxic activity of compounds 4b, 6b, and 8b against the WI-38 cell line in comparison with donepezil was examined using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results revealed that compounds 6b and 8b were less cytotixic than donepezil, while compound 4b showed nonsignificant cytotoxicity compared to donepezil. For more insights about the binding patterns of the most promising compounds (4b, 6b, and 8b) with the AChE at molecular levels; molecular docking and molecular dynamics simulations were performed. The density functional theory calculations and absorption, distribution, metabolism, excretion and toxicity properties were described as well. The results highlighted compound 6b, which incorporates a phenylpiperazine moiety coupled to a thienopyrimidone scaffold via two-atom spacer, to be a promising multifunctional therapeutic agent for the treatment of Alzheimer's disease. It is a potent dual AChE and BuChE inhibitor. Furthermore, it had stronger Aβ aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.
基于多奈哌齐骨架，我们设计并合成了一系列 12 个 S-取代的四氢苯并噻吩并嘧啶类化合物。所有新合成的化合物均进行了乙酰胆碱酯酶（AChE）抑制活性评估，最具活性的化合物还进行了丁酰胆碱酯酶（BuChE）抑制活性测试。此外，所有合成的化合物均通过氧自由基吸收能力法评估了它们对 Aβ 聚集的抑制作用和抗氧化活性。化合物 4b、6b 和 8b 表现出与多奈哌齐相当的最显著的 AChE 抑制作用。化合物 6b 表现出最强的 AChE 抑制作用（IC = 0.07 ± 0.003 µM）和最强的 BuChE 抑制作用（IC = 0.059 ± 0.004 µM）。此外，这三种化合物均表现出显著的抗氧化活性。化合物 6b 和 8b 对 Aβ 聚集的抑制作用强于多奈哌齐。通过 3-(4,5-二甲基噻唑基-2)-2,5-二苯基四氮唑溴盐测定法，比较了化合物 4b、6b 和 8b 对 WI-38 细胞系的细胞毒性与多奈哌齐的作用。结果表明，化合物 6b 和 8b 比多奈哌齐的细胞毒性小，而化合物 4b 与多奈哌齐相比无显著细胞毒性。为了更深入地了解最有前途的化合物（4b、6b 和 8b）与 AChE 在分子水平上的结合模式，进行了分子对接和分子动力学模拟。此外，还描述了密度泛函理论计算和吸收、分布、代谢、排泄和毒性特性。结果突出了化合物 6b，它将一个苯哌嗪部分与噻吩并嘧啶酮骨架通过两个原子间隔物连接起来，是一种有前途的多功能治疗阿尔茨海默病的药物。它是一种有效的双重 AChE 和 BuChE 抑制剂。此外，它对 Aβ 聚集的抑制作用强于多奈哌齐。此外，化合物 6b 表现出显著的抗氧化活性。
