Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Drug Dev Res. 2022 Sep;83(6):1394-1407. doi: 10.1002/ddr.21968. Epub 2022 Jun 24.
A series of tetrahydrobenzothienopyrimidines and tetrahydrobenzothienotriazines incorporating a pharmacophore from donepezil molecule were designed and synthesized. The 12 newly synthesized compounds were screened for their inhibition activity against acetylcholinesterase enzyme (AChE). Compounds that exerted the most potent AChE inhibitory action were further evaluated for their BChE inhibitory activity. In addition, the inhibitory effects of all newly synthesized compounds on Aβ and reactive oxygen species were assessed. Compounds 4d, 10b, and 10c showed potent inhibitory activity on AChE comparable to donepezil. Compound 10b (IC = 0.124 ± 0.006 nM) showed the greatest AChE inhibitory action and the most potent BChE inhibitory action (IC = 0.379 ± 0.02 nM). These three compounds showed more inhibitory action on Aβ accumulation than donepezil. Moreover, they showed potent antioxidant activity. The binding pattern of compounds 4d and 10b into AChE active site rationalized their remarkable AChE inhibitory activity. Taken together, these results indicated that these derivatives could be promising multifunctional agents for Alzheimer's disease management.
设计并合成了一系列包含多奈哌齐分子药效团的四氢苯并噻吩嘧啶和四氢苯并噻吩并三嗪。对 12 种新合成的化合物进行了乙酰胆碱酯酶（AChE）抑制活性筛选。对表现出最强 AChE 抑制作用的化合物进行了进一步的丁酰胆碱酯酶（BChE）抑制活性评价。此外，还评估了所有新合成化合物对 Aβ 和活性氧的抑制作用。化合物 4d、10b 和 10c 对 AChE 的抑制活性与多奈哌齐相当。化合物 10b（IC = 0.124 ± 0.006 nM）表现出最强的 AChE 抑制作用和最强的 BChE 抑制作用（IC = 0.379 ± 0.02 nM）。这三种化合物对 Aβ 积累的抑制作用强于多奈哌齐。此外，它们还具有很强的抗氧化活性。化合物 4d 和 10b 与 AChE 活性位点的结合模式解释了它们显著的 AChE 抑制活性。综上所述，这些结果表明，这些衍生物可能是治疗阿尔茨海默病的有前途的多功能药物。
