新型吡咯烷类化合物的设计、合成、体外及体内评价，具有潜在的胆碱酯酶抑制作用和抗阿尔茨海默病活性。
Design, synthesis, in vitro and in vivo evaluation of novel pyrrolizine-based compounds with potential activity as cholinesterase inhibitors and anti-Alzheimer's agents.
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, P.O. Box 11562, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, P.O. Box 11562, Cairo, Egypt.
出版信息
Bioorg Chem. 2019 Dec;93:103312. doi: 10.1016/j.bioorg.2019.103312. Epub 2019 Sep 24.
Novel series of pyrrolizine based compounds (4-6 and 9-11) were designed, synthesized and evaluated as potential anti-Alzheimer agents. Most of the tested compounds showed selectivity to hAChE over hBChE and effectively inhibited self-induced amyloid beta aggregation in vitro. Among these derivatives, compound 10 displayed high selectivity towards hAChE (Ki = 1.47 ± 0.63 μM for hAChE and Ki = 40.15 ± 3.31 μM for hBChE). However, compound 11 displayed dual inhibitory effect against hAChE and hBChE at submicromolar range (Ki = 0.40 ± 0.03 and 0.129 ± 0.009 μM, respectively). Kinetic studies of the new ligands showed competitive type inhibition for both hAChE and hBChE. Moreover, compounds 10 and 11 showed lower or comparable cytotoxicity to donepezil against human neuroblastoma (SH-SY5Y) and normal human hepatic (THLE2) cell lines. In vivo studies confirmed that both compounds were able to improve cognitive dysfunction of scopolamine-induced AD mice. Finally, molecular docking simulation of compounds 10 and 11 in hAChE active site showed good agreement with the obtained pharmaco-biological results.
我们设计、合成并评价了一系列新型吡咯里嗪类化合物（4-6 和 9-11），以期将其作为有潜力的抗阿尔茨海默病药物。大多数受试化合物对 hAChE 具有选择性，对 hBChE 的选择性较低，且能有效抑制体外淀粉样β自诱导聚集。在这些衍生物中，化合物 10 对 hAChE 具有较高的选择性（Ki 值分别为 1.47 ± 0.63 μM 和 40.15 ± 3.31 μM）。然而，化合物 11 对 hAChE 和 hBChE 具有双重抑制作用，其 Ki 值分别为 0.40 ± 0.03 μM 和 0.129 ± 0.009 μM。新配体的动力学研究表明，它们对 hAChE 和 hBChE 的抑制类型均为竞争性抑制。此外，化合物 10 和 11 对人神经母细胞瘤（SH-SY5Y）和正常人类肝细胞（THLE2）的细胞毒性与多奈哌齐相比均较低或相当。体内研究证实，这两种化合物均能改善东莨菪碱诱导的 AD 小鼠的认知功能障碍。最后，化合物 10 和 11 在 hAChE 活性部位的分子对接模拟结果与获得的药物生物学结果吻合较好。
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