Multitarget molecular hybrids of N-benzyl pyrrolidine derivatives were designed, synthesized, and biologically evaluated for the treatment of Alzheimer’s disease (AD). Among the synthesized compounds, 4k and 4o showed balanced enzyme inhibitions against cholinesterases (AChE and BChE) and BACE-1. Both leads showed considerable PAS-AChE binding capability, excellent brain permeation, potential disassembly of Aβ aggregates, and neuroprotective activity against Aβ-induced stress. Compounds 4k and 4o also ameliorated cognitive dysfunction against the scopolamine-induced amnesia model in the Y-maze test. The ex vivo study signified attenuated brain AChE activity and antioxidant potential of compounds 4k and 4o. Furthermore, compound 4o also showed improvement in Aβ-induced cognitive dysfunction by the Morris water maze test with excellent oral absorption characteristics ascertained by the pharmacokinetic study. In silico molecular docking and dynamics simulation studies of leads suggested their consensual binding affinity toward PAS-AChE in addition to aspartate dyad of BACE-1.

N-苄基吡咯烷衍生物的多靶分子杂合体被设计，合成并进行生物学评估以治疗阿尔茨海默氏病（AD）。在合成的化合物中，4k和4o对胆碱酯酶（AChE和BChE）和BACE-1表现出平衡的酶抑制作用。两条引线均显示出相当大的PAS-AChE结合能力，出色的大脑渗透能力，潜在的Aβ聚集体分解以及对Aβ诱导的应激的神经保护活性。在Y迷宫测试中，化合物4k和4o还改善了针对东pol碱诱导的健忘症的认知功能障碍。在体外这项研究表明化合物4k和4o的脑AChE活性和抗氧化能力减弱。此外，化合物4o还通过莫里斯水迷宫试验显示出Aβ诱导的认知功能障碍的改善，并通过药代动力学研究确定了优异的口服吸收特性。在对分子的计算机分子对接和动力学模拟研究中，发现它们除BACE-1的天冬氨酸二聚体外，还对PAS-AChE达成共识的结合亲和力。