Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Institute of Pharmaceutical Research, GLA University, Matura 281406, India.
Bioorg Chem. 2021 Jun;111:104922. doi: 10.1016/j.bioorg.2021.104922. Epub 2021 Apr 17.
Novel N-Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aβ aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aβ. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1.
新型 N-苄基吡咯烷类化合物经过多种体内外参数的测试。在所有合成的分子中，8f 和 12f 对β-分泌酶-1（hBACE-1）、人乙酰胆碱酯酶（hAChE）和人丁酰胆碱酯酶（hBuChE）表现出广泛的抑制作用。这些分子还具有显著的乙酰胆碱酯酶-外周阴离子部位（PAS）结合能力、血脑屏障通透性、潜在的 Aβ 聚集物的解离能力以及对 SHSY-5Y 细胞系的神经保护作用。Y 迷宫和 Morris 水迷宫测试的结果表明，化合物 8f 和 12f 改善了东莨菪碱和 Aβ 引起的认知功能障碍。在大鼠脑匀浆上进行的离体活性实验表明，化合物能降低 AChE 水平和氧化应激。药代动力学研究证实了先导化合物 12f 具有良好的口服吸收特性。基于计算机的对接研究和分子动力学模拟结果表明，化合物 8f 和 12f 与 hAChE、hBuChE 和 hBACE-1 的靶标残基之间存在稳定的相互作用。
