El-Sayed_2019_Bioorg.Chem_93_103312

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+/-0.63muM for hAChE and Ki=40.15+/-3.31muM for hBChE). However, compound 11 displayed dual inhibitory effect against hAChE and hBChE at submicromolar range (Ki=0.40+/-0.03 and 0.129+/-0.009muM, 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.