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Arch Pharm (Weinheim) ; 354(3): e2000258, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33226157

ABSTRACT

The complex pathophysiology of Alzheimer's disease (AD) has prompted researchers to develop multitarget-directed molecules to find an effective therapy against the disease. In this context, a novel series of N-(1-benzylpiperidin-4-yl)-5-arylisoxazole-3-carboxamide derivatives were designed, synthesized, and evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro biological evaluation demonstrated that compound 4e was the best AChE (IC50 = 16.07 µM) and BuChE inhibitor (IC50 = 15.16 µM). A kinetic study of 4e was also conducted, which presented a mixed-type inhibition for both enzymes. Molecular docking studies revealed that compound 4e fitted well into the active sites of AChE and BuChE, forming stable and strong interactions with key residues Glu199, Trp84, Asp72, Tyr121, and Phe288 in AChE and His438, Trp82, Ala328, Tyr332, Phe329, Thr120, and Pro285 in BuChE. Besides, the inhibition of BACE1 by 4e and the biometal chelation activity of 4e were measured. The neuroprotective assessment revealed that 4e exhibited 23.2% protection at 50 µM toward amyloid-beta-induced PC12 neuronal cells. Overall, this study exhibited that compound 4e was a promising compound targeting multiple factors associated with AD.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Isoxazoles/pharmacology , Neuroprotective Agents/pharmacology , Piperidines/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Isoxazoles/chemistry , Molecular Docking Simulation , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , PC12 Cells , Piperidines/chemical synthesis , Piperidines/chemistry , Rats , Structure-Activity Relationship
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