Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Novel N-Benzylpiperidine Derivatives of 5-Arylisoxazole-3-Carboxamides As Anti-Alzheimer's Agents Publisher Pubmed



Saeedi M1, 2 ; Felegari P3 ; Iraji A4 ; Hariri R3 ; Rastegari A2 ; Mirfazli SS5 ; Edraki N4 ; Firuzi O4 ; Mahdavi M6 ; Akbarzadeh T2, 3
Authors
Show Affiliations
Authors Affiliations
  1. 1. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5. Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran
  6. 6. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: Archiv der Pharmazie Published:2021


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. © 2020 Deutsche Pharmazeutische Gesellschaft