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Design and Synthesis of Selective Acetylcholinesterase Inhibitors: Arylisoxazole-Phenylpiperazine Derivatives Publisher Pubmed



Saeedi M1, 2 ; Mohtadihaghighi D3 ; Mirfazli SS4 ; Mahdavi M5 ; Hariri R2 ; Lotfian H3 ; Edraki N6 ; Iraji A6 ; Firuzi O6 ; Akbarzadeh T2, 3
Authors
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Authors Affiliations
  1. 1. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14155, Iran
  2. 2. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, 14155, Iran
  3. 3. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14176, Iran
  4. 4. Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, 14665, Iran
  5. 5. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, 14155, Iran
  6. 6. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348, Iran

Source: Chemistry and Biodiversity Published:2019


Abstract

In this work, a novel series of arylisoxazole-phenylpiperazines were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that [5-(2-chlorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC 50 of 21.85 μm. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and [5-(2-fluorophenyl)-1,2-oxazol-3-yl](4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC 50 =51.66 μm). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC 50 =76.78 μm. Finally, neuroprotectivity of compound 5c on Aβ-treated neurotoxicity in PC12 cells depicted low activity. © 2019 Wiley-VHCA AG, Zurich, Switzerland
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