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

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 IC₅₀ 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 (IC₅₀ =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 IC₅₀ =76.78 μm. Finally, neuroprotectivity of compound 5c on Aβ-treated neurotoxicity in PC12 cells depicted low activity.

Keywords: arylisoxazole; beta-secretase (BACE1); cholinesterase; docking; inhibitory activity; kinetic study; neuroprotection; phenylpiperazine; synthesis design.