Benzothiazole‐Propanamide Linker Pyrrolidine (Morpholine) as Monoamine Oxidase‐B and Butyrylcholinesterase Inhibitors

Abstract

AbstractAccording to the fusion technique create effective multi‐target‐directed ligands, in this study, we designed and synthesized a series of benzo[d]thiazol‐2‐yl)‐3‐(pyrrolidin‐1‐yl) or 3‐(morph‐ olino‐1‐yl)propanamide derivatives, and evaluated their inhibitory potency against MAOs, AChE, BuChE by in vitro enzyme effect assays. Based on activity results, we found that derivatives N‐(5‐methylbenzo[d]thiazol‐2‐yl)‐3‐(pyrrolidin‐1‐yl)propanamide (2 c) and N‐(6‐bromobenzo[d]thiazol‐2‐yl)‐3‐(pyrrolidin‐1‐yl)propanamide (2 h) showed good inhibitory potency against BuChE with IC50 values of 15.12 μM and 12.33 μM, respectively. Besides, 2 c and 2 h also exhibited selective MAO‐B inhibitory effects with inhibition rates of 60.10 % and 66.30 % at 100 μM, respectively. In contrast, all designed derivatives were poor active against AChE and MAO‐A at a concentration of 100 μM. The toxicity analysis in vitro by MTT and AO/EB fluorescence staining confirmed that 2 c and 2 h were nontoxic up to 100 μM. Molecular modeling studies showed that 2 c and 2 h could bind to the active site of BuChE. This research paves the way for further study aimed at designing MAO‐B and BuChE inhibitors for the treatment of neurodegenerative disorders.