Design, Synthesis and Anticholinesterase Activity of Coumarin‐1,3,5‐triazine Derivatives

Abstract

AbstractA series of coumarin‐1,3,5‐triazine derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors. The structures of those compounds were characterized by IR, NMR, HRMS, HPLC, and X‐ray. The structures of those coumarin‐1,3,5‐triazine derivatives are the mixtures of two geometric isomers. The 1H‐NMR of compound 3 g without coumarin structure and its hydrochloride and single crystal structure of compound 3 g were studied to prove the coumarin‐1,3,5‐triazine derivatives are the mixtures of two geometric isomers. The acetylcholinesterase and butyrylcholinesterase inhibitory activities of the synthesized compounds were determinated by Ellman's method. The results showed that all the compounds could inhibit acetylcholinesterase selectively. Among them, compound 3 b was found to have the strongest inhibitory effect on acetylcholinesterase with an IC50 value of 0.018 μM, which was closest to the IC50 of the positive control donepezil (IC50=0.016 μM). Enzyme kinetic studies indicate that this compound inhibited acetylcholinesterase with a mixed mode. Molecular docking, molecular dynamics simulation study and binding free energy calculation experiments demonstrated that compound 3 b could stably interact with key amino acids in the catalytically active site and the peripheral anion site of acetylcholinesterase. According to the results, compound 3 b demonstrates promising potential as acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.