Design, synthesis and biological activity of the novel acetylcholinesterase inhibitors 6-arylmethyl-3-(4-alkoxyphenyl)-7H-thiazolo[3, 2-b]-1, 2, 4-triazin-7-one derivatives

Objective: To design and synthesize nine 6-arylmethyl-3-(4-alkoxyphenyl)-7H-thiazolo[3, 2-b]-1,2,4-triazin-7-one derivatives based on our previous work and molecular modeling, and to determine the acetylcholinesterase (AChE) inhibitory activity, the structure-activity relationship and the influences of group types on C6 arylmethyl and the side chain containing nitrogen at C3 phenyl on the 7H-thiazolo[3, 2-b]-1, 2, 4-triazin-7-one scaffold. Methods: Benzaldehyde or substituted benzaldehyde was reacted with N-acetoglycine by using Erlenmeyer-Plöchl reaction, hydrolyzation reaction and condensation reaction to obtain 6-arylmethyl-3-(4-hydroxyphenyl)-7H-thiazolo[3, 2-b]-1,2,4-triazin-7-one derivatives. Then the derivatives were transferred to nine target compounds 6-arylmethyl-3-(4-alkoxyphenyl)-7H-thiazolo[3, 2-b]-1,2,4-triazin-7-one derivatives by using Williamson reaction. AChE inhibitory activity was determined by the Ellman colorimetric assay with huperzine-A as the positive control. Results: The structures of all of the target compounds were characterized by mass spectra, infrared spectra and proton NMR. All of the target compounds exhibited inhibitory activities against human AChE in vitro, eight of them exhibited more than 40% inhibition at 10 μmol·L-1. Conclusion: 6-Arylmethyl-3-(4-alkoxyphenyl)-7H-thiazolo[3, 2-b]-1,2,4-triazin-7-one derivatives would be a kind of highly active AChE inhibitors. The inhibitory activities of target compounds with electron-donating group are more powerful than those of target compounds with electron-withdrawing group at C6 arylmethyl on the 7H-thiazolo[3, 2-b]-1, 2, 4-triazin-7-one scaffold.