Design, Synthesis, and Biological Activity of Novel 1,3,5-Triazine-1,2,4-Triazine Hybrids as Cholinesterase Inhibitors

Fourteen 1,3,5-triazine-1,2,4-triazine hybrids were designed and synthesized. Their structures were confirmed by IR, NMR, and high-resolution mass spectra, as well as by single crystal X-ray diffraction. The cholinesterase inhibitory activities of the hybrids were assayed by Ellman's method. Five of the fourteen hybrids inhibited acetylcholinesterase by more than 50% at a concentration of 50 mu M. Only two hybrids inhibited butyrylcholinesterase by more than 50% at a concentration of 50 mu M. Compound 5c possessed the best acetyl-cholinesterase and butyrylcholinesterase inhibitory activities with IC50 of 6.80 +/- 0.14 mu M and 1.91 +/- 0.12 mu M, respectively. Molecular docking showed that compound 5c interacted with both catalytic active site and peripheral anionic site of acetylcholinesterase.