Phenyldiazenyl-phenoxy-1,2,3-triazol-acetamide derivatives as new dual cholinesterase Inhibitors: Design, synthesis, in vitro, and in silico enzymatic inhibition evaluations

In this work, phenyldiazenyl-phenoxy-1,2,3-triazol-acetamide as new scaffold was designed by molecular hybridization of the active pharmacophores in the cholinesterase inhibitors. Twelve derivatives 7a-l of the title scaffold were synthesized in high yields using simple and efficient chemical reactions. The inhibitory activities of all the title compounds 7a-l were investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as two important enzymatic targets in Alzheimer's disease (AD). The obtained in vitro data showed that all new compounds were more potent than positive control galantamine against both studied enzymes. Representatively, the most potent compound against AChE (compound 7 g) was 2.7-times and the most potent compound against BChE (compound 7k) was 40.5-times more potent than galantamine. Docking study demonstrated that the most potent compounds interacted with main components of the active sites of AChE and BChE. Molecular dynamics of the most potent compounds showed that these compounds formed stable complex with target enzymes AChE and BChE. The most potent compounds also had acceptable pharmacokinetic properties as oral agents.