4-Oxobenzo[d]1,2,3-triazin-pyridinium-phenylacetamide derivatives as new anti-Alzheimer agents: design, synthesis, in vitro evaluation, molecular modeling, and molecular dynamic study

A new series of 4-oxobenzo[d]1,2,3-triazin-pyridinium-phenylacetamide hybrids 8a-p was designed, synthesized, and screened as the potential cholinesterase inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Obtained anti-cholinesterase activities demonstrated that all the title compounds exhibited excellent inhibition against BuChE and moderate inhibitory activity toward AChE in comparison to standard cholinesterase inhibitor donepezil. For example, compound 8e exhibited about 49-fold higher inhibitory activity than donepezil (IC50 = 3.2 +/- 0.3 mu M) against BuChE. This compound inhibited BuChE via a mixed-type inhibition mode. This finding demonstrated that compound 8e in addition to catalytic anionic site (CAS) can also interact with the peripheral anionic site (PAS) of BuChE. Molecular modeling and molecular dynamic studies were also performed on synthesized compounds.