Novel 2,6-disubstituted-3-(2H)-pyridazones as Cholinesterase Inhibitors: In vitro Enzyme Inhibition and In silico Molecular Modelling and Dynamic Studies

The approach proposed as the cholinergic hypothesis for Alzheimer's Disease contributed significantly to the explanation of cognitive decline observed in the elderly and Alzheimer's patients due to dysfunction of neurons containing acetylcholine in the brain. To date, this notion has formed the basis of most of the treatment strategies and drug development approaches for Alzheimer Disease. Within the scope of this study, in which the synthesis and biological evaluation of pyridazinones, which are designed for multi-enzyme targets and expected to act as AChE and BChE inhibitors, were performed, 12 new compounds were synthesized, their in vitro enzyme inhibitor activities were evaluated and molecular modeling studies were carried out. While the compounds did not show significant AChE inhibition, they showed a high degree of BChE inhibition. D2e was determined as the most potent BChE inhibitor and molecular modeling and molecular dynamics simulation studies were also carried out for D2e and tacrine. The obtained results suggest that new pyridazinone derivatives can act as BChE inhibitory agents. Although the synthesized compounds are less effective than the reference drugs, it has been concluded that it is possible to reach the precursor compounds as a result of suitable modifications.