Synthesis, biological evaluation, molecular docking and MD simulation studies of some new picolinohydrazide derivatives as cholinesterase inhibitors

Cholinesterase inhibitors play an important role in the fight against Alzheimer's disease. For this purpose, some new N'-substitutedbenzylidene-6-methylpicolinohydrazide derivatives (3a-3k) were synthesized sequentially under hydrazide and hydrazone reaction conditions, beginning with the starting material ethyl 6-methylpicolinate. Their structures were elucidated by some spectral techniques (IR, 1H-NMR, 13C-NMR, 13C-APT NMR, 2D-NMR). In vitro antioxidant (ABTS(center dot)+, DPPH center dot, CUPRAC and beta-carotene/linoleic acid assays) and cholinesterase (AChE and BChE) inhibitory activities of the synthesized compounds were tested. Compound 3f, which carries a nitro group on the phenyl ring in the series, was found to have the highest antioxidant activity. The same derivative (3f) was observed to have the highest inhibition values against both AChE and BChE with IC50 values of 0.99+0.04 mu M and 10.16+0.27 mu M, respectively. The interactions of the most potent compound 3f with AChE and BChE enzymes were explained by molecular docking and MD simulation studies. All compounds were found to be compatible with drug-like properties and non-toxic by in silico methods.