Design, synthesis and molecular docking studies of tailored coumarin and chromone derivatives for use as anti-Alzheimer agents

Two new series of coumarin hydrazide and chromone pyrazole derivatives were designed and synthesized to evaluate their in vitro and in vivo anti-Alzheimer activity. All the derivatives were tested for their ability to inhibit cholinesterases. Compound 14 displayed the highest in vitro inhibitory activity against acetylcholinesterase and butyrylcholinesterase with IC₅₀ values of 3.31 µM and 1.60 µM, respectively. The in vivo study revealed the capability of the promising derivative to cause a decline in acetylcholinesterase levels, ameliorate the antioxidative activities of TAC and GSH, decrease the levels of MDA and NO, and down regulate that of MAP-TAU and APP. Moreover, the examination of the AD-brain regions treated with the synthetic compound 14 revealed an improvement of AD histological hallmarks. Molecular modeling of compound 14 demonstrated the interactions of the derivative with the key amino acids in AChE active site. A molecular dynamic simulation and an in silico pharmacokinetic study were conducted as well.