Multifunctional anti-Alzheimer's agents: Synthesis, biological evaluation, and molecular docking study of new 2-phenoxyacetamide/3-phenoxypro-panamide/4-oxobutanamide derivatives

In the current study, three series of new compounds were designed and synthesized through hit optimization, based on the hit compound with a structure ( E )-N-(4-{[benzyl(methyl)amino]methyl}thiazol-2-yl)-3-(3,4- dimethoxyphenyl)prop-2-enamide, which was found as a potential multifunctional anti-Alzheimer agent in our previous study. Then, the biological activities of synthesized compounds ( 4a -c, 13a -b and 15a -c ) were evaluated. The results indicated that 4b , a 2-phenoxyacetamide derivative, exhibited good multifunctional activities. Namely, compound 4b displayed better BChE inhibition (BChE IC 50 = 2.10 mu M) and antioxidant activity (ORAC = 1.18 Trolox equivalents) compared to the hit compound (BChE IC 50 = 14.70 mu M, ORAC = 0.5 Trolox equivalents). Additionally, 4b was able to chelate all tested biometals and it also exhibited a neuroprotective effect (63 %), comparable to reference ferulic acid (77 %) while maintaining its safety upon PC12 cell line. When it comes to lowering the levels of TNF- alpha, NO, IL-1 beta , and IL -6, 4b performed better activity, relative to the other synthesized compounds. Subsequently, in silico studies such as physicochemical properties, density functional theory (DFT) computational approach and molecular docking studies were performed.