Design, synthesis, acetylcholinesterase, butyrylcholinesterase, and amyloid-β aggregation inhibition studies of substituted 4,4'-diimine/4,4'-diazobiphenyl derivatives.

Abstract

A series of 4,4'-diimine/4,4'-diazobiphenyl derivatives were designed, synthesized, and evaluated for their ability to inhibit both the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, as well as Aβ1-42 aggregation, in vitro. The AChE and BChE inhibition assays demonstrated that all compounds displayed moderate AChE inhibitory activity in the range of IC50 = 5.77-16.22 μM, while they displayed weak or no BChE inhibition. Among the title compounds, compound 2l, 4,4'-bis(quinolin-8-yldiazenyl)-1,1'-biphenyl, having a diazo-quinoline moiety demonstrated the most potent inhibition against AChE with an IC50 value of 5.77 μM. Furthermore, diazo derivatives 2d, 4,4'-bis[(4-methoxyphenyl)diazenyl]-1,1'-biphenyl, and 2i, 4,4'-bis(pyridin-3-yldiazenyl)-1,1'-biphenyl, provided better potency on Aβ1-42 aggregation, with an inhibition value of 74.08% and 78.39% at 100 μM and 55.35% and 61.36% at 25 μM, respectively. Molecular modeling studies were carried out for the most active compound against AChE, compound 2l. All the results suggested that compounds 2d and 2i have better inhibitory potencies on Aβ1-42 aggregation and moderate AChE enzyme activity, and therefore can be highlighted as promising compounds.