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

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 Aβ aggregation, in vitro. The AChE and BChE inhibition assays demonstrated that all compounds displayed moderate AChE inhibitory activity in the range of IC  = 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 IC 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 Aβ 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 Aβ aggregation and moderate AChE enzyme activity, and therefore can be highlighted as promising compounds.