Design, synthesis, acetylcholinesterase, butyrylcholinesterase, and amyloid-ß 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 Aß1-42 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 Aß1-42 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 Aß1-42 aggregation and moderate AChE enzyme activity, and therefore can be highlighted as promising compounds.

Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p-propoxyphenylsubstituted-1H-benzimidazole derivatives.

This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o- and p-(3-substitutedethoxyphenyl)-1H-benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC50 values of 0.14 and 0.22 µM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH-SY5Y cells exposed to H2 O2 . Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H2 O2 -induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi-target-directed ligands against Alzheimer's disease.