Development of novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as balanced multifunctional agents against Alzheimer's disease

Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate A beta(1-42) aggregation inhibition. Taken both efficacy and balance into account, 12a was identified as the optimal multifunctional ligand with significant inhibition of AChE (EeAChE, IC50 = 0.20 mu M; HuAChE, IC50 = 37.02 mu M) and anti-Ab activity (IC50 = 1.92 mu M for self-induced A beta(1-42) aggregation; IC50 = 1.80 mu M for disaggregation of A beta(1-42) fibrils; IC50 = 2.18 mu M for Cu2+-induced A beta(1-42) aggregation; IC50 = 1.17 mu M for disaggregation of Cu2+-induced A beta(1-42) fibrils; 81.7% for HuAChE-induced A beta(1-40) aggregation). Moreover, it was equipped with the potential to serve as antioxidant (3.03 Trolox equivalents), metals chelator and anti-neuroinflammation agent for synergetic treatment. Finally, in vivo study demonstrated that 12a, with suitable BBB permeability (log BB = similar to 0.61), could efficaciously ameliorate cognitive dysfunction on scopolamine-treated mice by regulating cholinergic system and oxidative stress simultaneously. Altogether, these results highlight the potential of 12a as an innovative balanced multifunctional candidate for Alzheimer's disease treatment. (C) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

Based on the multitarget-directed ligands approach, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized, and evaluated as innovative multifunctional agents against Alzheimer's disease. Compound 12a showed significant inhibition of AChE and anti-A beta activity, as well as potential antioxidant, metal chelation, and anti-neuroinflammation properties. In vivo studies demonstrated that 12a effectively ameliorated cognitive dysfunction in scopolamine-treated mice by regulating the cholinergic system and oxidative stress simultaneously.