Shi_2022_Eur.J.Med.Chem_230_114098

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 Abeta(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, IC(50) = 0.20 microM; HuAChE, IC(50) = 37.02 nM) and anti-Abeta activity (IC(50) = 1.92 microM for self-induced Abeta(1-42) aggregation; IC(50) = 1.80 microM for disaggregation of Abeta(1-42) fibrils; IC(50) = 2.18 microM for Cu(2+)-induced Abeta(1-42) aggregation; IC(50) = 1.17 microM for disaggregation of Cu(2+)-induced Abeta(1-42) fibrils; 81.7% for HuAChE-induced Abeta(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 = -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.