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

• Published in: European journal of medicinal chemistry 2022-02, Vol.230, p.114098-114098, Article 114098
• Main Authors: Shi, Yichun, Zhang, Heng, Song, Qing, Yu, Guangjun, Liu, Zhuoling, Zhong, Feng, Tan, Zhenghuai, Liu, Xiuxiu, Deng, Yong
• Format: Article
• Language: English
• Subjects: 6-(2-Hydroxyphenyl)pyridazin-3(2H)-ones; Acetylcholinesterase - metabolism; Acetylcholinesterase inhibitors; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides; Animals; Anti-Aβ inhibitors; Anti-neuroinflammatory agents; Antioxidants; Antioxidants - pharmacology; Cholinesterase Inhibitors - pharmacology; Drug Design; Mice; Multitarget-directed ligands; Protein Aggregates; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114098

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 Aβ1-42 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 μM; HuAChE, IC50 = 37.02 nM) and anti-Aβ activity (IC50 = 1.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.80 μM for disaggregation of Aβ1-42 fibrils; IC50 = 2.18 μM for Cu2+-induced Aβ1-42 aggregation; IC50 = 1.17 μM for disaggregation of Cu2+-induced Aβ1-42 fibrils; 81.7% for HuAChE-induced Aβ1-40 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. [Display omitted] •Novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were synthesized.•Most compounds exhibited significant AChE inhibitory and antioxidant activities.•Compound 12a was endowed with the excellent comprehensive activity and good druggability.•12a could effectively ameliorate cognitive dysfunction on scopolamine-treated mice.