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

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

  • Eur J Med Chem. 2022 Feb 15;230:114098. doi: 10.1016/j.ejmech.2021.114098.
Yichun Shi 1,  Heng Zhang 1,  Qing Song 1,  Guangjun Yu 1,  Zhuoling Liu 1,  Feng Zhong 1,  Zhenghuai Tan 2,  Xiuxiu Liu 3,  Yong Deng 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 2 Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: liuxiuxiu@scu.edu.cn.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: dengyong@scu.edu.cn.
PMID: 35026532 DOI: 10.1016/j.ejmech.2021.114098
Abstract

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.

Keywords

6-(2-Hydroxyphenyl)pyridazin-3(2H)-ones; Acetylcholinesterase inhibitors; Alzheimer's disease; Anti-Aβ inhibitors; Anti-neuroinflammatory agents; Antioxidants; Multitarget-directed ligands.

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