2. Academic Validation
  3. Discovery of novel 3-butyl-6-benzyloxyphthalide Mannich base derivatives as multifunctional agents against Alzheimer's disease

Discovery of novel 3-butyl-6-benzyloxyphthalide Mannich base derivatives as multifunctional agents against Alzheimer's disease

  • Bioorg Med Chem. 2022 Mar 15;58:116660. doi: 10.1016/j.bmc.2022.116660.
Zhuoling Liu 1,  Yichun Shi 1,  Xiaoyu Zhang 1,  Guangjun Yu 1,  Jingjing Li 1,  Shiqin Cong 1,  Yong Deng 2
Affiliations

Affiliations

  • 1 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 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: [email protected].
PMID: 35183029 DOI: 10.1016/j.bmc.2022.116660
Abstract

Based on the multitarget-directed ligands strategy, a series of 3-butyl-6-benzyloxyphthalide Mannich base derivatives were designed, synthesized and identified for Alzheimer's disease (AD). Biological activity studies demonstrated that the designed hybrids showed multitarget activities toward AD. Among them, compound 7d was the most potent agent with excellent inhibitory activities on EeAChE (IC50 = 0.087 μM), HuAChE (IC50 = 0.041 μM) and MAO-B (IC50 = 0.30 μM). Furthermore, molecular docking studies were conducted to investigate the interaction mode with enzymes. Besides, 7d also possessed good effects of Cu2+ chelation, ameliorate oxidative stress, and anti-neuroinflammation, desirable BBB permeability and eligible drug-like properties. Altogether, the multifunctional profiles of 7d prove that it deserves further investigation as a novel drug candidate for AD treatment.

Keywords

3-butyl-6-benzyloxyphthalide Mannich bases; Acetylcholinesterase inhibitors; Alzheimer's disease; Anti-neuroinflammation; Antioxidant; Monoamine oxidase B inhibitors; Neuroprotection.

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