2. Academic Validation
  3. Design, synthesis and biological evaluation of novel coumarin derivatives as multifunctional ligands for the treatment of Alzheimer's disease

Design, synthesis and biological evaluation of novel coumarin derivatives as multifunctional ligands for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2022 Nov 15:242:114689. doi: 10.1016/j.ejmech.2022.114689.
Wenjie Liu 1,  Limeng Wu 1,  Wenwu Liu 2,  Liting Tian 1,  Huanhua Chen 1,  Zhongchan Wu 1,  Nan Wang 3,  Xin Liu 4,  Jingsong Qiu 1,  Xiangling Feng 1,  Zihua Xu 5,  Xiaowen Jiang 6,  Qingchun Zhao 7
Affiliations

Affiliations

  • 1 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, People's Republic of China.
  • 3 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
  • 4 School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 5 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China.
  • 6 School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China. Electronic address: jxwphu@syphu.edu.cn.
  • 7 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, 110840, People's Republic of China. Electronic address: zhaoqingchun1967@163.com.
PMID: 36007469 DOI: 10.1016/j.ejmech.2022.114689
Abstract

Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been utilized to develop innovative anti-neurodegenerative properties and is a desirable starting point for the construction of MTDLs. Herein, we explored and synthesized a series of novel coumarin derivatives and assessed their inhibitory effects on cholinesterase (AChE, BuChE), GSK-3β, and BACE1. Among these compounds, compound 30 displayed the multifunctional profile of targeting the AChE (IC50 = 1.313 ± 0.099 μM) with a good selectivity over BuChE (SI = 24.623), GSK-3β (19.30% inhibition at 20 μM), BACE1 (IC50 = 1.227 ± 0.112 μM), along with moderate HepG2 cytotoxicity, SH-SY5Y cytotoxicity, low HL-7702 cytotoxicity, as well as good blood-brain barrier (BBB) permeability. Kinetic and docking studies indicated that compound 30 was a competitive AChE Inhibitor. Furthermore, acute toxicity experiments revealed that it was non-toxic at a dosage of 1000 mg/kg. The ADME prediction results indicate that 30 has acceptable physicochemical properties. Collectively, these findings demonstrated that compound 30 would be a potential multifunctional candidate for AD therapy.

Keywords

AChE; Alzheimer's disease; BACE1; Coumarin; GSK-3β.

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