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

• Published in: European journal of medicinal chemistry Vol. 242; p. 114689
• Main Authors: Liu, Wenjie, Wu, Limeng, Liu, Wenwu, Tian, Liting, Chen, Huanhua, Wu, Zhongchan, Wang, Nan, Liu, Xin, Qiu, Jingsong, Feng, Xiangling, Xu, Zihua, Jiang, Xiaowen, Zhao, Qingchun
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.11.2022; Elsevier
• Subjects: AChE; Alzheimer's disease; BACE1; Chemistry, Medicinal; Coumarin; GSK-3β; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; BACE1; AChE; GSK-3β; Coumarin; Alzheimer's disease; ACETYLCHOLINESTERASE; ANALOGS; DIRECTED LIGANDS; GSK-3 beta; BACE1 INHIBITORS; HYBRIDS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114689

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. [Display omitted] •Synthesis of novel coumarin derivatives as multifunctional ligands for the treatment of AD.•Compound 30 inhibits AChE (IC50 = 1.313 μM), BACE1 (IC50 = 1.227 μM) and the detailed SARs were discussed.•Compound 30 demonstrates good blood-brain barrier permeability.•Compound 30 possesses low cytotoxicity and acute toxicity.•Compound 30 has acceptable predicted ADME and physicochemical properties.