2. Academic Validation
  3. Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease

Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2026 Aug 5:312:118844. doi: 10.1016/j.ejmech.2026.118844.
Xingyi Zhao 1,  Yu Bao 2,  Ximeng Wan 1,  Ruifeng Miao 1,  Chunting Li 1,  Jiaqi Wang 1,  Huimin Zhang 1,  Yuling Xiang 1,  Yuqi Pang 1,  Zhenyu Miao 3,  Minghui Tong 3,  Xuan Shi 3,  Han Wang 3,  Ping Gong 4,  Yanfang Zhao 5,  Yunlei Hou 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 2 School of Clinical Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
  • 3 SunShine Innovation Co., Ltd, Xiamen Torch Hi-Tech Industrial Zone Software Park, Phase III Unit 209-0887, No. 62 Chengyi North Street, Xiamen, 361021, PR China.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: gongpinggp@126.com.
  • 5 Key Laboratory of Structure-Based Drugs Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: yanfangzhao@126.com.
  • 6 Key Laboratory of Structure-Based Drugs Design & Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: houyunlei901202@163.com.
PMID: 42013744 DOI: 10.1016/j.ejmech.2026.118844
Abstract

In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC50 = 1.7 nM; sEH IC50 = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H2O2-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.

Keywords

AChE; Alzheimer's disease; Dual inhibitors; sEH.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z