2. Academic Validation
  3. Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease

Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2019 Apr 15:168:207-220. doi: 10.1016/j.ejmech.2019.02.053.
Dongmei Wang 1,  Min Hu 1,  Xinpeng Li 2,  Dan Zhang 3,  Chengjuan Chen 1,  Junmin Fu 1,  Shuai Shao 1,  Gaona Shi 1,  Yu Zhou 1,  Song Wu 4,  Tiantai Zhang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Food and Drug Administration of Beijing, Yanqing District, Beijing, 102100, China.
  • 3 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, China.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: ws@imm.ac.cn.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: ttzhang@imm.ac.cn.
PMID: 30822710 DOI: 10.1016/j.ejmech.2019.02.053
Abstract

A series of novel isoflavone analogs were designed, synthesized, and evaluated as multitarget-directed ligands for the treatment of Alzheimer's disease. In vitro evaluations revealed that some ligands had multifunctional profiles, including potent blockage of histamine 3 receptor (H3R), excellent inhibition of acetylcholinesterase (AChE), neuroprotective effects and anti-neuroinflammatory properties. Among these derivatives, compound 9b exhibited the highest ability to block H3R (IC50 = 0.27 μM) and good inhibitory activity against AChE (IC50 = 0.08 μM). Additionally, compound 9b showed obvious neuroprotective effect on SH-SY5Y by preventing copper-induced neuronal damage and potent anti-neuroinflammatory activity by inhibiting the production of inflammatory factors on BV-2 cells. A molecular modeling study revealed that 9b acts as a mixed-type inhibitor that interacts simultaneously with H3R and AChE. Moreover, in vivo data revealed that compound 9b did not cause acute toxicity in mice at doses up to 1000 mg/kg, and had desirable pharmacokinetic properties, as well as a good blood-brain barrier (BBB) permeability (log BB = 1.24 ± 0.07). Further studies demonstrated that chronic oral treatment with 9b significantly improved cognitive dysfunction in scopolamine-induced AD mice in the step-down passive avoidance test. Taken together, the present study showed that compound 9b is a promising multifunctional drug candidate for the treatment of Alzheimer's disease.

Keywords

Acetylcholinesterase; Alzheimer's disease; Histamine 3 receptor; Isoflavone analogs; Multifunctional agents; Neuroprotection.

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