Synthesis, cholinesterase inhibition and hepatotoxicity of tacrine-phenol-bifendate hybrids
10.16438/j.0513-4870.2022-0437
- VernacularTitle:他克林-苯酚-联苯双酯杂合物的合成、胆碱酯酶抑制活性及肝毒性评价
- Author:
Chen HONG
1
;
Yong-mei ZHAO
2
;
Hui-yan GUO
3
;
Wen LUO
3
Author Information
1. Huaihe Hospital, Henan University, Kaifeng 475004, China
2. Pharmaceutical Engineering Department, Henan Vocational College of Applied Technology, Kaifeng 475004, China
3. Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China
- Publication Type:Research Article
- Keywords:
tacrine;
cholinesterase;
hepatotoxicity;
Alzheimer's disease
- From:
Acta Pharmaceutica Sinica
2022;57(9):2759-2766
- CountryChina
- Language:Chinese
-
Abstract:
A series of tacrine-phenol-bifendate hybrids (7a-7e, 8a-8e) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs) with low hepatotoxicity. All the compounds had potent ChEs inhibitory activity with half-inhibitory concentration (IC50) values at the nanomolar range. Compound 8d exhibited the strongest inhibition to acetylcholinesterase (AChE) with an IC50 value of 156.39 nmol·L-1 and compound 7b showed the most potent inhibition for butyrylcholinesterase with IC50 value of 16.33 nmol·L-1. Kinetic and molecular modeling studies showed that 8d targeted both the catalytic active site and the peripheral anionic site of AChE. In addition, these compounds showed low toxicity to hepatocytes, and compound 8d did not increase the level of reactive oxygen species in HepG2 cells.
