Synthesis and biological activity evaluation of phthalimide-donepezil hybrids
10.16438/j.0513-4870.2023-0863
- VernacularTitle:邻苯二甲酰亚胺-多奈哌齐杂合物的合成及活性评价
- Author:
Jun-jie WANG
1
,
2
;
Ye-shu MU
3
,
4
;
Chen HONG
1
;
Wen LUO
3
Author Information
1. Huaihe Hospital, Henan University, Kaifeng 475004, China
2. Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China
3. Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China
4. School of Pharmacy, Henan University, Kaifeng 475004, China
- Publication Type:Research Article
- Keywords:
phthalimide;
onepezil;
cholinesterase;
italic>β-amyloid;
Alzheimer's disease
- From:
Acta Pharmaceutica Sinica
2024;58(3):651-660
- CountryChina
- Language:Chinese
-
Abstract:
A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.
