Design, synthesis and evaluation of quinoline-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Abstract

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer’s disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC₅₀ values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound 3f presented significant neuroprotective effect on Aβ_25-35-induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl₃-induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.

Keywords:

• Alzheimer’s disease
• quinoline-O-carbamate derivatives
• multifunctional agent
• zebrafish AD model

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was financially supported by the State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University (Grant number FAMP202107K); Science and Technology Project of Henan Province (NO.2121023111000); The Special Project of Nanyang Normal University (SYKF2020032, 2020ZX015, 2020QN036, 2020QN045 and 2021CX002); Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region (NMGIRT2216); Natural Science Foundation of Inner Mongolia Autonomous Region of China (2020MS08103); Open project from Key Laboratory of Traditional Mongolian Medicine Research & Development Engineering, State Ethnic Afairs Commission and Ministry of Education (MDK2022042).