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

Hongsong Chen; Jing Mi; Sen Li; Zhengwei Liu; Jing Yang; Rui Chen; Yujie Wang; Yujuan Ban; Yi Zhou; Wu Dong; Zhipei Sang

doi:10.1080/14756366.2023.2169682

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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2169682. doi: 10.1080/14756366.2023.2169682.

Authors

Hongsong Chen¹, Jing Mi², Sen Li³, Zhengwei Liu², Jing Yang², Rui Chen⁴, Yujie Wang⁴, Yujuan Ban⁴, Yi Zhou², Wu Dong¹, Zhipei Sang^{2

5}

Affiliations

¹ Inner Mongolia Key Laboratory of Toxicant Monitoring and Toxicology, College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, Inner Mongolia, China.
² College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, Henan, China.
³ Department of Orthopaedics Surgery, Nanyang Central Hospital, Nanyang, Henan, China.
⁴ State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, Guizhou, China.
⁵ School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, China.

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; multifunctional agent; quinoline-O-carbamate derivatives; zebrafish AD model.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease* / drug therapy
Amyloid beta-Peptides
Animals
Carbamates / pharmacology
Cholinesterase Inhibitors / pharmacology
Drug Design
Hydroxyquinolines*
Molecular Structure
Neuroprotective Agents*
Quinolines* / pharmacology
Structure-Activity Relationship
Zebrafish

Substances

Amyloid beta-Peptides
Carbamates
Cholinesterase Inhibitors
Neuroprotective Agents
Hydroxyquinolines
Quinolines
Acetylcholinesterase

Grants and 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).