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.
Hongsong Chen  1 ,  Jing Mi  2 ,  Sen Li  3 ,  Zhengwei Liu  2 ,  Jing Yang  2 ,  Rui Chen  4 ,  Yujie Wang  4 ,  Yujuan Ban  4 ,  Yi Zhou  2 ,  Wu Dong  1 ,  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.
PMID: 36688444 DOI: 10.1080/14756366.2023.2169682
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 Aβ25-35-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.
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