2. Academic Validation
  3. Discovery of quinazolin-4(3H)-one derivatives as novel AChE inhibitors with anti-inflammatory activities

Discovery of quinazolin-4(3H)-one derivatives as novel AChE inhibitors with anti-inflammatory activities

  • Eur J Med Chem. 2023 Apr 6;254:115346. doi: 10.1016/j.ejmech.2023.115346.
Ling Lv 1,  Mireguli Maimaitiming 1,  Yan Huang 1,  Jichen Yang 1,  Shuxia Chen 1,  Yanfeng Sun 1,  Xuetao Zhang 1,  Xin Li 1,  Changhu Xue 1,  Pingyuan Wang 2,  Chang-Yun Wang 3,  Zhiqing Liu 4
Affiliations

Affiliations

  • 1 College of Food Science and Engineering, Institute of Evolution & Marine Biodiversity, Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
  • 2 College of Food Science and Engineering, Institute of Evolution & Marine Biodiversity, Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: [email protected].
  • 3 College of Food Science and Engineering, Institute of Evolution & Marine Biodiversity, Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: [email protected].
  • 4 College of Food Science and Engineering, Institute of Evolution & Marine Biodiversity, Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: [email protected].
PMID: 37043994 DOI: 10.1016/j.ejmech.2023.115346
Abstract

A series of quinazolin-4(3H)-one derivatives was designed through scaffold-hopping strategy and synthesized as novel multifunctional anti-AD agents demonstrating both cholinesterase inhibition and anti-inflammatory activities. Their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated, and the Enzyme kinetics study as well as detailed binding mode via molecular docking were performed for selected compounds. MR2938 (B12) displayed promising AChE inhibitory activity with an IC50 value of 5.04 μM and suppressed NO production obviously (IC50 = 3.29 μM). Besides, it was able to decrease the mRNA levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CCL2 at 1.25 μM. Further mechanism study suggested that MR2938 suppressed the neuroinflammation through blocking MAPK/JNK and NF-κB signaling pathways. All these results indicate that MR2938 is a good starting point to develop multifunctional anti-AD lead compounds.

Keywords

Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Multifunctional inhibitor; Quinazolin-4(3H)-one; anti-inflammatory activity.

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