2. Academic Validation
  3. Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer's disease

Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer's disease

  • Eur J Med Chem. 2020 Dec 1;207:112751. doi: 10.1016/j.ejmech.2020.112751.
Xueyang Jiang 1,  Junting Zhou 1,  Yang Wang 2,  Lei Chen 3,  Yan Duan 4,  Jianping Huang 4,  Chang Liu 2,  Yao Chen 5,  Wenyuan Liu 2,  Haopeng Sun 6,  Feng Feng 7,  Wei Qu 8
Affiliations

Affiliations

  • 1 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 School of Pharmacy, Gannan Medical University, Ganzhou, 341000, China.
  • 4 School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 6 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 7 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Food and Pharmaceutical Science College, No.4 Meicheng Road, Huai'an, 223003, China.
  • 8 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: popoqzh@126.com.
PMID: 32950908 DOI: 10.1016/j.ejmech.2020.112751
Abstract

A key factor in the success of the MTDLs drug discovery approach is the selection of suitable target proteins. Based on the results of our previous research regarding dual-target inhibitors of AChE/GSK-3β and analysis of target proteins, in the current study, 28 hybrids were designed and synthesized. Docking studies allowed us to rationalize the binding mode of the synthesized compounds in both targets. In vitro Enzyme inhibition studies identified compound GT15 as a lead molecule with preferential AChE/GSK-3β inhibition (hAChE IC50 = 1.2 ± 0.1 nM; hGSK-3β IC50 = 22.2 ± 1.4 nM). In addition, GT15 showed high kinase selectivity for GSK-3, except for DYRK1, with inhibition rate of 83.69% and 67.94% against DYRK1α and DYRK1β at a concentration of 20 μM. The compound also exhibited good permeability across the blood-brain-barrier and ability to inhibit the phosphorylation of Tau Protein. Upon oral administration, GT15 exhibited promising cognitive improvement in the scopolamine-induced cognitive deficit mice in the Morris water maze model. These results suggest that AChE and GSK-3 based multitargeted approach have therapeutic potential for Alzheimer's disease.

Keywords

Acetylcholinesterase; Alzheimer’s disease; Glycogen synthase kinase3β; Multi-target-directed ligands.

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