title: Synthesis and Evaluation of 3-(furo[2,3-b]pyridin-3-yl)-4-(1H-indol-3-yl)-maleimides as Novel GSK-3β Inhibitors and Anti-Ischemic Agents.
abstract: A series of novel 3-(furo[2,3-b]pyridin-3-yl)-4-(1H-indol-3-yl)-maleimides were designed, synthesized, and biologically evaluated for their GSK-3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK-3β protein. Among them, compounds 5n, 5o, and 5p significantly reduced GSK-3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK-3β activity. In the in vitro neuronal injury models, compounds 5n, 5o, and 5p prevented neuronal death against glutamate, oxygen-glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK-3β inhibitors with potential neuroprotective activity against brain ischemic stroke.
authors.affiliation: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310032, China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310032, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310032, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Mao
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yuanxue
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310032, China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D060326:Chemistry Techniques, Synthetic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018698:Glutamic Acid / Q000009:adverse effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D020128:Inhibitory Concentration 50; D008301:Maleimides / Q000737:chemistry; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008301:Maleimides; D018696:Neuroprotective Agents; C043592:maleimide; D018698:Glutamic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: GSK-3β inhibitors; anti-ischemic agents; kinase activity; maleimides