title: Synthesis and anti-neuroinflammatory activity of lactone benzoyl hydrazine and 2-nitro-1-phenyl-1h-indole derivatives as p38α MAPK inhibitors.
abstract: Inhibition of p38 mitogen-activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF-κB and p38α MAPK inhibitor 5,6-dehydrokawain and p38α MAPK inhibitors 1a, 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl)ureas, and 1b, a class of indole-pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2-nitro-1-phenyl-1H-indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)-induced microglia activation with IC50 less than the control 5,6-dehydrokawain. Notably, compound 27, 6-methoxy-2-nitro-1-(1H-1, 2, 3-triazol-1-yl)-1H-indole, with IC50 values of 1.6 μm can markedly inhibit p38α MAPK and NO release in BV-2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood-brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti-neuroinflammatory agents for AD.
authors.affiliation: Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory against Metabolic Diseases, Guangzhou Higher Education Mega Centre, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory against Metabolic Diseases, Guangzhou Higher Education Mega Centre, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Kuang
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Fang
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong TCM Key Laboratory against Metabolic Diseases, Guangzhou Higher Education Mega Centre, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
authors.forename: Laiyou
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D056004:Molecular Dynamics Simulation; D009569:Nitric Oxide / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D006834:Hydrazines; D007211:Indoles; D007783:Lactones; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D048308:Mitogen-Activated Protein Kinase 14
keywords: 2-nitro-1-phenyl-1H-indole derivatives; 5,6-dehydrokawain; molecular dynamics; neuroinflammation; nitric oxide; p38α MAPK