Synthesis and Anti‐neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2‐nitro‐1‐phenyl‐1H‐Indole Derivatives as p38α MAPK Inhibitors. (1st June 2015)

• Record Type: Journal Article
• Authors: Cheng, Bao; Lin, Yongsheng; Kuang, Ming; Fang, Sai; Gu, Qiong; Xu, Jun; Wang, Laiyou
• Is Part Of: Chemical biology & drug design. Volume 86:Number 5(2015:Nov.)
• Page Start: 1121
• Page End: 1130
• Publication Date: 2015-06-01
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12581
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12581-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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‐<italic>κ</italic>B and p38<italic>α </italic>MAPK inhibitor 5, 6‐dehydrokawain and p38<italic>α </italic>MAPK inhibitors 1a, 1‐pyrazolyl‐3‐(4‐((2‐anilinopyrimidin‐4‐yl)oxy)napththalen‐1‐yl)ureas, and <bold>1b</bold>, a class of indole–pyrimidinyl compounds which were patented respectively, we designed, <italic>de novo</italic> synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2‐nitro‐1‐phenyl‐1<italic>H</italic>‐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 IC<sub>50</sub> less than the control 5, 6‐dehydrokawain. Notably, compound <bold>27</bold>, 6‐methoxy‐2‐nitro‐1‐(1<italic>H</italic>‐1, 2, 3‐triazol‐1‐yl)‐1<italic>H</italic>‐indole, with IC<sub>50</sub> values of 1.6 <bold><italic>μ</italic></bold><sc>m</sc> can markedly inhibit p38<bold><italic>α</italic></bold> MAPK and NO release in BV‐2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound <bold>27</bold> inhibits p38<bold><italic>α</italic></bold> MAPK through binding to the Glu71 and Asp168 residues. Moreover, <italic>in vitro</italic> 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.</p> </abstract>