Synthesis and Anti‐neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2‐nitro‐1‐phenyl‐1 H ‐Indole Derivatives as p38 α MAPK Inhibitors

Inhibition of p38 mitogen‐activated protein kinases ( MAPK s) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease ( AD ). Inspired from the pharmacophore of natural NF ‐ κ B and p38 α MAPK inhibitor 5,6‐dehydrokawain and p38 α 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‐1 H ‐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 50 less than the control 5,6‐dehydrokawain. Notably, compound 27 , 6‐methoxy‐2‐nitro‐1‐(1 H ‐1, 2, 3‐triazol‐1‐yl)‐1 H ‐indole, with IC 50 values of 1.6  μ m can markedly inhibit p38 α MAPK and NO release in BV ‐2 microglial cells. The molecular dynamic ( MD ) simulations demonstrate that compound 27 inhibits p38 α 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 .