Furman_2014_Bioorg.Med.Chem.Lett_24_2283

A prolonged increase in pro-inflammatory cytokines, TNF-alpha and IL-6 occurs in inflammatory diseases. Although existing therapies like steroids and TNF-alpha antagonists are effective they may cause serious adverse effects. We describe the preparation and evaluation for anti-inflammatory activity of 11 novel derivatives of indoline carbamates with a propionic ester, 2-aminoethyl, 3-aminopropyl 2-(dimethylamino)ethyl or 3-(dimethylamino)propyl group in positions 3 or 1. Compounds 25, 26 and 29 were previously shown to inhibit acetylcholinesterase with IC50s ranging from 0.4 to 55muM and to prevent cytotoxicity induced by reactive oxygen species in a concentration range of 100pM-1muM. Compounds 25, 26, 29, 9, 10, 17 and 18, reduced NO, TNF-alpha and IL-6 at concentrations of 1-10pM in LPS-activated RAW-264.7 and mouse peritoneal macrophages. The reduction in cytokines by compound 25 was associated with an increase in IkappaBalpha degradation and a decrease in the phosphorylation of p38 but not that of ERK. Conclusion: Indoline derivatives substituted at position 3 with chains carrying ester or amino groups may have potential for the treatment of chronic inflammatory and neurodegenerative diseases.