Discovery and structure–activity relationship of coumarin derivatives as TNF-α inhibitors

The discovery and structure–activity relationship of a novel series of coumarin-based TNF-α inhibitors is described. Starting from the initial lead 1a, various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-α production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-α production in rats.