Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-kappa B signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38 alpha MAPK (IC50=1.95 mu M) and COX-2 (IC50=0.036 mu M). By virtue of the concomitant inhibition of p38 alpha MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-kappa B and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.