Synthesis and biological evaluation of potential small molecule inhibitors of tumor necrosis factorElectronic supplementary information (ESI) available. See DOI: 10.1039/c5md00023h

Inhibition of tumor necrosis factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of rheumatoid arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNF inhibitors. Our results show that small structural changes produce ligands with similar binding affinities ( K d ) for TNF, but significantly different potencies in a L929 cell-based assay. In addition, contrary to the high affinity of compounds 4e , 8c and 10e for TNF in vitro , the potency of these compounds was determined to be low. We propose that these differences can partly be explained by the physicochemical characteristics of the synthesized SPD-304 analogs. Our findings were supplemented by molecular docking studies on the TNF dimer. These synthesized analogs may serve as a starting point for developing novel TNF inhibitors. A series of 39 novel SPD-304 analogs were designed synthesized and evaluated as inhibitors of TNF.