Based on the realization that N-alkyl 5-arylidene-2-thioxo-1, 3-thiazolidin-4-ones are tumor necrosis factor-α antagonists, we discovered two additional classes of antagonists: 3-thioxo- 2, 3-dihydro-1H-imidazo [1, 5-a] indol-1-ones (via rational design) and 5-arylidene-2- thioxodihydropyrimidine-4, 6 (1H, 5H)-diones (via computer-guided screening). Chemical modification of the lead structures showed that the structure–activity relationship profiles ...