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The pro-inflammatory cytokine interleukin-1 (IL-1) drives the pathogenesis of several inflammatory diseases. Recent studies have revealed that 2-indolinones can modulate cytokine responses. Therefore, we screened several 2-indolinone derivatives in preliminary studies to develop agents with anti-IL-1 activity. First, the putative efficacies and binding interactions of 2-indolinones were evaluated by docking studies. Second, previously synthesized 5-fluoro/(trifluoromethoxy)-1H-indole-2,3-dione 3-(4-phenylthiosemicarbazones) (compounds 47-69) which had the highest inhibitory effect in the screening were evaluated for inhibitory effects on the IL-1 receptor (IL-1R). Compounds 52 (IC50 = 0.09 mu M) and 65 (IC50 = 0.07 mu M) were selected as lead compounds for the subsequent synthesis of new derivatives. The novel 5-fluoro/(trifluoromethoxy)-1H-indole-2,3-dione 3-(4-phenylthiosemicarbazones) (compounds 70-116) were designed, synthesized, and in vitro studies were completed. The compounds 76, 78, 81, 91, 100, 105, and 107 tested showed nontoxic inhibitory effects on IL-1R-dependent responses in the range of 0.01-0.06 mu M and stronger than the lead compounds 52 and 65. In vitro and in silico findings showed that compounds 78 (IC50 = 0.01 mu M) and 81 (IC50 = 0.02 mu M) had the strongest IL-1R inhibitory effects and the most favorable drug-like properties. Molecular modeling studies of the compounds 78 and 81 were carried out to determine the possible binding interactions at the active site of the IL-1R. Novel 5-fluoro/(trifluoromethoxy)-2-indolinone derivatives were designed and synthesized based on in silico and preliminary in vitro test results from lead compounds. All compounds tested displayed nontoxic IL-1 receptor inhibitory effects at IC50 values in the range of 10 nM to 13 mu M, and seven compounds showed inhibitory responses stronger than the lead compounds at 0.01-0.06 mu M.image, Scientific and Technological Research Council of Turkey (TÜBİTAK)