5‐Fluoro/(trifluoromethoxy)‐2‐indolinone derivatives with anti‐interleukin‐1 activity

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 µM) and 65 (IC50 = 0.07 µM) 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 µM and stronger than the lead compounds 52 and 65. In vitro and in silico findings showed that compounds 78 (IC50 = 0.01 µM) and 81 (IC50 = 0.02 µM) 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 µM, and seven compounds showed inhibitory responses stronger than the lead compounds at 0.01–0.06 µM.