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.

中文翻译：

---

具有抗 IL-1 活性的 5-氟/(三氟甲氧基)-2-二氢吲哚酮衍生物

促炎细胞因子白介素-1 (IL-1) 驱动多种炎症性疾病的发病机制。最近的研究表明，2-吲哚酮可以调节细胞因子反应。因此，我们在初步研究中筛选了几种2-二氢吲哚酮衍生物，以开发具有抗IL-1活性的药物。首先，通过对接研究评估了 2-吲哚酮的假定功效和结合相互作用。其次，评估了先前合成的在筛选中具有最高抑制效果的5-氟/(三氟甲氧基)−1 H-吲哚-2,3-二酮3-(4-苯硫代缩氨基脲)（化合物47-69 ）的抑制效果。 IL-1 受体 (IL-1R)。选择化合物52 (IC ₅₀  = 0.09 µM) 和65 (IC ₅₀  = 0.07 µM) 作为先导化合物，用于随后合成新衍生物。设计、合成了新型5-氟/(三氟甲氧基)−1 H-吲哚-2,3-二酮3-(4-苯硫代缩氨基脲)（化合物70-116），并完成了体外研究。测试的化合物76、78、81、91、100、105和107在 0.01–0.06 µM 范围内显示出对 IL-1R 依赖性反应的无毒抑制作用，并且比先导化合物52和65更强。体外和计算机研究结果表明，化合物78 (IC ₅₀  = 0.01 µM) 和81 (IC ₅₀  = 0.02 µM) 具有最强的 IL-1R 抑制作用和最有利的药物样特性。对化合物78和81进行分子模型研究以确定 IL-1R 活性位点可能的结合相互作用。