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


SOYLU ETER Ö., Sevinçli Z. Ş., Ersoy B., Hasanusta B., Gatfar U., Lack N. A., ...More

Archiv der Pharmazie, vol.356, no.12, 2023 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 356 Issue: 12
  • Publication Date: 2023
  • Doi Number: 10.1002/ardp.202300217
  • Journal Name: Archiv der Pharmazie
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, International Pharmaceutical Abstracts, Veterinary Science Database
  • Keywords: biological activity, cytokines, molecular modeling, structure–activity relationships, synthesis design
  • Van Yüzüncü Yıl University Affiliated: Yes

Abstract

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.