Design, synthesis, and evaluation of fused Indolin-2-one derivatives as potent anti-inflammatory and anti-cancer agents targeting the CXCR6 pathway

The pathological condition known as cancer requires inflammatory processes for tumor growth while simultaneously impairing immune system monitoring. The research presents an analysis of heterocyclic compound synthesis and assessment including fused pyrazole and indolin-2-one derivatives. The researchers performed additional in silico and in vivo analysis on compounds 5a and 5i from the designed heterocyclic compounds. Performed using graph theoretical methods the investigators identified CXCR6 as a potential key target for therapy. The binding affinity evaluation of 5a and 5i showed strong interactions with CXCR6 receptors which exceeded the binding capacity of Celecoxib. The interactions between the receptor and ligands 5a and 5i exhibited notable stability over a 100 ns simulation period, as revealed by molecular dynamics analysis. Further extended simulations of the 6KVA–5a complex over 1000 ns provided valuable insights into the system's stability, highlighting key structural features. The analysis of RMSD, RMSF, and protein-ligand contact profiles demonstrated consistent structural stability, residue flexibility, and identified crucial binding interactions, reinforcing the reliability of the receptor-ligand binding. The drug-likeness aspects and electronic stability of synthesized compounds received backing from density functional theory and SwissADME predictions. Results from carrageenan-induced paw oedema tests showed 5a and 5i reduced inflammation in living conditions in the same way as Diclofenac but 5a produced 48.57 % inhibition while Diclofenac reached 52.85 % inhibition. The study indicates that compound 5a demonstrates particular efficacy as a potential lead drug candidate for future anti-inflammatory treatment development through CXCR6 inhibition.