Synthesis, biological evaluations and molecular modelling studies of novel indolin-2-ones designing as FGFR inhibitors.

A series of novel 3,5-disubstituted indolin-2-ones were designed and synthesized as selective FGFR inhibitors. In the design process of 3,5-disubstituted indolin-2-ones for FGFRs, molecular docking studies were performed to generate and optimize novel compounds which have FGFR inhibitory potency, theoretically. enzyme inhibitory and selectivity profiles of the synthesized compounds, and their cytotoxicity against NIH-3T3 cells were evaluated. According to enzyme inhibition assay, compound (FGFR1-4; IC = 19.82; 5.95; 1419; 37150 nM), compound (FGFR1-4; IC = 1890; ; 6.50; 18590 nM) and compound (FGFR1-4; IC = 6.99; 1022; 17090; 8993 nM) have displayed best inhibitory potency against FGFR2, FGFR3 and FGFR1, respectively. The studied compounds have displayed low affinity to FGFR4 in comparison with other isoforms. Molecular docking study data were used to determine the binding orientations of the synthesized compounds inside FGFRs in accordance with enzyme inhibition assay data. Molecular dynamics simulations and free energy calculations were performed to determine stability, binding modes and dynamics behaviors of compound , and inside FGFR-2, FGFR-3 and FGFR-1, respectively. The compounds bearing aromatic groups at the C5 position of indolin-2-one could be lead compounds for the development of more effective and selective FGFR1-3 inhibitors.