Synthesis and bioevaluation and doking study of 1H-pyrrolo[2,3-b]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors

Two series of aromatic hydrazone derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (7a-r, 8a-i, 12a-b, 13a-c, 16a-d and 17a-e) were designed, synthesized and evaluated for the IC₅₀ values against four Cancer cell lines (A549, HepG2, MCF-7and PC-3). Two selected compounds (7c and 17e) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2 and EGFR kinases. The data indicated that targets compounds were selective for c-Met kinase. And the most promising compound 7c was further studied in terms of dose-dependent, time-dependent and cell Apoptosis. Most of the compounds showed excellent cytotoxicity activity, especially the most promising compound 7c with the IC₅₀ values of 0.82 ± 0.08 μM, 1.00 ± 0.11 μM, 0.93 ± 0.28 μM and 0.92 ± 0.17 μM against A549, HepG2, MCF-7 and PC-3 cell lines and 0.506 μM against c-Met kinase. Structure-activity relationships (SARs) and docking studies indicated that the activities of the phenyl hydrazone derivatives (7a-r and 8a-i) were superior to that of the heterocyclic hydrazone series (12a-b, 13a-c, 16a-d and 17a-e). What's more, the further studies indicated that the target compounds can induce Apoptosis of A549 cells and arrest efficiently the cell cycle progression in G2/M phase of A549 cells.