Design, synthesis, and biological evaluation of new series of pyrrol-2(3H)-one and pyridazin-3(2H)-one derivatives as tubulin polymerization inhibitors

[Display omitted] •Novel Pyrrol-2-one, Pyridazin-3(2H)-one derivatives has been synthesized and tested by NCI for anticancer activity.•IVc and IVg showed excellent activity and were further selected for a five-dose assay.•In vitro antiproliferative activity of IVc, IVf, and IVg was evaluated using MTT assay.•Compounds IVc, IVf, and IVg have been evaluated against EGFR, BRAFV600E and Tubulin anticancer targets.•A docking study of IVc, IVf and IVg showed a strong fitting to the CA-4 binding sites in tubulin. A potential microtubule destabilizing series of new thirty-five Pyrrol-2-one, Pyridazin-3(2H)-one and Pyridazin-3(2H)-one/oxime derivatives has been synthesized and tested for their antiproliferative activity against a panel of 60 human cancer cell lines. Compounds IVc, IVg and IVf showed a broad spectrum of growth inhibitory activity against cancer cell lines representing renal, cancer of lung, colon, central nervous system, ovary, and kidney. Among them, compound IVg was found to have broad spectrum anti-tumor activity against the tested nine tumor subpanels with selectivity ratios ranging between 0.21 and 3.77 at the GI50 level. In vitro assaying revealed tubulin polymerization inhibition by all active compounds IVc, IVg and IVf. The results of the docking study revealed nice fitting of compounds IVc, IVf, and IVg into CA-4 binding site in tubulin. The three compounds exhibited high binding affinities (ΔGb = −12.49 to −12.99 kcal/mol) toward tubulin compared to CA-4 (−8.87 kcal/mol). Investigation of the binding modes of the three compounds IVc, IVf, and IVg revealed that they interacted mainly hydrophobically with tubulin and similar binding orientations to that of CA-4. These observations suggest that tubulin is a possible target for these compounds.