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.