Topo II inhibition and DNA intercalation by new phthalazine-based derivatives as potent anticancer agents: design, synthesis, anti-proliferative, docking, and <i>in vivo</i> studies

Abstract

This research presents the design and synthesis of a novel series of phthalazine derivatives as Topo II inhibitors, DNA intercalators, and cytotoxic agents. <i>In vitro</i> testing of the new compounds against HepG-2, MCF-7, and HCT-116 cell lines confirmed their potent cytotoxic activity with low IC₅₀ values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC₅₀ values determination demonstrated Topo II inhibitory activities and DNA intercalating affinities of the tested compounds at a micromolar level. Amongst, compound <b>9d</b> was the most potent member. It inhibited Topo II enzyme at IC₅₀ value of 7.02 ± 0.54 µM with DNA intercalating IC₅₀ of 26.19 ± 1.14 µM. Compound <b>9d</b> was then subjected to an <i>in vivo</i> antitumor examination. It inhibited tumour proliferation reducing solid tumour volume and mass. Additionally, it restored liver enzymes, proteins, and CBC parameters near-normal, indicating a remarkable amelioration in their functions along with histopathological examinations.