Exploration of anticancer potency of N(4) thiomorpholinyl isatin/5-haloisatin thiosemicarbazones on coordination to Cu2+ ion

• Copper (II) complexes of thiosemicarbazones exhibit prominent anti-proliferative activity toward MCF-7 and A431 cell lines. • Coordination of Schiff’s bases to copper (II) ion accelerates their anticancer activity. • Single crystal X-ray study confirms the existence of thiosemicarbazones in thione tautomeric form with intra and intermolecular H-bondings. • Copper(II) thiosemicarbazones are mononuclear, thermally stable and possess distorted square planar geometry. • Substitution at parent ring and N (4) position plays a key role to enhance the anticancer activity of compounds. A series of N(4) thiomorpholinyl isatin/5-haloisatin thiosemicarbazones and their copper(II) complexes ( 1 – 8 ) were prepared and characterized by elemental analysis, NMR, IR, ESI-HRMS, UV–Visible, EPR, TGA, PXRD, and single-crystal X-ray diffraction studies. The copper(II) complexes possess distorted square planar geometry. The single-crystal X-ray study of compounds ( 1 – 3 ) revealed their existence in thione tautomeric form. The in vitro antiproliferative study of the compounds against cancer cells; MCF-7 (breast cancer), A431(skin cancer), and PNT2 (human normal prostate epithelium) showed significant antiproliferative activity for both ligands and complexes. Compound 4 showed higher cell growth inhibition (39%) than the corresponding complex 8 (27%) toward the MCF-7 cell line. Although compound 4 did not show a good effect in the A431 cell line, it was the least toxic in the PNT2 cell line. Compounds 3 and 5 showed notable antiproliferative activity against the A431 with the cell growth inhibition of 53% and 54% respectively. Chelation of ligands to Cu(II) ion resulted in the increased cell growth inhibition toward MCF-7 and/or A431cell lines. Compound 1 exhibited the lowest antiproliferative activity against the MCF-7 with inhibition of 6%. Overall, out of all the studied compounds, compound 4 showed good antiproliferative activity and the least toxicity toward the MCF-7 and PNT2 cell lines respectively. Also, they could be further studied at a different level of anticancer tests to be used as high efficacy non-platinum anticancer drugs.