Synthesis, characterization, anticancer, pharmacokinetics and molecular docking investigation of N (3)-alkyl incorporated-3-acetyl-4-hydroxycoumarin thiosemicarbazones and their copper(II) complexes

Coumarin based thiosemicarbazones (TSC), (E)-2-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)-N-methylhydrazine-1-carbothioamide (HACmMeTsc) (3), (E)-N-ethyl-2-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)hydrazine-1-carbothioamide (HACmEtTsc) (4) and (E)-N,N-diethyl-2-(1-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethylidene)hydrazine-1-carbothioamide (HACmDEtTsc) (5) and their respective copper(II) complexes ([Cu(ACmMeTsc)Cl] (3a), [Cu(ACmEtTsc)Cl] (4a) and [Cu(ACmDEtTsc)Cl] (5a)) are synthesized and characterized by elemental analysis, FTIR, UV-Vis, ESI HRMS, H-1 NMR, C-13 NMR and single crystal X-ray diffraction analysis. The in vitro anticancer activity of the synthesized compounds by MTT assay against breast cancer cell lines MCF-7 and MDA-MB-231 exhibited strong anti-cancer potential in a dose dependent manner with IC50 value in the range of 12.94 -23.70 mu g/mL and 42.18- >100 mu g/mL in MCF-7 and MDA-MB-231 cells respectively. Molecular docking study showed that compounds 3, 4 and 5 have significant binding affinity (Delta G = -6.8 to -8.4 kcal/mol) along with interactions including hydrogen bonding with active sites of amino acid residues of both studied proteins, EGFR and HER 2, which may be responsible for the inactiveness of the receptors.