Structure-activity relationship of Cu(II) and Pd(II) thiosemicarbazone complexes with anticancer and antibacterial properties

Abstract

Twelve thiosemicarbazones and twenty-four of their Cu(II) and Pd(II) complexes were synthesized and studied in terms of physicochemical properties and biological activities. Single crystal X-ray diffraction and mass spectrometry confirmed ligand deprotonation and the formation of ML2-type complexes. All compounds were tested for anticancer activity against melanoma cells, and for antimicrobial activity against a panel of Gram-negative and Gram-positive bacteria. Several complexes bearing 3,4-dimethoxybenzylidene- or 4-bromobenzylidene-substituted ligands exhibited substantial cytotoxicity, with IC50 values in the sub-micromolar range. Two lead complexes, Pd(dm-TSC-pCl)2, and Cu(b-TSC)2, were selected for the mechanism of action studies, which revealed apoptosis induction via cell cycle arrest, pro-apoptotic gene activation, and DNA damage. Notably, Cu(b-TSC)2 retained its activity in vemurafenib-resistant SK-MEL-28 and A375 cells. For structure-activity relationship analysis, the parent ligands were functionalized with various substituents at the N1 and N4 positions. We found that, in most cases, the introduction of a chlorine substituent negatively affected anticancer activity. In contrast, antimicrobial activity was more strain-specific, with MIC values against E. coli as low as 3.125 mg/L.