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

Twelve thiosemicarbazones and 24 corresponding Cu(II) and Pd(II) complexes were synthesised and evaluated for their physicochemical properties and biological activities. Single-crystal X-ray diffraction and mass spectrometry confirmed ligand deprotonation and the formation of neutral ML2-type complexes. Several complexes containing 3,4-dimethoxybenzylidene- or 4-bromobenzylidene-substituted ligands exhibited submicromolar cytotoxicity against melanoma cells. Cu(b-TSC)2 and Pd(dm-TSC-pCl)2 were selected for mechanistic studies and induced cell-cycle arrest, pro-apoptotic gene activation, DNA damage, and apoptosis. Notably, Cu(b-TSC)2 retained activity against vemurafenib-resistant SK-MEL-28 and A-375 cells. Structure-activity analysis showed that additional chlorine substitution generally reduced anticancer activity. Calculated physicochemical descriptors suggested that increased chlorination enhanced lipophilicity and reduced hydrophilicity, which was associated with lower apparent solution stability. These findings highlight the importance of balancing lipophilicity, hydrophilicity, and solution stability in future design of potential drugs based on thiosemicarbazones. In contrast, antibacterial activity was more strain-dependent, with MIC values against E. coli as low as 3.125 mg/L.