Antibiotic resistance is a problem repeatedly reported by health authorities. Metalloantibiotics, i.e., biologically active compounds containing one or more metal ions, can be an important resource in the fight against bacteria and fungi. Here, we report the results obtained with a panel of copper(II), nickel(II) and zinc(II) complexes with thiosemicarbazone, semicarbazone and acylhydrazone ligands on Staphylococcus aureus, Escherichia coli and Candida albicans, taken as model systems of human pathogens. To increase the solubility in water, the sulfonic group was introduced on some of the ligands, isolating them as sodium salts (NaH₂L4-NaH₂L7). Complexes 1–14 were isolated, fully characterized and the X-ray structures of 11, 12 and 13 were obtained. While all the ligands have no antimicrobial activity, the copper(II) complexes 1 and 4 and the nickel(II) complex 2, obtained from thiosemicarbazone ligands, showed good activity, in particular against S. aureus; these complexes were investigated in depth, calculating their respective IC₅₀ values (4.2 μM, 3.5 μM and 61.8 μM, respectively). It should be noted that nickel(II) complex 2 does not show hemolytic activity and has a favorable SI value. While all the copper(II) complexes completely degraded the plasmid DNA in presence of H₂O₂, nickel(II) complex 2 cleaved the plasmid DNA leading to the formation of the relaxed nicked conformation, thus suggesting a different mechanism of action.

Research in the field of metallodrugs is continually increasing. However, it is often limited by the poor solubility in water of the metal complexes. To try to overcome this problem, the two new ligands bis-(sodium 3-methoxy-5-sulfonate-salicylaldehyde)thiocarbohydrazone (bis-TCH, Na₂H₄L¹) and bis-(sodium 3-methoxy-5-sulfonate-salicylaldehyde)carbohydrazone (bis-CH, Na₂H₄L²) were synthesized and characterized, both achieving high solubility in water. The speciation of the ligands and their coordinating behaviour towards the biologically relevant Cu(II) and Zn(II) ions were studied spectroscopically and potentiometrically, determining the pK_as of the ligands and the formation constants of the complex species. The monometallic and bimetallic Cu(II) and Zn(II) complexes were isolated, and the single-crystal X-ray structure of [Cu₂(NaHL¹)(H₂O)₇]^.3.5H₂O was discussed. Finally, preliminary studies of the in vitro cytotoxic properties of the new compounds were started on normal (Hs27) and cancer (U937) cell lines. bis-TCH was able to induce a growth inhibition effect between 40% and 45% in both cell lines; bis-CH did not produce a reduction in cell viability in Hs27 cells but revealed mild antiproliferative activity after 72 h of treatment in U937 cancer cells (GI₅₀ = 46.5 ± 4.94 μg/mL). Coordination of the Cu(II) ions increased the toxicity of the compounds, while, in contrast, Zn(II) complexes were not cytotoxic.

Despite the capability of bis-(thio)carbohydrazones to coordinate metals and the remarkable biological properties of the resulting complexes, no general information is known about their individual behavior in solution. This study is focused on two recently synthesized compounds, a bis-thiocarbohydrazone (bis-TCH) and a bis-carbohydrazone (bis-CH) isolated as sodium salts, that have shown chelating properties toward copper(II) and zinc(II) metal ions along with promising cytotoxic activity. In this work, an integrated theoretical–computational, nuclear magnetic resonance (NMR), and vibrational characterization of both bis-TCH and bis-CH anions in a non-protic solvent (dimethylsulfoxide) is presented to better elucidate their properties. Their protonic NMR spectra underline the presence of cis–trans, EE isomers, characterized by a significant conformational freedom at room temperature. The presence of oxygen or sulfur heteroatoms can tune the molecular conformational dynamics driving a different interaction with the solvent, as highlighted by density functional theory calculations and atomistic molecular dynamics simulations. Our results demonstrate that a quantitative agreement with the NMR and Raman signals is achieved only when an explicit solvent description is included. The insights achieved by this study can contribute to a better understanding of the behavior of bis-carbohydrazones and bis-thiocarbohydrazones in solution, a crucial and mandatory step to improve the design of novel, more potent analogs.

A panel of copper(I) complexes was isolated by metal-templated reactions starting from 2-(diphenylphosphino)benzaldehyde and some 4-substituted-benzylamines, and by changing the ratio between metal and ligand and the anion. The spectroscopic characterization of the copper(I) complexes was completed by discussion of some structures obtained by single-crystal X-ray diffraction. The copper(I) complexes were assayed in vitro against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Candida albicans ATCC 10231. Cell viability was assessed both in nonmalignant and malignant cell lines, namely Vero and Caco-2 cells, respectively. While the tested compounds show only a nonspecific antibacterial effect against S. aureus, some of them showed an interesting antiproliferative activity.

To overcome the limitations of conventional chemotherapy, specifically poor selectivity and systemic toxicity, this study explores a targeted approach leveraging the Warburg effect. We developed a series of novel copper(II) glucose-conjugated thiosemicarbazones (C1–C4), rationally designed to enhance water solubility and achieve good selectivity toward cancer cells. In vitro evaluations across a panel of human cancer cell lines demonstrated that free ligands were largely inactive, whereas copper(II) coordination significantly enhanced cytotoxicity. A strong linear correlation was observed between GLUT1 expression levels and cytotoxic potency, suggesting a possible involvement of GLUT-mediated uptake. Furthermore, when tested against HEK-293 cells, these complexes displayed a promising degree of selectivity, with selectivity indices (SI) up to four times higher than that of cisplatin. Mechanistic investigations indicated efficient intracellular accumulation together with inhibition of Protein Disulfide Isomerase (PDI). Morphological analysis via TEM and confocal microscopy in PSN-1 pancreatic cancer cells revealed features consistent with paraptosis rather than classical apoptosis. These findings suggest that metal-based glyco-conjugation is a highly effective strategy for developing selective, potent, and water-soluble anticancer agents capable of bypassing traditional drug resistance pathways.