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Complexes [In(2Ac4Ph)2]NO3·H2O (1), [In(2Ac4mClPh)2]NO3·1.5H2O (2), [In(2Ac4pClPh)2]NO3·2H2O (3) and [In(2Ac4pIPh)2]NO3·H2O (4) were obtained with N(4)-phenyl-2-acetylpyridine thiosemicarbazone (H2Ac4Ph), and its N(4)-meta-chlorophenyl-(H2Ac4mClPh), N(4)-para-chlorophenyl-(H2Ac4pClPh) and N(4)-para-iodophenyl-(H2Ac4pIPh) derivatives. The crystal structures of [In(2Ac4Ph)2]NO3·MeOH (1a), [In(2Ac4mClPh)2]NO3·EtOH·H2O (2a) and [In(2Ac4pClPh)2]·NO3 (3a) were determined. The cytotoxic effects of the thiosemicarbazone ligands and of complexes (1–4) were evaluated against HL-60, Jurkat and THP-1 leukemia cells and against MCF-7, MDA-MB-231 and HCT-116 solid tumor cells, as well as against mammalian healthy Vero cells. Upon coordination to indium(III) cytotoxicity increased in several cases. In addition, complex (1) was active in sub-micromolar doses against all tested cell lineages, with selectivity indexes (SI = IC50 Vero/IC50 tumor cell) ranging from 3 (against THP-1 cells) to 144 (against HCT-116 cells).

[Cu(HL)2Cl2] complexes (1–6) were prepared with trans-4-stilbenecarboxaldehyde-para-tolyl-hydrazone HStpT (HL1), trans-4-stilbenecarboxaldehyde-para-chloro-phenylhydrazone HStpClPh (HL2), trans-4-stilbenecarboxaldehyde-para-hydroxy-phenylhydrazone HStpOHPh (HL3), trans-4-stilbenecarboxaldehyde-para-nitro-phenylhydrazone HStpNO2Ph (HL4), trans-4-stilbenecarboxaldehyde-acetylhydrazone HStAc (HL5), and trans-4-stilbenecarboxaldehyde-benzoylhydrazone HStBz (HL6). Infrared spectra suggested that the hydrazones act as bidentate ligands which bind to the copper(II) center through the Nimine-O chelating system. EPR spectra of complexes (1–6) were recorded at room temperature for powder samples and at 77 K for DMSO solution. The EPR parameters were compatible with the presence of copper(II). Since the spectroscopic data for complexes (1–6) did not allow the unambiguous determination of the exact geometry of the complexes in the solid state or in solution, theoretical studies were carried out considering five possible isomers, in order to get information on the predominant species. However, although one of the isomers revealed to be the most thermodynamically favorable, free energy differences were not larger than 3 kcal·mol−1. Hence, differences in lattice energy or packing forces could influence the geometry adopted in the solid. The thermodynamic analysis of the five isomers indicated that all of them are in equilibrium in solution. EPR studies suggested that complexes (1–6) interact with bovine (BSA) and human (HSA) serum albumin, with displacement of the hydrazone ligands and coordination of copper(II) to site 1, together with formation of hydrazone-cysteine mixed-ligand copper(II) complexes at site 2 of the albumins.

Antimony(III) [Sb(L)Cl2] complexes were obtained with 2-acetylpyridine-phenylhydrazone (H2AcPh), 2-acetylpyridine-para-chloro-phenylhydrazone (H2AcpClPh), 2-acetylpyridine-para-nitro-phenylhydrazone (H2AcpNO2Ph) and 2-acetylpyridine-para-hydroxy-phenylhydrazone (H2AcpOHPh) along with the 2-benzoylpyridine-phenylhydrazone analogs H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh (HL). [Sb(2BzpClPh)Cl2], complex (6), (IC50 = 4.91 ± 1.20 μmol L−1) was as active as nystatin (IC50 = 4.44 ± 0.76 μmol L−1) and twofold more active than H2BzpClPh (IC50 = 10.05 ± 0.67 μmol L−1) against Candida dubliniensis. While H2BzpClPh proved to be inactive against Candida glabrata, 6 (IC50 = 10.11 ± 0.64 μmol L−1) was more active than miconazole nitrate (IC50 = 19.50 ± 4.53 μmol L−1). Similarly, H2BzpNO2Ph revealed to be inactive against Candida lusitaniae whereas complex [Sb(2BzpNO2Ph)Cl2] (7) (IC50 = 8.54 ± 2.21 μmol L−1) proved to be as active as nystatin (IC50 = 5.31 ± 0.84 μmol L−1).

Complexes [Bi(HCQ)2(H2O)Cl3] (1), [Pt(CQ)2]·2KCl (2) and [Pt(CQ)2Cl2]·KCl (3) were obtained with 5-chloro-7-iodo-8-hydroxyquinoline, “clioquinol”, HCQ. Upon coordination to bismuth(III) the antimicrobial activity improved. Complex (1) was 70-fold more active than fluconazole against Candida albicans. HCQ proved to be cytotoxic to HL-60 and Jurkat human leukemia cells. Although coordination to bismuth(III) did not result in significant modification of HCQ’s cytotoxic effect, on coordination to platinum(II, IV) cytotoxicity improved against both cell lines. Complexes (2) and (3) were more active than HCQ against HL-60 cells. Complex (2) also revealed to be the most cytotoxic compound against Jurkat cells, being fivefold more active than cisplatin. Although HCQ and 1 did not show a pro-apoptotic effect, 2 and 3 presented moderate pro-apoptotic activity.

Reaction of N(4)-phenyl-2-formylpyridine thiosemicarbazone (H2Fo4Ph), N(4)-phenyl-2-acetylpyridine thiosemicarbazone (H2Ac4Ph) and N(4)-phenyl-2-benzoylpyridine thiosemicarbazone (H2Bz4Ph) with gallium nitrate gave [Ga(H2Fo4Ph)2](NO3)3 (1), [Ga(2Ac4Ph)2]NO3 (2) and [Ga(2Bz4Ph)2]NO3 (3). In all complexes coordination of the thiosemicarbazone via the Npy–N–S chelating system occurs. In 1 the thiosemicarbazone acts as a neutral ligand while in 2 and 3 the ligand is anionic. Upon slow diffusion of 2 in DMSO [Ga(2Ac4Ph)2]NO3·DMSO (2a) was formed. The crystal structure of 2a was determined. Upon coordination the antibacterial activity of both gallium and thiosemicarbazones against Pseudomonas aeruginosa significantly increases.

Reaction of 2-acetylpyridine semicarbazone (H2APS), 3-acetylpyridine semicarbazone (H3APS) and 4-acetylpyridine semicarbazone (H4APS) with [VO(acac)2] (acac = acetylacetonate) gave [VO(H2APS)(acac)2] (1), [VO(H3APS)(acac)2] (2) and [VO(4APS)(acac)(H2O)] · 1/2H2O (3). Oxidation of complex 1 in acetonitrile gave [VO2(2APS)] (4). The crystal structures of complexes 1 and 4 have been determined. Complexes 1–3 were able to enhance glucose uptake and to inhibit glycerol release from adipocytes, which indicate their potential to act as insulin-mimics.