Gallium and indium complexes with isoniazid-derived ligands: Interaction with biomolecules and biological activity against cancer cells and Mycobacterium tuberculosis

Gallium and indium octahedral complexes with isoniazid derivative ligands were successfully prepared. The ligands, isonicotinoyl benzoylacetone (H₂L¹) and 4-chlorobenzoylacetone isonicotinoyl hydrazone (H₂L²), and their respective coordination compounds with gallium and indium [GaL¹(HL¹)] (GaL¹), [GaL²(HL²)] (GaL²), [InL¹(HL¹)] (InL¹) and [InL²(HL²)] (InL²) were investigated by NMR, ESI-MS, UV-Vis, IR, single-crystal X-ray diffraction and elemental analysis. In vitro interaction studies with human serum albumin (HSA) evidenced a moderate affinity of all complexes with HSA through spontaneous hydrophobic interactions. The greatest suppression of HSA fluorescence was caused by GaL² and InL², which was associated to the higher lipophilicity of H₂L². In vitro interaction studies with CT-DNA indicated weak interactions of the biomolecule with all complexes. Cytotoxicity assays with MCF-7 (breast carcinoma), PC-3 (prostate carcinoma) and RWPE-1 (healthy human prostate epithelial) cell lines showed that complexes with H₂L² are more active and selective against MCF-7, with the greatest cytotoxicity observed for InL² (IC₅₀ = 10.34 ± 1.69 μM). H₂L¹ and H₂L² were labelled with gallium-67, and it was verified that ⁶⁷GaL² has a greater lipophilicity than ⁶⁷GaL¹, as well as higher stability in human serum or in the presence of apo-transferrin. Cellular uptake assays with ⁶⁷GaL¹ and ⁶⁷GaL² evidenced that the H₂L²-containing radiocomplex has a higher accumulation in MCF-7 and PC-3 cells than the non-halogenated congener ⁶⁷GaL¹. The anti-Mycobacterium tuberculosis assays revealed that both ligands and metal complexes are potent growth inhibitors, with MIC₉₀ (μg mL^-1) values observed from 0.419 ± 0.05 to 1.378 ± 0.21.