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 (H 2 L 1 ) and 4-chlorobenzoylacetone isonicotinoyl hydrazone (H 2 L 2 ), and their respective coordination compounds with gallium and indium [GaL 1 (HL 1 )] (GaL 1 ), [GaL 2 (HL 2 )] (GaL 2 ), [InL 1 (HL 1 )] (InL 1 ) and [InL 2 (HL 2 )] (InL 2 ) 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 GaL 2 and InL 2 , which was associated to the higher lipophilicity of H 2 L 2 . 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 H 2 L 2 are more active and selective against MCF-7, with the greatest cytotoxicity observed for InL 2 (IC 50 = 10.34 ± 1.69 μM). H 2 L 1 and H 2 L 2 were labelled with gallium-67, and it was verified that 67 GaL 2 has a greater lipophilicity than 67 GaL 1 , as well as higher stability in human serum or in the presence of apo-transferrin. Cellular uptake assays with 67 GaL 1 and 67 GaL 2 evidenced that the H 2 L 2 -containing radiocomplex has a higher accumulation in MCF-7 and PC-3 cells than the non-halogenated congener 67 GaL 1 . The anti-Mycobacterium tuberculosis assays revealed that both ligands and metal complexes are potent growth inhibitors, with MIC 90 (μg mL -1 ) values observed from 0.419 ± 0.05 to 1.378 ± 0.21.