17756 | New J. Chem., 2019, 43, 17756--17773 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019 Cite this: New J. Chem., 2019, 43, 17756 Exploring oxidovanadium(IV) homoleptic complexes with 8-hydroxyquinoline derivatives as prospective antitrypanosomal agents† Gonzalo Scalese, a Ignacio Machado, b Isabel Correia, c Joao Costa Pessoa, c Lucı ´ a Bilbao, d Leticia Pe ´ rez-Diaz* d and Dinorah Gambino * a Ten structurally related homoleptic complexes, including three new compounds, were synthesized: five [V IV O(L-H) 2 ] and five [V V O(OCH 3 )(L-H) 2 ] compounds, where L–H = L1-H–L5-H are monodeprotonated L1–L5 8-hydroxyquinoline derivatives. The compounds were characterized in the solid state and in solution. All complexes show inhibitory activity against Trypanosoma cruzi and Leishmania infantum, most within the 0.2–5 mM range, T. cruzi being more sensitive to the compounds than L. infantum. The compounds show high selectivities towards the parasite, evaluated using VERO cells as a mammalian cell model, as well as higher activity against T. cruzi than the reference antitrypanosomal drug nifurtimox. The antitrypanosomal activity depends on the nature of the substituents on the 8-hydroxyquinoline moiety, [V IV O(L1-H) 2 ] (L1 = 5,7-dichloroquinolin-8-ol), with IC 50 = 0.21 mM, being the most active and selective compound of the series against T. cruzi, and one of the most active against L. infantum (IC 50 = 2.5 mM). A trypanocide effect of [V IV O(L1-H) 2 ] was observed when incubating parasites with 10Â the IC 50 value and a late apoptotic/necrotic cell death mechanism is suggested. A preferred association with the soluble protein fraction of cells is also observed (49.4% of total vanadium association). [V IV O(L1-H) 2 ] is shown to affect not only the infection potentiality of cell-derived trypomastigotes but also the proliferation of intracellular amastigotes, the two parasite stages more relevant in the mammalian host after infection. By measuring circular dichroism spectra of solutions containing either human serum apo-transferrin (apo-HTF) or bovine serum albumin (BSA) upon adding the compounds, it is shown that both the free ligands and the V IV - and V V -complexes bind to these proteins. From data determined from fluorescence quenching measurements with BSA, the determined Stern–Volmer constants are typically slightly higher for the ligand precursors than for the corresponding [V IV O(L1-H) 2 ] compounds, the calculated conditional binding constants at pH = 7.4 being ca. 10 5 –10 6 . The fluorescence competition measurements with DNA bound to ethidium bromide typically yield relatively small decreases in fluorescence, V IV - and V V -complexes with L1 showing higher quenching. Introduction The biological relevance of vanadium has led to abundant research on the potential medicinal uses of its compounds. +3, +4, and +5 are the most biologically relevant oxidation states of the wide range found in vanadium complexes. Due to the oxophilic nature of the +4 and +5 oxidation states, V IV is often present as oxidovanadium(IV), while V V occurs as V V O 3+ ,V V 2 O 4 2+ and V V O 2 + . Oxidovanadium(IV) and (V) moieties, V IV O 2+ ,V V O 2 + and V V O 3+ , have been the most relevant in medicinal chemistry, although oligomeric forms have also shown interesting bio- logical activity. 1 Being hard acids, both vanadium centers typically prefer O/N donor ligands. Vanadium-based drugs have been studied for more than 100 years, and after the discovery of inhibition of many classes of phosphatase enzymes by vanadate, 2,3 interest in enhanced insulin signaling and antidiabetic activity increased enormously. Research carried out has led to the development of many vanadium-based prospective drugs that have been proposed a A ´ rea Quı ´mica Inorga ´nica, Facultad de Quı ´mica, Universidad de la Repu ´blica, Montevideo, Uruguay. E-mail: dgambino@fq.edu.uy; Fax: +598-29241906; Tel: +598-29249739 b A ´ rea Quı ´mica Analı ´tica, Facultad de Quı ´mica, Universidad de la Repu ´blica, Montevideo, Uruguay c Centro de Quı ´mica Estrutural, Departamento de Engenharia Quı ´mica, Instituto Superior Te ´cnico, Universidade de Lisboa, Lisboa, Portugal d Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la Repu ´blica, Montevideo, Uruguay. E-mail: lperez@fcien.edu.uy † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c9nj02589h Received 19th May 2019, Accepted 5th August 2019 DOI: 10.1039/c9nj02589h rsc.li/njc NJC PAPER