New oxidovanadium(IV) N-acylhydrazone complexes: promising antileishmanial and antitrypanosomal agents.
Searching for new promising metal-based hits against Trypanosoma cruzi and Leishmania parasites, two related oxidovanadium(IV) N-acylhydrazone complexes, [V(IV)O(LASSBio1064-2H)(H2O)], 1, and [V(IV)O(LASSBio1064-2H)(phen)]·(H2O), 2, where LASSBio1064=(E)-N'-(2-hydroxybenzylidene-4-chlorobenzohydrazide and phen = 1,10-phenanthroline, were synthesized and characterized in the solid state and in solution by elemental analysis, conductimetric measurements and ESI-MS, FTIR, EPR and (51)V NMR spectroscopies and were evaluated on T. cruzi and Leishmania major. In addition, their unspecific cytotoxicity was tested against murine macrophages. Furthermore, to provide insight into the possible mechanism of its antiparasitic action, [VO(LASSbio1064-2H)(phen)].(H2O) was tested for its DNA interaction ability on plasmid DNA by atomic force microscopy (AFM) and on CT DNA by using DNA viscosity measurements and fluorescence spectroscopy. Both complexes were active in vitro against the epimastigote form of T. cruzi (Tulahuen 2 strain) showing IC50 values of the same order or significantly lower than that of the reference trypanosomicidal drug Nifurtimox. However, only the mixed-ligand oxidovanadium(IV) complex 2, which includes phen in its coordination sphere, showed activity on L. major promastigotes with a IC50 value of 22.1 ± 0.6 μM. The compounds show low toxicity on mammalian cells (IC50 > 100 μM). DNA interaction studies showed that the mixed-ligand complex is able to interact with this biomolecule probably through an intercalative mode, pointing out at DNA as a potential target in the parasite. The results suggest that [V(IV)O(LASSBio1064-2H)(phen)]·(H2O) may be a promising compound for further drug development stages.
Cátedra de Química Inorgánica, Facultad de Química, UDELAR, Gral. Flores 2124, 11800 Montevideo, Uruguay.
Julio
J
Benítez
Aline
A
Cavalcanti de Queiroz
Isabel
I
Correia
Marina Amaral
MA
Alves
Magna S
MS
Alexandre-Moreira
Eliezer J
EJ
Barreiro
Lidia Moreira
LM
Lima
Javier
J
Varela
Mercedes
M
González
Hugo
H
Cerecetto
Virtudes
V
Moreno
João Costa
JC
Pessoa
Dinorah
D
Gambino
D000818:Animals; D000977:Antiparasitic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006835:Hydrazones / Q000737:chemistry*; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014639:Vanadium / Q000737:chemistry*
D000977:Antiparasitic Agents; D006835:Hydrazones; D009942:Organometallic Compounds; D014639:Vanadium