New oxidovanadium(IV) N-acylhydrazone complexes: Promising antileishmanial and antitrypanosomal agents

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• 作者：Julio Bení ; tez^a ; Aline Cavalcanti de Queiroz^b ; Isabel Correia^c ; Marina Amaral Alves^d ; ^e ; Magna S. Alexandre-Moreira^b ; Eliezer J. Barreiro^d ; ^e ; Lidia Moreira Lima^d ; ^e ; Javier Varela^f ; Mercedes Gonzá ; lez^f ; Hugo Cerecetto^f ; Virtudes Moreno^g ; Joã ; o Costa Pessoa^c ; Dinorah Gambino^a ; ^{dgambino@fq.edu.uy}
• 关键词：Oxidovanadium(IV) compounds ; N-Acylhydrazones ; Heteroleptic complexes ; Chagas disease ; Leishmaniasis ; Oxidovanadium(IV) phenanthroline complexes
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：62
• 期：Complete
• 页码：20-27
• 全文大小：763 K

文摘

Searching for new promising metal-based hits against Trypanosoma cruzi and Leishmania parasites, two?related oxidovanadium(IV) N-acylhydrazone complexes, [V^IVO(LASSBio1064-2H)(H₂O)], 1, and [V^IVO(LASSBio1064-2H)(phen)]¡¤(H₂O), 2, where LASSBio1064 = (E)-N¡ä-(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 ⁵¹V 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?¡À?0.6?¦ÌM. The compounds show low toxicity on mammalian cells (IC₅₀?>?100?¦ÌM). 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^IVO(LASSBio1064-2H)(phen)]¡¤(H₂O) may be a promising compound for further drug development stages.