Pt-II, Pd-II and Au-III complexes with a thiosemicarbazone derived from diacethylmonooxime: Structural analysis, trypanocidal activity, cytotoxicity and first insight into the antiparasitic mechanism of action

Author(s):Show less -

Goncalves, Ana C. R. ^[1] ; Carneiro, Zumira A. ^[2] ; Oliveira, Carolina G. ^[3] ; Danuello, Amanda ^[1] ; Guerra, Wendell ^[4] ; Oliveira, Ronaldo J. ^[1] ; Ferreira, Francis B. ^[5] ; Veloso-Silva, Laudimir L. W. ^[3] ; Batista, Fernanda A. H. ^[3] ; Borges, Julio C. ^[3] ; de Albuquerque, Sergio ^[2] ; Deflon, Victor M. ^[3] ; Maia, Pedro I. S. ^[1]

Affiliation

^[1] Univ Fed Triangulo Mineiro, Nacleo Dev Compostos Bioat NDCBio, Av Dr Randolfo Borges 1400, BR-38025440 Uberaba, MG - Brazil

^[2] Univ Sao Paulo, FCFRP, Dept Anal Clin Toxicol & Bromatol, Ave Caf S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Inst Quim Sao Carlos, Av Trabalhador Sao Carlense 400, BR-13566590 Sao Carlos, SP - Brazil

^[4] Univ Fed Uberlandia, Inst Quim, Av Joao Naves de Avila 2121, BR-38400902 Uberlandia, MG - Brazil

^[5] Fac Associadas Uberaba, Av Tutuna 720, BR-38061500 Uberaba, MG - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 141, p. 615-631, DEC 1 2017.
• Web of Science Citations: 10

Abstract

New complexes of composition {[}MX(HL1)] (M = Pt-II, Pd-II, X = Cl- or I-) and {[}MX(L1)] (M = Au-III, X = Cl-; M = Pt-II, Pd-II, X = PPh3) have been synthesized using a potentially tridentate thiosemicarbazone (H(2)L1) containing an additional oxime binding site. Among other analytical methods, all the seven complexes have been structurally characterized by single crystal X-ray diffractometry. Interesting structural features such as the influence of the halide ligands on hydrogen bonds and the formation of supramolecular structures for the phosphine derivatives are discussed. The in vitro trypanocidal activity of the free ligand H(2)L1 and its derivatives against both extracellular trypomastigote and intracellular amastigote (IC(50)try/ama) forms of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity was assessed on LLC-MK2 cell line. The results showed that complexation of the thiosemicarbazone ligand H(2)L1 to Pt-II, Pd-II and Au-III metal centers enhances the in vitro trypanocidal activity and that the cytotoxicity is dependent on both the metal center and coligands. Within the studied series, the Au-III complex showed the greatest potential, being not the most active but the most selective compound with a similar selectivity index to that of the standard drug benznidazole. In order to get a preliminary insight into the mechanism of action of these compounds, in vitro experiments of fluorescence quenching and enzymatic activity were performed using the Au-III complex and Trypanosoma cruzi Old Yellow Enzyme (TcOYE) which indicated that the gold derivative was capable of abstracting the hydride from the prosthetic FMN group of the enzyme. Additionally, molecular docking studies followed by semiempirical simulations showed that the {[}AuCl(L1)] binds to the binary complex TcOYE/FMN, almost parallel to the FMN prosthetic group, in a close distance that an electron/proton transfer might occur among them. (C) 2017 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 09/54011-8 - Acquisition of a single-crystal X-ray diffractometer for the structural analysis of small molecules and proteins
• Grantee: Victor Marcelo Deflon
• Support Opportunities: Multi-user Equipment Program