Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs

Author(s)

Rettondin, Andressa R. ^[1] ; Carneiro, Zumira A. ^[2] ; Goncalves, Ana C. R. ^[1] ; Ferreira, Vanessa F. ^[3] ; Oliveira, Carolina G. ^[3] ; Lima, Angelica N. ^[4] ; Oliveira, Ronaldo J. ^[4] ; de Albuquerque, Sergio ^[2] ; Deflon, Victor M. ^[3] ; Maia, Pedro I. S. ^[1]

Affiliation

^[1] Univ Fed Triangulo Mineiro, Dept Quim, Ave Dr Randolfo Borges 1400, BR-38025440 Uberaba, MG - Brazil

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

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

^[4] Univ Fed Triangulo Mineiro, Lab Biofis Teor, Dept Fis, Ave Dr Randolfo Borges 1400, BR-38025440 Uberaba, MG - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 120, p. 217-226, SEP 14 2016.
• Web of Science Citations: 14

Abstract

Tridentate thiosemicarbazone ligands with an ONS donor set, H2LR (R = Me and Et) were prepared by reactions of 1-phenyl-1,3-butanedione with 4-R-3-thiosemicarbazides. H2LR reacts with Na{[}AuCl4]center dot 2H(2)O in MeOH in a 1:1 M ratio under formation of green gold(III) complexes of composition {[}AuCl(L-R)]. These compounds represent the first examples of gold(III) complexes with ONS chelate-bonded thio-semicarbazones. The in vitro anti Trypanosoma cruzi activity against both trypomastigote and amastigote forins (IC50try/ama) of CL Brener strains as well as the cytotoxicity against LLC-MK2 cells of the free ligands and complexes was evaluated. The complex {[}AuCl(L-ME)] was found to be more active and more selective than its precursor ligand and the standard drug benznidazole with a SItry/ama value higher than 200, being considered as a lead candidate for Chagas disease treatment. Moreover the in vitro activity against the replicative amastigote form (IC50ama) of T. cruzi was additionally investigated revealing that {[}AuCl(L-ME)] was also more potent than benznidazole still with a similar selectivity index. Finally, docking studies showed that free ligands and complexes interact with the same residues of the parasite protease cruzain but with different intensities, suggesting that this protease could be a possible target for the trypanocidal action of the obtained compounds. (C) 2016 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