Heterobimetallic nickel(II) and palladium(II) complexes derived from S-benzyl-N- (ferrocenyl)methylenedithiocarbazate: Trypanocidal activity and interaction with Trypanosoma cruzi Old Yellow Enzyme (TcOYE)

Author(s):Show less -

Carneiro, Zumira A. ^[1] ; Lima, Jackelinne C. ^[2] ; Lopes, Carla D. ^[1] ; Gaspari, Ana P. S. ^[3] ; de Albuquerque, Sergio ^[1] ; Dinelli, Luis R. ^[4] ; Veloso-Silva, Laudimir L. W. ^[5] ; Paganelli, Marcella O. ^[5] ; Libardi, Silvia H. ^[5] ; Oliveira, Carolina G. ^[6] ; Deflon, Fvictor M. ^[5] ; Oliveira, Ronaldo J. ^[2] ; Borges, Julio C. ^[5] ; Maia, Pedro I. S. ^[2]

Affiliation

^[1] Univ Sao Paulo, FCFRP, Dept Anal Clin Toxicol & Bromatol, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Fed Triangulo Mineiro, Nucleo Desenvolvimento Compostos Bioat NDCBio, Ave Dr Randolfo Borges 1400, BR-38025440 Uberaba, MG - Brazil

^[3] Inst Fed Parana, Campus Paranavai, Ave Jose Felipe Tequinha 1400, BR-87703536 Paranavai, PR - Brazil

^[4] Univ Fed Uberlandia, Fac Ciencias Integrada Pontal, Rua Vinte 1600, BR-38304402 Ituiutaba, MG - Brazil

^[5] Univ Sao Paulo, Sao Carlos Inst Chem, POB 780, BR-13560970 Sao Carlos, SP - Brazil

^[6] Univ Fed Uberlandia, Inst Quim, Ave Joao Naves Avila 2121, BR-38400902 Uberlandia, MG - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 180, p. 213-223, OCT 15 2019.
• Web of Science Citations: 4

Abstract

Reactions of Ni(II) and Pd(II) precursors with S-benzyl-N-(ferrocenyl)methylenedithiocarbazate (HFedtc) led to the formation of heterobimetallic complexes of the type {[}M-II(Fedtc)(2)] = Ni and Pd). The characterization of the compounds involved the determination of melting point, FTIR, UV-Vis, H-1 NMR, elemental analysis and electrochemical experiments. Furthermore, the crystalline structures of HFedtc and {[}Ni-II(Fedtc)(2)] were determined by single crystal X-ray diffraction. The compounds were evaluated against the intracellular form of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity assays were assessed using LLC-MK2 cells. The results showed that the coordination of HFedtc to Ni(II) or Pd(II) decreases the in vitro trypanocidal activity while the cytotoxicity against LLC-MK2 cells does not change significantly. {[}Pd-II(Fedtc)(2)] showed the greater potential between the two complexes studied, showing an SI value of 8.9. However, this value is not better than that of the free ligand with an SI of 40, a similar value to that of the standard drug benznidazole (SI=48). Additionally, molecular docking simulations were performed with Trypanosoma cruzi Old Yellow Enzyme (TcOYE), which predicted that HFedtc binds to the protein, almost parallel to the flavin mononucleotide (FMN) prosthetic group, while the {[}Ni-II(Fedtc)(2)] complex was docked into the enzyme binding site in a significantly different manner. In order to confirm the hypothetical interaction, in vitro experiments of fluorescence quenching and enzymatic activity were performed which indicated that, although HFedtc was not processed by the enzyme, it was able to act as a competitive inhibitor, blocking the hydride transfer from the FMN prosthetic group of the enzyme to the menadione substrate. (C) 2019 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 14/17754-0 - Biological evaluation and structure-activity relationship of dithiocarbazate compounds and their metal complexes as trypanocidal agents
• Grantee: Zumira Aparecida Carneiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• 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