Dithiocarbazate complexes with the [M(PPh 3 )] 2+ (M=Pd or Pt) moiety Synthesis, characterization and anti-Tripanosoma cruzi activity Pedro I. da S. Maia a, ⁎, André G. de A. Fernandes a , Jean Jerley N. Silva b , Adriano D. Andricopulo b , Sebastião S. Lemos c , Ernesto S. Lang d , Ulrich Abram e , Victor M. Deflon a, ⁎ a Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São Carlos, SP, Brazil b Instituto de Física de São Carlos, Universidade de São Paulo, 13560-970 São Carlos, SP, Brazil c Instituto de Química, Universidade de Brasília, 70919-970 Brasília, DF, Brazil d Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil e Freie Universität Berlin, Institute of Chemistry and Biochemistry, Fabeckstr. 34-36, D-14195 Berlin, Germany abstract article info Article history: Received 20 February 2010 Received in revised form 13 August 2010 Accepted 13 August 2010 Available online 21 August 2010 Keywords: Platinum(II) complexes Palladium(II) complexes Dithiocarbazates Pyrazolines Anti-trypanosomal activity Crystal structures New neutral Pd(II) and Pt(II) complexes of the type [M(L)(PPh 3 )] (M Pd or Pt) were prepared in crystalline form in high-yield synthesis with the S-benzyldithiocarbazates and S-4-nitrobenzyldithiocarbazates derivatives from 2-hydroxyacetophenone, H 2 L 1a and H 2 L 1b , and benzoylacetone, H 2 L 2a and H 2 L 2b . The new complexes [Pt(L 1a )(PPh 3 )] (1), [Pd(L 1a )(PPh 3 )] (2), [Pt(L 1b )(PPh 3 )] (3), [Pd(L 1b )(PPh 3 )] (4), [Pt(L 2a )(PPh 3 )] (5), [Pd(L 2a )(PPh 3 )] (6), [Pt(L 2b )(PPh 3 )] (7) and [Pd(L 2b )(PPh 3 )] (8) were characterized on the basis of elemental analysis, conductivity measurements, UV–visible, IR, electrospray ionization mass spectrometry (ESI-MS), NMR ( 1 H and 31 P) and by X-ray diffraction studies. The studies showed that differently from what was observed for the H 2 L 1a and H 2 L 1b ligands, H 2 L 2a and H 2 L 2b assume cyclic forms as 5-hydroxypyrazolinic. Upon coordination, H 2 L 2a and H 2 L 2b suffer ring-opening reaction, coordinating in the same manner as H 2 L 1a and H 2 L 1b , deprotonated and in O,N,S-tridentate mode to the (MPPh 3 ) 2+ moiety. All complexes show a quite similar planar fourfold environment around the M(II) center. Furthermore, these complexes exhibited biological activity on extra and intracellular forms of Trypanosoma cruzi in a time- and concentration- dependent manner with IC 50 values ranging from 7.8 to 18.7 μM, while the ligand H 2 L 2a presented a trypanocidal activity on trypomastigote form better than the standard drug benznidazole. © 2010 Elsevier Inc. All rights reserved. 1. Introduction American Trypanosomiasis or Chagas disease is endemic in Latin America. Its etiological agent is the Trypanosoma cruzi, a hemoflagel- late protozoan, whose life cycle involves vertebrate and invertebrate hosts [1]. According to the World Health Organization (WHO), 18 million people are infected with the T. cruzi, resulting in an annual death toll of 50,000 [2]. The current treatment of Chagas disease is unsatisfactory, depending on two nitroheterocycles, nifurtimox and benznidazole. Although effective for acute infections, they may cause undesirable side effects, frequently leading to the abandonment of the treatment [3]. Their efficacy during the chronic phase is still controversial, with poor indices of apparent cure and a lack of consensus regarding a parasitological cure in the future [3]. Thus, considerable efforts are being directed to developing new chemother- apeutical agents for chagasic patients, especially using inorganic complexes [4–7]. Metal chelates of dithiocarbazic acid, its S-alkyl/arylesters and their Schiff bases have been studied, mainly due to their potential anticancer, antibacterial, antifungal, antiamoebic and insecticidal activities [8–14]. Although the synthesis and complexation of S- benzyldithiocarbazate and its derivatives have been under study for many years, considerable attention continues to be given to these and related ligands and their metal complexes, since their properties can be greatly modified by introducing different substituents [10]. As reported for acylhydrazones and of 1,3-diketones [14], S-dithiocarba- zate derivatives are also supposed to undergo cycle-chain equilibrium (Fig. 1) and can exist in several distinct isomeric forms. In contrast, thiosemicarbazone derivatives from 1,3-diketones were reported to suffer cyclization only in the presence of a metal substrate to form pyrazolate compounds, besides they were just found to act as bidentate ligands upon complexation with Pd(II) and Pt(II) [15]. On the other hand, transition metal-phosphine complexes, espe- cially with the platinum group elements, are considerably important for both industrial and laboratory scale catalytic applications [16–18]. In the literature there is a number of complexes of Pd(II) and Pt(II) Journal of Inorganic Biochemistry 104 (2010) 1276–1282 ⁎ Corresponding authors. Tel.: +55 16 3373 8038; fax: +55 16 3373 9985. E-mail addresses: pedovivo@iqsc.usp.br (P.I.S. Maia), deflon@iqsc.usp.br (V.M. Deflon). 0162-0134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2010.08.009 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio