Toward a Novel Metal-Based Chemotherapy against Tropical Diseases. 6. Synthesis and Characterization of New Copper(II) and Gold(I) Clotrimazole and Ketoconazole Complexes and Evaluation of Their Activity against Trypanosoma cruzi

Abstract

The complexes [Cu(CTZ)(4)]Cl(2).2H(2)O (1), [Cu(CTZ)Cl(2)](2) (2), [Cu(KTZ)(3)Cl(2)] (3), and [Cu(KTZ)Cl(2)](2).2H(2)O (4) were prepared by reaction of CuCl(2) with CTZ and KTZ (where CTZ = 1-[[(2-chlorophenyl)diphenyl]methyl]-1H-imidazole and KTZ = cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine), respectively, in acetonitrile at different ligand to metal molar ratios. Gold complexes [Au(PPh(3))(CTZ)]PF(6) (5) and [Au(PPh(3))(KTZ)]PF(6).H(2)O (6) were synthesized by reaction of AuClPPh(3), with KPF(6) and CTZ or KTZ in acetonitrile. All the new compounds were characterized by NMR spectroscopy and microanalytical methods, and for the paramagnetic species EPR spectroscopy and DC magnetic susceptibility measurements were also employed. The solid-state structure of 1 has been determined by X-ray crystallography. 1 crystallizes in the triclinic space group P(-)1, with a = 12.773(2) A, b = 15.326(4) A, c = 11.641(2) A, V = 1957.4(7) A(3), Z = 1, and D(calcd) = 1.284 g/cm(3). The structure refinement converged at R1 = 0.0731 and wR2 = 0.1962. Complex 1 displayed a square-planar structure typical for tetrakis(imidazole)copper(II) complexes. The new compounds were tested for in vitro activity against cultures of epimastigotes of Trypanosoma cruzi, the causative agent of Chagas disease. At concentrations equivalent to 10(-6) M of total CTZ or KTZ (in DMSO) all the complexes exhibited significantly higher growth inhibitory activity than their respective parental compounds.

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

“…We have previously discussed the concept of enhancing the activity of organic compounds of known therapeutic value by coordination to a metalcontaining fragment through a metal-drug synergy [21,22]. We demonstrated the merit of this approach against Trypanosoma cruzi, the causative agent of Chagas disease, using metal complexes of clotrimazole and ketoconazole [23][24][25][26]; some of those complexes were also found to be active as antitumor agents [27]. We also modified CQ through coordination to metalcontaining fragments, notably ruthenium [28], rhodium [28], and gold [29,30], and found enhanced antimalarial activity in several instances.…”

The role of nanogold in human tropical diseases: research, detection and therapy

“…3, middle) showed an anti-T. cruzi epomastigotes activity only slightly higher than the free CTZ (60 % vs. 58 %), with a poor performance compared other metal-CTZ complexes [36,40]. In another paper [38] (Fig. 3, bottom) complexes.…”

“…3, bottom) complexes. Both complexes (1 μM) showed an inhibition of the proliferation of the T. cruzi epimastigotes around 70 %, while the free CTZ has no effect on the growth and KTZ only inhibited 39 % at the same concentration [38,40].…”

“…A series of seven papers regarding metal-based chemotherapy against tropical diseases was published by Sánchez-Delgado and co-workers [33][34][35][36][37][38][39], from 1993 to 2004. Navarro, who wrote a very interesting review in 2009 about gold complexes as potential anti-parasitic agents [40], published since 1997, together with different co-workers, also some papers in this series [35,36,38,39].…”

“…Navarro, who wrote a very interesting review in 2009 about gold complexes as potential anti-parasitic agents [40], published since 1997, together with different co-workers, also some papers in this series [35,36,38,39]. In one of those publications [36], the authors dealt with a group of metalclotrimazole complexes evaluating their activity against T. cruzi, including AuCl 3 (clotrimazole).…”