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.
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.
Navarro
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M
Chemistry Center, Instituto Venezolano de Investigaciones Científicas (IVIC), Apartado 21827, Caracas 1020-A, Venezuela. mnavarro@ivic.ve
Cisneros-Fajardo
E J
EJ
Lehmann
T
T
Sánchez-Delgado
R A
RA
Atencio
R
R
Silva
P
P
Lira
R
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Urbina
J A
JA
D000465:Algorithms; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D014355:Chagas Disease / Q000473:pathology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003022:Clotrimazole / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D006046:Gold / Q000737:chemistry*; D007654:Ketoconazole / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects*
D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D006046:Gold; D003300:Copper; D003022:Clotrimazole; D007654:Ketoconazole