Maribel Navarro

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.

Toward a novel metal based chemotherapy against tropical diseases 4. Synthesis and characterization of new metal-clotrimazole complexes and evaluation of their activity against Trypanosoma cruzi

Abstract The syntheses and characterization of metal imidazole complexes showing activity against Trypanosoma cruzi, the causative agent of Chagas disease, are presented, RuCl2(CTZ)2 (2) and RuCl2(BTZ)2 (4) were prepared by reaction of RuCl2(NCCH3)4 (1) with the appropriate ligand (CTZ, clotrimazole = 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole; BTZ = 1-[(2-bromophenyl)diphenylmethyl]-1H-imidazole) [Ru(bipy)(CTZ)2](PF6)2 (3) (bipy=2,2′-bipyridyl) was obtained by reaction of 2 with bipy and NH4PF6 in MeCN. Reaction of [RhCl(COD)]2 with CTZ yielded RhCl(COD)(CTZ) (5) (COD=1,5-cyclooctadiene), while AuCl1CTZ (6), K2[PtCl4(CTZ)2] (7) and [Cu(CTZ)2]PF6 (8) were obtained by interaction of CTZ with AuCl1·HCl, K2PtCl4 and [Cu(CH3CN)4]PF6, respectively. All the new complexes were characterized by NMR and other appropriate techniques, X-ray diffraction studies of 4·3H2O, 5 and 6 were also carried out. The structure of 4·3H2O consists of a distorted tetrahedral arrangement of two N atoms from the BTZ ligands and two Cl atoms around the Ru(II) ion; 4·3H2O crystallizes in the orthorhombic space group Puma (No. 62) with a=12.818(5), b=29.115(5), c=12.040(5) A , V=4493.2(8) A and Z=4. Complex 5 displayed a square planar structure typical for Rh(1) bound to N from CTZ, Cl, and the two CC bonds of COD; 5 crystallized in the triclinic space group (P(= l) (No. 2) with a=12.407(3), b=12.876(4), c=10.069(3) A , α=111.59(2)°, β=107.80(2)°, γ=103.28(2)°, V=1313.4(8) A 3 and Z=2. Complex 6 also displayed a square arrangement of N from CTZ, plus three Cl atoms around the Au(III) ion; 6 crystallized in the monoclinic space group P21/n (No. 14) with a=9.507(1), b=18.280(4), c=12.877(1) A , β=100.59(1)°, V=2199.7(5) A 3 and Z=4. All the new compounds were found to be active against in vitro cultures of Trypanosoma cruzi, following the trend 3 = 7

Synthesis and characterization of a pyridine-2-thiol N-oxide gold(I) complex with potent antiproliferative effect against Trypanosoma cruzi and Leishmania sp. insight into its mechanism of action ☆

In the search for new therapeutic tools against parasitic diseases caused by the Kinetoplastids Leishmania spp. and Trypanosoma cruzi, a novel gold(I) triphenylphosphine complex with the bioactive coligand pyridine-2-thiol N-oxide (mpo) was synthesized and characterized by using analytical and conductometric measurements, electrospray ionization-mass spectrometry (ESI) and electronic, FTIR and (1)H and (31)P NMR spectroscopies. A dinuclear structure is suggested for the complex. At a 1 microM concentration the complex induced in vitro after 30 min a potent leishmanicidal effect (LD(50)) against promastigotes of Leishmania (L.) mexicana while on Leishmania (V.) braziliensis with the same concentration only a leishmanistatic effect (IC(75)) was observed 48 h after treatment. Similar differential susceptibilities were also found when testing the ligand mpo, but at a higher dose (5 microM). In addition, the compound showed growth inhibitory effect on Dm28c T. cruzi epimastigotes in culture (IC(50) 0.09 microM), being even more active than the anti-trypanosomal reference drug Nifurtimox (IC(50) 6 microM). DNA interaction studies showed that this biomolecule does not constitute a main target for the mpo complex currently tested. Instead, the significant potentiation of the antiproliferative effect against both Leishmania species and T. cruzi could be associated to the inhibition of NADH fumarate reductase, a kinetoplastid parasite-specific enzyme absent in the host. Furthermore, due to its low unspecific cytotoxicity on mammalian cells (J774 macrophages), the new gold complex showed a selective anti-parasite activity. It constitutes a promising new potent chemotherapeutic alternative to be evaluated in vivo in experimental models of leishmaniasis and Chagas disease.

Toward a novel metal-based chemotherapy against tropical diseases.: Part 5. Synthesis and characterization of new Ru(II) and Ru(III) clotrimazole and ketoconazole complexes and evaluation of their activity against Trypanosoma cruzi

The complexes [Cu(CTZ)4]Cl2·2H2O (1), [Cu(CTZ)Cl2]2 (2), [Cu(KTZ)3Cl2] (3), and [Cu(KTZ)Cl2]2·2H2O (4) were prepared by reaction of CuCl2 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(PPh3)(CTZ)]PF6 (5) and [Au(PPh3)(KTZ)]PF6·H2O (6) were synthesized by reaction of AuClPPh3, with KPF6 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 P1, with a = 12.773(2) A, b = 15.326(4) A, c = 11.641(2) A, V = 1957.4(7) A3, Z = 1, and Dcalcd = 1.284 g/cm3. The structure...

Synthesis and characterization of platinum–sterol hydrazone complexes with biological activity against Leishmania (L.) mexicana

Leishmaniasis is a parasitic zoonosis caused by protozoans of the genus Leishmania transmitted by insects known as phlebotomines, which are found in wild or urban environments. The disease occurs in tropical and sub-tropical areas, mainly in Asia, Europe, Africa and the Americas. At present, there is no effective treatment for this disease. In the search for new rational chemotherapeutic alternatives, two novel trans [Pt(Hpy1)(2)(Cl)(2)] (1) and trans [Pt(Hpy2)(2) (Cl)(2)] (2) complexes were synthesized by the reaction of K(2)PtCl(4) with sterol hydrazone ligands 20-hydrazone-pyridin-2-yl-5alpha-pregnan-3beta-ol (Hpy1) and 22-hydrazone-pyridin-2-yl-chol-5-ene-3beta-ol (Hpy2). These organic compounds are specific inhibitors of sterol methyl transferase (SMT). The new platinum complexes were characterized by a combination of ESI-MS (electrospray ionization-mass spectroscopy), UV-vis, infrared and NMR spectroscopies; elemental analysis and molar conductivity. Promastigotes of Leishmania (L.) mexicana were treated for 48 h with 10 microM of the sterol hydrazones Hpy1 or Hpy2 alone or coordinated to Pt. Hpy1 produced higher leishmanistatic activity than Hpy2 (39% growth inhibition vs. 16%), which significatively increased (71%, p<0.001) when the complex trans-[Pt(Hpy1)(2)(Cl)(2)] was used. This complex represents a new chemotherapeutic alternative to be evaluated in depth in experimental models of leishmaniasis.

Synthesis, characterization and biological activity of trans-platinum(II) complexes with chloroquine

Three platinum-chloroquine complexes, trans-Pt(CQDP)(2)(I)(2) [1], trans-Pt(CQDP)(2)(Cl)(2) [2] and trans-Pt(CQ)(2)(Cl)(2) [3], were prepared and their most probable structure was established through a combination of spectroscopic analysis and density functional theory (DFT) calculations. Their interaction with DNA was studied and their activity against 6 tumor cell lines was evaluated. Compounds 1 and 2 interact with DNA primarily through electrostatic contacts and hydrogen bonding, with a minor contribution of a covalent interaction, while compound 3 binds to DNA predominantly in a covalent fashion, with weaker secondary electrostatic interactions and possibly hydrogen bonding, this complex also exerted greater cytotoxic activity against the tumor cell lines.

The mechanism of antimalarial action of [Au(CQ)(PPh3)]PF6: Structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces

The mechanism of antimalarial action of [Au(CQ)(PPh(3))]PF(6) (1), which is active in vitro against CQ-resistant P. falciparum and in vivo against P. berghei, has been investigated in relation to hemozoin formation and DNA as possible important targets. Complex 1 interacts with heme and inhibits β-hematin formation both in aqueous medium and near water/n-octanol interfaces at pH ~5 to a greater extent than chloroquine diphosphate (CQDP) or other known metal-based antimalarial agents; the higher inhibition activity is probably related to the higher lipophilicity observed for 1 through partition coefficient measurements at low pH, with respect to CQDP. The interactions of complex 1 with DNA were explored using spectrophotometric and fluorimetric titrations, circular dichroism spectroscopy, viscosity and melting point studies, as well as electrophoresis and covalent binding assays. The experimental data indicate that complex 1 interacts with DNA predominantly by intercalation and electrostatic association of the CQ moiety, similarly to free CQDP, while no covalent metal-DNA binding seems to take place. The most likely antimalarial mechanism for complex 1 is thus heme aggregation inhibition; the high activities observed against resistant parasites are probably due to the structural modification of CQ introduced by the presence of the gold-triphenylphosphine fragment, together with the enhanced lipophilic character.

Medicinal potential of ciprofloxacin and its derivatives

Ciprofloxacin (CP) is a fluoroquinolone that is highly active against diverse microorganisms. At concentrations less than 1 µg/ml it is active against a diverse types of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Bacillius subtilius, Escherichia coli and Mycobacterium tuberculosis. In addition, it has shown to be effective against other diseases such as malaria, cancer and AIDS. The extended antimicrobial activity, lack of plasmid-mediated resistance, large volume of distribution and minimal adverse effects of CP are therapeutically advantageous. In the pursuit of increasing their effectiveness against these diseases and prevent unwanted resistance, researchers have begun to synthesize a class of organic, inorganic and organometallic derivatives, which have displayed interesting activities. This review describes the development and recent advances on the evaluation of CP and its derivatives as a new class of drugs with potential for clinical development.

Palladium polypyridyl complexes: synthesis, characterization, DNA interaction and biological activity on Leishmania (L.) mexicana

This paper describes the search for new potential chemotherapeutic agents based on transition metal complexes with planar ligands. In this study, palladium polypyridyl complexes were synthesized and characterized by elemental analysis, NMR, UV-VIS and IR spectroscopies. The interaction of the complexes with DNA was also investigated by spectroscopic methods. All metal-to-ligand charge transfer (MLCT) bands of the palladium polypyridyl complexes exhibited hypochromism and red shift in the presence of DNA. The binding constant and viscosity data suggested that the complexes [PdCl2(phen)] and [PdCl2(phendiamine)] interact with DNA by electrostatic forces. Additionally, these complexes induced an important leishmanistatic effect on L. (L.) mexicana promastigotes at the final concentration of 10 µmol L-1 in 48 h.

Synthesis, characterization and some catalytic properties of ruthenium complexes Ru(PPh3)2Cl2(L)2 [L = 4-But-py, 4-vinyl-py, 4-CN-py, 4-Me-py, 3-Me-py, L2 = 4,4′-bipy]. Kinetics of cyclohexene hydrogenation catalysed by Ru(PPh3)2Cl2(4-But-py)2

Abstract The complexes Ru(PPh3)2Cl2(L)2 (L = 4-But-py, 4-vinyl-py, 4-CN-py, 4-Me-py, 3-Me-py, L2 = 4,4′-bipy) have been prepared by reaction of RuCl2(PPh3)3 with the appropriate ligand under mild conditions and characterized by elemental analysis, IR, NMR (1H and 31P) and UV-vis spectra; the RuII derivatives display a RuP2Cl2N2 core with a trans, cis, cis arrangement of the donor atoms. Ru(PPh3)2Cl2(4-But-py)2 is an efficient catalyst precursor for the homogeneous hydrogenation of cyclohexene and benzaldehyde under moderate conditions. A kinetic study of the hydrogenation of cyclohexene led to a rate law r = kcat[Ru][H2], which corresponds to a mechanism involving a fast coordination of cyclohexene to an electronically unsaturated hydride RuHCl(PPh3)2(4-But-py), followed by a rate-limiting oxidative addition of H2 and rapid reductive elimination of the product.