RESUMO
In the search for new metal-based drugs against diseases produced by trypanosomatid parasites, four organoruthenium(II) compounds [Ru2(p-cymene)2(L)2]X2, where L are bioactive 5-nitrofuryl-containing thiosemicarbazones and X = Cl or PF6, had been previously obtained. These compounds had shown activity on Trypanosoma brucei, the etiological agent of African trypanosomiasis. Because of genomic similarities between trypanosomatides, these ruthenium compounds were evaluated, in the current work, on Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas disease). Two of them showed significant in vitro growth inhibition activity against the infective trypomastigote form of T. cruzi (Dm28c clone, IC50 = 11.69 and 59.42 µM for [Ru2(p-cymene)2(L4)2]Cl2 and [Ru2(p-cymene)2(L1)2]Cl2, respectively, where HL4 = 5-nitrofuryl-N-phenylthiosemicarbazone and HL1 = 5-nitrofurylthiosemicarbazone), showing fairly good selectivities toward trypanosomes with respect to mammalian cells (J774 murine macrophages). Moreover, [Ru2(p-cymene)2(L2)2]Cl2, where HL2 = 5-nitrofuryl-N-methylthiosemicarbazone, was synthesized in order to evaluate the effect of improved solubility on biological behavior. This new chloride salt showed higher activity against T. cruzi than that of the previously synthesized hexafluorophosphate one (Dm28c clone, IC50 = 14.30 µM for the former and 231.3 µM for the latter). In addition, the mode of antitrypanosomal action of the organoruthenium compounds was investigated. The complexes were not only able to generate toxic free radicals through bioreduction but they also interacted with two further potential parasite targets: DNA and cruzipain, a cysteine protease which plays a fundamental role in the biological cycle of these parasites. The results suggest a "multi-target" mechanism of trypanosomicidal action for the obtained complexes.
Assuntos
Compostos Orgânicos/farmacologia , Compostos de Rutênio/farmacologia , Tiossemicarbazonas/farmacologia , Tripanossomicidas/farmacologia , Animais , Cristalografia por Raios X , Microscopia de Força Atômica , Compostos Orgânicos/química , Compostos de Rutênio/química , Tiossemicarbazonas/química , Tripanossomicidas/químicaRESUMO
American trypanosomiasis or Chagas disease, caused by the protist parasite Trypanosoma cruzi (T. cruzi), is a major health concern in Latin America. In the search for new bioactive compounds, eight Pd(II) and Pt(II) complexes of thiosemicarbazones derived from 1-indanones (HL) were evaluated as potential anti-T. cruzi compounds. Their unspecific cytotoxicity was determined on human erythrocytes. Two physicochemical features, lipophilicity and redox behavior, that could be potentially relevant for the biological activity of these complexes, were determined. Crystal structure of [Pd(HL1)(L1)]Cl·CH(3)OH, where HL1=1-indanone thiosemicarbazone, was solved by X-ray diffraction methods. Five of the eight metal complexes showed activity against T. cruzi with IC(50) values in the low micromolar range and showed significantly higher activity than the corresponding free ligands. Four of them resulted more active against the parasite than the reference antitrypanosomal drug Nifurtimox. Anti-T. cruzi activity and selectivity towards the parasite were both higher for the Pd(II) compounds than for the Pt(II) analogues, showing the effect of the metal center selection on the biological behavior. Among both physicochemical features tested for this series of compounds, lipophilicity and redox behavior, only the former seemed to show correlation with the antiproliferative effects observed. Metal coordination improved bioactivity but lead to an increase of mammalian cytotoxicity. Nevertheless, some of the metal complexes tested in this work still show suitable selectivity indexes and deserve further developments.
Assuntos
Eritrócitos/efeitos dos fármacos , Indanos/química , Paládio/química , Platina/química , Tiossemicarbazonas/química , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacos , Proliferação de Células , Cristalografia por Raios X , Eritrócitos/citologia , Ligantes , Tiossemicarbazonas/farmacologia , Tripanossomicidas/farmacologiaRESUMO
In the search for a pharmacological answer to treat Chagas disease, eight metal complexes with two bioactive bisphosphonates, alendronate (Ale) and pamidronate (Pam), were described. Complexes of the formula [M(2)(II)(Ale)(4)(H(2)O)(2)]·2H(2)O, with M = Cu, Co, Mn, Ni, and ([CuPam]·H(2)O)(n) as well as [M(II)(Pam)(2)(H(2)O)(2)]·3H(2)O, with M = Co, Mn and Ni, were synthesized and fully characterized. Crystal structure of [Cu(2)(II)(Ale)(4)(H(2)O)(2)]·2H(2)O, [Co(II)(Pam)(2)(H(2)O)(2)] and [Ni(II)(Pam)(2)(H(2)O)(2)] were solved by X-ray single crystal diffraction methods and the structures of [M(2)(II)(Ale)(4)(H(2)O)(2)]·2H(2)O complexes M = Co, Mn and Ni were studied by X-ray powder diffraction methods. All obtained complexes were active against the amastigote form of Trypanosoma cruzi (T. cruzi), etiological agent of Chagas disease. Most of them were more active than the corresponding free ligands showing no toxicity for mammalian cells. The main mechanism of the antiparasitic action of bisphosphonates, inhibition of parasitic farnesyl diphosphate synthase (TcFPPS), remains in the obtained metal complexes and an increase in the inhibiting enzyme levels was observed upon coordination. Observed enzymatic inhibition was selective for TcFPPS as the metal complexes showed no or little inhibition of human FPPS. Additionally, metal complexation might improve the bioavailability of the complexes through the hindrance of the phosphonate group's ionization at physiological pH and, eventually, through the ability of plasma proteins to work as complex transporters.
Assuntos
Difosfonatos/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Geraniltranstransferase/antagonistas & inibidores , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Trypanosoma cruzi/enzimologia , Animais , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Concentração Inibidora 50 , Compostos Organometálicos/síntese química , Compostos Organometálicos/metabolismo , Soroalbumina Bovina/metabolismo , Trypanosoma cruzi/citologia , Trypanosoma cruzi/efeitos dos fármacos , Células VeroRESUMO
In the search for new therapeutic tools against neglected diseases produced by trypanosomatid parasites, and particularly against African Trypanosomiasis, whose etiological agent is Trypanosoma brucei, organoruthenium compounds with bioactive nitrofuran containing thiosemicarbazones (L) as co-ligands were obtained. Four ruthenium(II) complexes with the formula [Ru(2)(p-cymene)(2)(L)(2)]X(2), where X = Cl or PF(6), were synthesized and the crystal structures of two of them were solved by X-ray diffraction methods. Two of the complexes show significant in vitro growth inhibition activity against Trypanosoma brucei brucei and are highly selective towards trypanosomal cells with respect to mammalian cells (J774 murine macrophages). These promising results make the title organoruthenium compounds good lead candidates for further developments towards potential antitrypanosomal organometallic drugs.
Assuntos
Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Bovinos , Linhagem Celular , Cristalografia por Raios X , DNA/metabolismo , Humanos , Ligantes , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Tripanossomíase Africana/tratamento farmacológicoRESUMO
In the search for new metal-based drugs for the treatment of Chagas disease, the most widespread Latin American parasitic disease, novel complexes of the bioactive ligand risedronate (Ris, (1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonate), [M(II)(Ris)(2)]·4H(2)O, where MâCu, Co, Mn and Ni, and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were synthesized and characterized by using analytical measurements, thermogravimetric analyses, cyclic voltammetry and infrared and Raman spectroscopies. Crystal structures of [Cu(II)(Ris)(2)]·4H(2)O and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were solved by single crystal X-ray diffraction methods. The complexes, as well as the free ligand, were evaluated in vitro against epimastigotes and intracellular amastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas disease. Results demonstrated that the coordination of risedronate to different metal ions improved the antiproliferative effect against T. cruzi, exhibiting growth inhibition values against the intracellular amastigotes ranging the low micromolar levels. In addition, this strong activity could be related to high inhibition of farnesyl diphosphate synthase enzyme. On the other hand, protein interaction studies showed that all the complexes strongly interact with albumin thus providing a suitable means of transporting them to tissues in vivo.
Assuntos
Doença de Chagas/tratamento farmacológico , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Ácido Etidrônico/análogos & derivados , Trypanosoma cruzi/efeitos dos fármacos , Animais , Ácido Etidrônico/química , Ácido Etidrônico/uso terapêutico , Geraniltranstransferase/metabolismo , Modelos Químicos , Ácido Risedrônico , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/patogenicidade , Difração de Raios XRESUMO
Sodium alginates obtained by alkaline extraction of Lessonia flavicans, Desmarestia ligulata and Desmarestia distans (Phaeophyta) from southern Chile were partially hydrolyzed with HCl. Each alginate gave three fractions that were characterized using FT-IR spectroscopy. The fractions soluble in 0.3M HCl presented in the fingerprint region four vibrations at around 960, 911, 890 and 815 cm(-1) that were assigned to heteropolymeric blocks. The fractions soluble at pH 2.85 showed bands at around 948, 888 and 820 cm(-1) attributed to homopolymannuronic acid blocks, the first band is resolved in the second-derivative spectra into two bands at 951 and 936 cm(-1). The fractions insoluble at pH 2.85 presented four bands at around 947, 903, 812 and 781 cm(-1), which were assigned to homopolyguluronic acid blocks. For some samples, the second derivative FT-IR spectra showed new bands indicating the presence of other structures, in low proportions. Structures deduced by FT-IR spectroscopy were corroborated by solution (1)H and (13)C NMR spectroscopy. Two-dimensional spectra were collected to confirm the fine structure of the hetero- and homopolymeric fractions. A geometrically optimized model for the disaccharide alpha-l-gulopyranuronosyl-(1-->4)-alpha-l-gulopyranuronic acid was calculated using density functional theory; good agreement was obtained between its corresponding calculated vibrations and the experimental bands assigned to homopolyguluronic acid blocks.