New limonene-hybrid derivatives with anti-T. cruzi activity

The development of hybrid compounds containing limonene- and recognized anti-T. cruzi-heterocycle-frameworks is described. The six new compounds displayed broad antitrypanosomal activities having 5-nitrofuran and 5-nitroindazole derivatives, the best profiles. In addition, a 5-nitroindazole derivative evaluated against a panel of fungi exhibited relevant activities. Knowing that free-radical-production operates as one of the mechanisms of action on these heterocycles, we studied a potential extra-mechanism, membrane-sterols changes. Non-relevant T. cruzi squalene accumulation was observed for any of the tested hybrid-limonene derivatives. © 2010 Bentham Science Publishers Ltd.Fil: Alvarez, Guzmán. Universidad de la República; UruguayFil: Gerpe, Alejandra. Universidad de la República; UruguayFil: Benitez, Diego. Universidad de la República; UruguayFil: Garibotto, Francisco Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Zacchino, Susana Alicia Stella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Graebin, Cedric Stephan. Universidade Federal do Rio Grande do Sul; BrasilFil: Gomes da Rosa, Ricardo. Universidade Federal do Rio Grande do Sul; BrasilFil: Eifler Lima, Vera. Universidade Federal do Rio Grande do Sul; BrasilFil: González, Mercedes. Universidad de la República; UruguayFil: Cerecetto, Hugo. Universidad de la República; Urugua

Novel antiprotozoal products: Imidazole and benzimidazole N-oxide derivatives and related compounds

The syntheses and biological evaluation of the first anti-protozoa imidazole N-oxide and benzimidazole N-oxide and their derivatives are reported. They were tested in vitro against two different protozoa, Trypanosoma cruzi and Trichomonas vaginalis. Derivative 7c, ethyl-1-(i-butyloxycarbonyloxy)-6-nitrobenzimid-azole-2-carboxylate, displayed activity on both protozoa. Lipophilicity and redox potential were experimentally determined in order to study the relationship with activity of the compounds. These properties are well related with the observed bioactivity. Imidazole and benzimidazole N-oxide derivatives are becoming leaders for further chemical modifications and advanced biological studies

Synthesis and biological properties of new 5-nitroindazole derivatives

A series of new 3-alkoxy- or 3-hydroxy-1-[ω-(dialkylamino)alkyl]-5- nitroindazoles have been synthesized and their trichomonacidal, antichagasic and antineoplastic properties studied. Five derivatives (5, 6, 8, 9 and 17) showed remarkable trichomonacidal activity against Trichomonas vaginalis at 10 μg/mL concentration. Three compounds (8, 10, 11) exhibited interesting antichagasic activity and these same compounds moderate antineoplastic activity against TK-10 and HT-29 cell lines. Unspecific cytotoxicity against macrophages has also been evaluated and only compounds 9, 10 and 11 resulted cytotoxic at the higher dose evaluated (100 μg/mL), loosing cytotoxicity at lower doses. QSAR studies have been carried out. X-ray crystallographic study of compound 8 has been performed. © 2005 Elsevier Ltd. All rights reserved.Peer Reviewe

Pharmacological properties of indazole derivatives: Recent developments

The chemistry of indazole and its N-oxide derivatives is very well-known. Indazole derivatives were extensively studied as bioactive compounds, such as anti-aggregatory and vasorelaxant activity by NO release and increase of cGMP levels and anticancer effects, antimicrobial and antiparasitic properties, among others. Recently, the research and development in the medicinal chemistry of these systems have produced compounds with contraceptive activities for men, for the treatment of osteoporosis, inflammatory disorders and neurodegenerative diseases. On the other hand, indazole N-oxide derivatives were poorly studied as bioactive compounds, but recently compounds with antiparasitic properties were produced. In this presentation, recent developments in the chemistry and medicinal chemistry of indazole and its N-oxide derivatives will be reviewed. © 2005 Bentham Science Publishers Ltd.Peer Reviewe

Linking cadmium and mercury accumulation to nutritional intake in common dolphins (Delphinus delphis) from Patagonia, Argentina

Bioaccumulation of Hg and Cd from food is a complex ecological process that has been oversimplified in the past. Common dolphins (Delphinus delphis) provide a powerful model to biomonitor metal concentrations in marine environments worldwide. We combined proportions-based nutritional geometry with metal analysis, stomach content analysis and the proximate composition of prey, to yield novel insights into the accumulation of Hg and Cd. Our analysis showed an age-related accumulation trend for Cd and Hg in kidney and liver, with highest concentrations found at 18 years of age. When view through the lens of nutritional ecology, Argentine anchovy (58.1 Mass %) and South American long-finned squid (22.7 Mass %), provided most of the dietary intake of protein (P) and lipids (L) (P:L ratio = 2.6:1.0) and also represented the main source for Cd and Hg levels accumulated in their bodies. This study presents unprecedented evidence on metal accumulation in relation to age and nutritional intake in a marine predator.Fil: Machovsky-capuska, Gabriel. University of Sydney; Estados UnidosFil: von Haeften, Gabriela. No especifíca;Fil: Romero, Maria Alejandra. Universidad Nacional del Comahue. Centro de Investigación Aplicada y Transferencia Tecnológica en Recursos Marinos "Almirante Storni". - Provincia de Río Negro. Ministerio de Agricultura, Ganadería y Pesca. Centro de Investigación Aplicada y Transferencia Tecnológica en Recursos Marinos "Almirante Storni". Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Centro Nacional Patagónico. Centro de Investigación Aplicada y Transferencia Tecnológica en Recursos Marinos "Almirante Storni"; ArgentinaFil: Rodríguez, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Gerpe, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias Marinas. Laboratorio de Ecotoxicología; Argentin

ESR and electrochemical study of 5-nitroindazole derivatives with antiprotozoal activity

The electrochemistry of 3-alkoxy- and 3-hydroxy-1-[ω-(dialkylamino)alkyl]-5-nitroindazole derivatives were characterized using cyclic voltammetry in DMSO. The nitro reduction process was studied and this was affected by the acid moieties present in these compounds. A nitro anion self-protonation process was observed. This phenomenon was studied by cyclic voltammetry in presence of increasing amount of NaOH. The reactivity of the nitro anion radical of these derivatives with glutathione was also studied by cyclic voltammetry. The oxidizing effect of glutathione is supported by the parallel decrease of the anodic peak current and increase of the cathodic peak in the cyclic voltammograms, corresponding to the wave of the nitro anion radical from uncharged species with the addition of glutathione. Nitro anion radicals obtained by electrolytic reduction of these derivatives were measured and analyzed in DMSO using electron spin resonance spectroscopy. © 2005 Elsevier B.V. All rights reserved.Peer Reviewe

Naftifine-analogues as anti-Trypanosoma cruzi agents

Chagas disease represents a relevant health problem in Central and South America. The first line of treatment is Nifurtimox and Benznidazole which have a great deal of disadvantages that demands the rapid generation of therapeutic alternatives. Based in our research on aza-thiaheterocycles as anti-Trypanosoma cruzi agents we identified pharmacophores that act through oxidative stress. Here, we describe the synthesis and the activity of new containing bioactive-heterocycles analogues of naftifine as potential T. cruzi membrane sterol biosynthesis inhibitors. Benzimidazole 1,3-dioxides (11 and 13) and quinoxaline 1,4-dioxides (22 and 23) displayed excellent parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated with the compounds showed that any of them are able to accumulate squalene suggesting that in the anti-T. cruzi mechanism of action is not involved the inhibition of sterol biosynthesis. Some derivatives were also tested as antifungal agents. The results obtained in the present work open potential therapeutic possibilities of new compounds for these infectious diseases.Fil: Gerpe, Alejandra. Universidad de la República; UruguayFil: Boiani Santurio, Lucia. Universidad de la República; Uruguay. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hernández, Paola. Universidad de la República; UruguayFil: Sortino, Maximiliano Andrés. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Area Farmacognosia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zacchino, Susana. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Area Farmacognosia; ArgentinaFil: González, Mercedes. Universidad de la República; UruguayFil: Cerecetto, Hugo. Universidad de la República; Urugua

New heteroaryl nitrones with spin trap properties: Identification of a 4-furoxanyl derivative with excellent properties to be used in biological systems

A new series of heteroaryl nitrones, 1–7, bearing furoxanyl and thiadiazolyl moieties, were evaluated for their free radical-trapping properties. The physicochemical characterization by electron paramagnetic resonance (EPR) demonstrated its capability to trap and stabilize oxygen-, carbon-, sulfur-, and nitrogen- centered free radicals. The 4-furoxanyl nitrone 3 (FxBN), a(Z)-(3-methylfuroxan-4-yl)-N-tert-butylnitrone, showed appropriate solubility in aqueous solution and taking into account that this physicochemical property is very important for biological applications, we studied it deeply in terms of its trapping and kinetic behaviors. For this, kinetic studies of the hydroxyl adduct decay gave rate constants kST of 1.22 1010 dm3 mol 1 s 1 and half-live up to 7200 s at physiological pH, without any artifactual signals. The ability of FxBN to directly traps and stabilizes superoxide free radical, with a half-life of 1620 s at physiological pH, was also demonstrated. Besides, FxBN-hydroxyl and -superoxide adducts exhibited distinct and characteristic EPR spectral patterns. Finally, we confirmed the ability of FxBN to act as spin trap in a specific biological system, that is, in the free radical production of experimental anti-trypanosomatid drugs using Trypanosoma cruzi microsomes as biological system. Moreover, previous observations of low FxBN toxicity transform it in a good candidate for in vivo spin trapping.The authors thank to Collaborative Project UdelaR (Uruguay)— CSIC (Spain) (#2006UY0009) and FONDECYT 1071068, 7040037, 7070282. W.P. thanks to PEDECIBA and CSIC (UdelaR) for fellowships

Avulsion at a drift-dominated mesotidal estuary: The Chubut River outlet, Patagonia, Argentina

The Chubut River flows from the Andes to the Atlantic Ocean, and is interrupted by a single dam built at the middle valley. The lower valley is dominated by the aggradation of an alluvial plain induced by a complex of spits that enclosed the inlet in the last 5000years. The river has reduced its flow because the blocking of the upper basin by terminal moraines during the Upper Pleistocene. At least the last two marine transgressions have flooded this estuary, and contributed to the aggradation during regressions. The area is of particular interest in regard to irrigation channels practiced since the XIX century. Today, the mean monthly flow is less than 10m3/s although peaks of 95m3/s have been recorded in Gaiman in July 2001. The dynamics of the estuary is dominated by waves (wave-dominated estuary) as tidal effects attenuate in less than 5km. Three vibracores were collected within this floodplain: (a) at Gaiman, an area without any effect of the sea (35km from the coast); (b) at Trelew, at the former avulsion plain of the river (18km from the coast); and (c) at Playa Magagna, a saltmarsh located 0.4km from the beach.(a)At the Gaiman core (1.54m long) fresh-water epiphytic diatoms dominate (Epithemia sorex, Cocconeis placentula, Ulnaria ulna) suggesting the aggradation of an alluvial plain.(b)The Trelew core (2.19m long) was collected from a deltaic plain. It was composed by fine sand with organic matter at the base that evolved into silty layers to the top. Several unconformities and laminae with heavy minerals were detected by their geochemical composition analysed by micro X-ray fluorescence (Itrax XRF core scanner). Fine-sand laminated layers were perfectly detected by their high content in S and Cl. On the other hand, mud layers presented lower content in Mg and Al with increments in Ca and V.(c)The core from the marsh area (1.67m long) was analysed in terms of the diatom evolution in order to detect Holocene sea-level and salinity effects. The sand flats from the bottom of the core were dominated by Nitzchia navicularis (mesohalobous and benthic taxa) and evolved into mixed flats, mudflats and marshes to the top. Sharp contacts have been detected between these facies, with wavy and lenticular bedding characterising the mixed flat deposits. The middle of the sequence is dominated by a coastal marine diatom (Paralia sulcata) while the top was dominated by Pinnularia borealis, an aerophilous and brackish/freshwater taxa.Fil: Isla, Federico Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Espinosa, Marcela Alcira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Rubio, Belén. Universidad de Vigo; EspañaFil: Escandell, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Gerpe, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Miglioranza, Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencia Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Rey, Daniel. Universidad de Vigo; EspañaFil: Vilas, Federico. Universidad de Vigo; Españ