Vicente, E. (Esther)
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- Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives(Instituto Oswaldo Cruz, Ministério da Saúde, 2008) Aldana, I. (Ignacio); Deharo, E. (Eric); Vicente, E. (Esther); Sauvain, M. (Michel); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Castillo, D. (Denis); Solano, B. (Beatriz); Raquel; Estevez, Y. (Yannick); Gonzalez, G. (Germán)A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl)-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.
- Substitutions of fluorine atoms and phenoxy groups in the synthesis of quinoxaline 1,4-di-N-oxide derivatives.(MDPI, 2008) Aldana, I. (Ignacio); Ancizu, S. (Saioa); Vicente, E. (Esther); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Solano, B. (Beatriz); RaquelThe unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy- 3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction. The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced by a methoxy group when dissolved in an ammonia saturated solution of methanol was clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous ammonia.
- Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives(MDPI, 2008) Aldana, I. (Ignacio); Vivas, L. (Livia); Ancizu, S. (Saioa); Vicente, E. (Esther); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Bongard, E. (Emily); Charnaud, S. (Sarah); Solano, B. (Beatriz); RaquelThe aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenylquinoxaline- 2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC50 < 1 μM against the 3D7 strain. Derivative 1 demonstrated high potency (IC50= 0.63 μM) and good selectivity (SI=10.35), thereby becoming a new lead-compound.
- Quinoxaline 1,4-di-N-oxide and the Potential for Treating Tuberculosis(Bentham Science Publishers, 2011) Goldman, R.C. (Robert C.); Aldana, I. (Ignacio); Ancizu, S. (Saioa); Zarranz, B. (Belén); Vicente, E. (Esther); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Marin, A. (Adoración); Solano, B. (Beatriz); Jaso, A. (Andrés); RaquelNew drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed.
- Derivados de 1,4-di-N-óxido de quinoxalina y enfermedades olvidadas(Real Academia de Farmacia, 2007) Aldana, I. (Ignacio); Ancizu, S. (Saioa); Vicente, E. (Esther); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Solano, B. (Beatriz); RaquelLas enfermedades olvidadas son un grupo de enfermedades infecciosas médicamente diversas entre las que se encuentran tuberculosis, malaria, leishmaniasis y la enfermedad de Chagas, que afectan a millares de personas en todo el mundo pero, principalmente, a la gente pobre en países en vías de desarrollo. Son un reto para la Salud Pública Internacional ya que no existen vacunas parar controlarlas y los medicamentos existentes para su tratamiento no son adecuados. La necesidad de buscar nuevas terapias económicamente accesibles para la población afectada es cada vez más urgente y palpable, lo que ha dado lugar a la puesta en marcha de nuevas iniciativas internacionales que buscan la erradicación de estas enfermedades. A lo largo de los años, nuestro grupo de investigación ha llevado a cabo el diseño y la síntesis, mediante métodos sintéticos sencillos y de bajo coste, de diversos derivados de 1,4-di-N-óxido de quinoxalina con el objetivo de encontrar nuevos líderes para el tratamiento de algunas enfermedades olvidadas. Como resultado de varios proyectos de investigación, se han desarrollado nuevas estructuras activas como agentes antituberculosos, antimaláricos, antichagas y, más recientemente, como agentes antileishmania. Este resumen presenta los resultados más importantes obtenidos en este campo, de los que se puede concluir que el núcleo de 1,4-di-N-óxido de quinoxalina representa un posible avance en la búsqueda de nuevos compuestos activos.
- Unexpected reduction of ethyl 3-phenylquinoxaline-2- carboxylate 1,4-di-N-oxide derivatives by amines.(MDPI, 2008) Lima, L.M. (Lidia M.); Aldana, I. (Ignacio); Vicente, E. (Esther); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Solano, B. (Beatriz)The unexpected tendency of amines and functionalized hydrazines to reduce ethyl 3-phenylquinoxaline-2-carboxylate 1,4-di-N-oxide (1) to afford a quinoxaline 1c and mono-oxide quinoxalines 1a and 1b is described. The experimental conditions were standardized to the use of two equivalents of amine in ethanol under reflux for two hours, with the aim of studying the distinct reductive profiles of the amines and the chemoselectivity of the process. With the exception of hydrazine hydrate, which reduced compound 1 to a 3-phenyl-2-quinoxalinecarbohydrazide derivative, the amines only acted as reducing agents.
- Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis(American Society for Microbiology, 2008) Goldman, R.C. (Robert C.); Aldana, I. (Ignacio); Franzblau, S.G. (Scott G.); Vicente, E. (Esther); Burguete, A. (Asunción); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Maddry, J.A. (Joseph A.); Cho, S.H. (Sang-Hyun); Lenaerts, A.J. (Anne J.); Solano, B. (Beatriz); RaquelThis study extends earlier reports regarding the in vitro efficacies of the 1,4-di-N-oxide quinoxaline derivatives against Mycobacterium tuberculosis and has led to the discovery of a derivative with in vivo efficacy in the mouse model of tuberculosis. Quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives were tested in vitro against a broad panel of single-drug-resistant M. tuberculosis strains. The susceptibilities of these strains to some compounds were comparable to those of strain H(37)Rv, as indicated by the ratios of MICs for resistant and nonresistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to those of the currently used antitubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays, including evaluations of the maximum tolerated doses, the levels of oral bioavailability, and the efficacies in a low-dose aerosol model of tuberculosis in mice. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found to be (i) active in reducing CFU counts in both the lungs and spleens of infected mice following oral administration, (ii) active against PA-824-resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from that of PA-824 (a bioreduced nitroimidazole that is in clinical trials), and (iii) very active against nonreplicating bacteria adapted to low-oxygen conditions. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis.
- In vitro and in vivo antimycobacterial activities of ketone and amide derivatives of quinoxaline 1,4-di-N-oxide(Oxford University Press, 2008) Goldman, R.C. (Robert C.); Aldana, I. (Ignacio); Franzblau, S.G. (Scott G.); Vicente, E. (Esther); Pérez-Silanes, S. (Silvia); Monge, A. (Antonio); Maddry, J.A. (Joseph A.); Cho, S.H. (Sang-Hyun); Lenaerts, A.J. (Anne J.); Solano, B. (Beatriz); RaquelAbstract: Objectives: To evaluate a novel series of quinoxaline 1,4-di-N-oxides for in vitro activity against Mycobacterium tuberculosis and for efficacy in a mouse model of tuberculosis (TB). Methods: Ketone and amide derivatives of quinoxaline 1,4-di-N-oxide were evaluated in in vitro and in vivo tests including: (i) activity against M. tuberculosis resistant to currently used antitubercular drugs including multidrug-resistant strains (MDR-TB resistant to isoniazid and rifampicin); (ii) activity against non-replicating persistent (NRP) bacteria; (iii) MBC; (iv) maximum tolerated dose, oral bioavailability and in vivo efficacy in mice; and (v) potential for cross-resistance with another bioreduced drug, PA-824. Results: Ten compounds were tested on single drug-resistant M. tuberculosis. In general, all compounds were active with ratios of MICs against resistant and non-resistant strains of <= 4.00. One compound, 5, was orally active in a murine model of TB, bactericidal, active against NRP bacteria and active on MDR-TB and poly drug-resistant clinical isolates (resistant to 3-5 antitubercular drugs). Conclusions: Quinoxaline 1,4-di-N-oxides represent a new class of orally active antitubercular drugs. They are likely bioreduced to an active metabolite, but the pathway of bacterial activation was different from PA-824, a bioreducible nitroimidazole in clinical trials. Compound 5 was bactericidal and active on NRP organisms indicating that activation occurred in both growing and non-replicating bacteria leading to cell death. The presence of NRP bacteria is believed to be a major factor responsible for the prolonged nature of antitubercular therapy. If the bactericidal activity and activity on non-replicating bacteria in vitro translate to in vivo conditions, quinoxaline 1,4-di-N-oxides may offer a path to shortened therapy.