Substitutions of fluorine atoms and phenoxy groups in the synthesis of quinoxaline 1,4-di-N-oxide derivatives.

The 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

Quinoxaline 1,4-di-N-oxide and the Potential for Treating Tuberculosis

New 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

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti-inflammatory and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave assisted methods have been used in order to optimize reaction times and to improve the yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase. Two of the best lipoxygenase inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug

Derivados de 1,4-di-N-óxido de quinoxalina y enfermedades olvidadas

Las 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

New 3-methylquinoxaline-2-carboxamide 1,4-di-N-oxide derivatives as anti- Mycobacterium tuberculosis agents.

Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents,obtaining biological values similar to the reference compound, Rifampin (RIF)

New quinoxaline 1,4-di-N-oxide derivatives: Trypanosomaticidal activities and enzyme docking simulation

Two series of pyrazol and propenone quinoxaline derivatives were tested for parasiticidal activity (against amastigotes of Leishmania peruviana and trypomastigotes of Trypanosoma cruzi) and for toxicity against proliferative and non-proliferative cells. The pyrazol series was almost inactive against T. cruzi but, 2,6-Dimethyl-3-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-1H-pyrazol-3-yl] - quinoxaline 1,4-dioxide inhibited 50% of Leishmania growth at 8.9 µM with no impact against proliferative kidney cells and low toxicity against Thp-1 and murine macrophages. The compounds of the propenone series were moderately active against T. cruzi. Among them, 2 compounds were particularly interesting: (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone, that showed a selective activity against proliferative cells (cancer and parasites), being inactive against normal murine peritoneal macrophages and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone that was only active against Leishmania and inactive against the other tested cells. Furthermore in silico studies were performed for ADME properties and docking studies, both series of compounds respected the Lipinski’s rules and show linear correlation between tripanosomaticidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi

Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis

This 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

Synthesis, biological evaluation and structure-activity relationships of new quinoxaline derivatives as anti-Plasmodium falciparum agents

We report the synthesis and antimalarial activities of eighteen quinoxaline and quinoxaline 1,4-di-N-oxide derivatives, eight of which are completely novel. Compounds 1a and 2a were the most active against Plasmodium falciparum strains. Structure-activity relationships demonstrated the importance of an enone moiety linked to the quinoxaline ring

Derivados de 1,4-di-N-óxido de quinoxalina y enfermedades olvidadas

Las 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

New 3-methylquinoxaline-2-carboxamide 1,4-di-N-oxide derivatives as anti- Mycobacterium tuberculosis agents.

Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents,obtaining biological values similar to the reference compound, Rifampin (RIF)