New quinoxaline derivatives as potential MT₁ and MT₂ receptor ligands.

Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligand

Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives.

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenyl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC(50) less than 1 microM against the 3D7 strain. Derivative 1 demonstrated high potency (IC(50)= 0.63 microM) and good selectivity (SI=10.35), thereby becoming a new lead-compound

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

1,4-Di-N-oxide quinoxaline-2-carboxamide: Cyclic voltammetry and relationship between electrochemical behavior, structure and anti-tuberculosis activity

To gain insight into the mechanism of action, the redox properties of 37 quinoxaline-2-carboxamide 1,4-di-N-oxides with varying degrees of anti-tuberculosis activity were studied in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. For all compounds studied, electrochemical reduction in DMF is consistent with the reduction of the N-oxide functionality to form a radical anion. The influence of molecular structure on reduction potential is addressed and it can be said that a general relationship exists between reduction potential and reported antimicrobial activity. For those compounds which have demonstrated promising biological activity, the more active the compound the less negative the reduction potential typically is. The results suggest the possible participation of charge transfer processes in the mechanism of action of quinoxaline di-N-oxides against tuberculosis and offer new insights into the design of future antitubercular drugs

Synthesis and antimycobacterial activity of new quinoxaline-2- carboxamide 1,4-di-N-oxide derivatives.

As a continuation of our research and with the aim of obtaining new anti-tuberculosis agents which can improve the current chemotherapeutic anti-tuberculosis treatments, forty-three new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis strain H37Rv. Active compounds were also screened to assess toxicity to a VERO cell line. Results indicate that compounds with a methyl moiety substituted in position 3 and unsubstituted benzyl substituted on the carboxamide group provide an efficient approach for further development of anti-tuberculosis agents

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

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

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 and indole derivatives as MT1 and MT2 receptor agonists

There is a vast amount of studies which state that sleep is necessary for many functions, such as for encoding and consolidation of memory, for regulation of cognitive and emotional brain processes, for saving energy, for removing free radicals and for regulation of some neurotransmitters. Sleep disorders include a very frequent pathology of diverse origins. These disorders can appear alone or associated with each other, thereby making this pathology even more complex. In the second international classification of sleep disorders (ICSD-2), more than 90 sleep disorders are included divided in eight main categories. The most common sleep disorders include insomnia, sleep apnea, restless legs syndrome, and narcolepsy, with insomnia being the most prevalent among them. The treatment of insomnia for example, involves a great variety of treatments including psychological and behavioral therapies as well as pharmacological therapies. In many cases, combining the behavioral and pharmacological strategies results in the most efficacious treatment. In the past few years, melatonin receptors MT1 and MT2 have become one of the most interesting pharmacological targets for the treatment of many sleep disorders. Ever since the idea arose with regard to melatonin (MLT) acting as a hormonal photoperiodic messenger controlling the biological ¿clocks¿ of the individuals, the hypothesis that MLT administration might be a potential therapy to treat sleep disorders gained more acceptance. MLT exerts too many effects in the body including initiation and maintenance of sleep by the activation of MLT receptors MT1 and MT2. In the last few decades, a multitude of research groups have centered their efforts on the obtainment of new MT1 and MT2 receptor agonists in order to find a new drug for the treatment of diverse sleep disorders. All those compounds contain, without exception, an aliphatic chain substituted on a central aromatic ring and linked to an alkylamide or a derivative. Moreover, in the majority of these cases, the structures also possess an alkoxy group, generally a methoxy, joined to the central core. The principal aim of this work has been to synthesize new molecules as agonists of the melatonin receptors MT1 and MT2 with potential activity for the treatment of sleep disorders. In this sense, after having carried out an extensive bibliographical review, some initial compounds have been designed. Later, after obtaining the biological activity values, a SAR study has been performed and the starting hypothesis has been then redefined, followed by optimization of the initially designed structures. In addition, when enough data has been collected, alternative molecular modeling techniques have been included in this cycle that allows the discrimination of inactive molecules in stages previous to their synthesis. During this project forty-eight final compounds have been synthesized, for which four different synthetic routes have been optimized. Once the new derivatives have been chemically characterized, they have been sent to the ¿Institute de Recherches Servier¿ in France for being biologically evaluated in order to know their affinity for MT1/MT2 receptors first and their agonism/antagonism profile then. With this data a SAR study have been carried out which in combination with new bibliographic reviews performed have permit the redefinition of the starting hypothesis as well as of the initially designed structures. All these approaches have provided significantly promising results that open a new line of research for the development of future MT1/MT2 receptor agonists