ABSTRACT
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 ligands.
Subject(s)
Quinoxalines/chemistry , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Indoles/chemistry , Ligands , Naphthalenes/chemistry , Quinolines/chemistry , Quinoxalines/chemical synthesis , Receptor, Melatonin, MT1/agonists , Receptor, Melatonin, MT2/agonists , Structure-Activity RelationshipABSTRACT
The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Hydrazines/chemical synthesis , Hydrazines/pharmacology , Mycobacterium tuberculosis/drug effects , Animals , Anti-Bacterial Agents/chemistry , Cells, Cultured , Chlorocebus aethiops , Hydrazines/chemistry , Inhibitory Concentration 50 , Isonicotinic Acids/chemical synthesis , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Quinoxalines/pharmacology , Vero CellsABSTRACT
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 to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX 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.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Female , Lipoxygenase/metabolism , Male , Molecular Structure , Quinoxalines/chemistry , RatsABSTRACT
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 H(37)Rv. 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.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Quinoxalines/chemistry , Quinoxalines/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Cell Survival/drug effects , Chlorocebus aethiops , Humans , Oxides/chemical synthesis , Oxides/chemistry , Oxides/pharmacology , Quinoxalines/chemical synthesis , Tuberculosis/drug therapy , Vero CellsABSTRACT
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).
Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Chlorocebus aethiops , Chromatography, Thin Layer , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Mycobacterium tuberculosis/growth & development , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Structure-Activity Relationship , Tuberculosis/epidemiology , Vero CellsABSTRACT
Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC(50) values in the same order as the anti-chagasic drug, nifurtimox.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Animals , Magnetic Resonance Spectroscopy , Molecular Structure , Mycobacterium tuberculosis/drug effects , Rifampin , Trypanosoma/drug effectsABSTRACT
New series of 3-phenylquinoxaline 1,4-di-N-oxide with selective activity against Mycobacterium tuberculosis have been prepared and evaluated. Thirty-four of the seventy tested compounds showed an MIC value less than 0.2 microg/mL, a value on the order of the MIC of rifampicin. Furthermore, 45% of the evaluated derivatives showed a good in vitro activity/toxicity ratio. The most active and selective compounds carry a fluorine atom in the quinoxaline 7-position or in the phenyl substituent para-position. In conclusion, the potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for synthesizing new analogues, particularly compound 7-methyl-3-(4'-fluoro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxide (MIC <0.2 microg/mL and SI > 500).
Subject(s)
Antitubercular Agents/chemical synthesis , Mycobacterium tuberculosis/drug effects , Quinoxalines/pharmacology , Antitubercular Agents/pharmacology , Fluorine , Humans , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Cyclic N-Oxides/chemical synthesis , Cyclic N-Oxides/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Oxides/chemical synthesis , Oxides/pharmacology , Plasmodium falciparum/drug effects , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Antimalarials/chemistry , Cell Death/drug effects , Cell Line , Cyclic N-Oxides/chemistry , Drug Resistance/drug effects , Nitriles/chemistry , Oxides/chemistry , Parasitic Sensitivity Tests , Quinoxalines/chemistryABSTRACT
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.
Subject(s)
Fluorine/chemistry , Phenols/chemistry , Quinoxalines/chemical synthesis , Antitubercular Agents/chemistry , Mass Spectrometry , Quinoxalines/chemistryABSTRACT
We report the synthesis, anti-inflammatory and antioxidant activities of novel ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl)-2-propen-1-one derivatives and of their 4,5-dihydro-(1H)-pyrazole analogues. The tested compounds inhibit the carrageenin-induced rat paw edema (4.5-56.1%) and present important scavenging activities. Compound 2a is the most potent (56.1%) in the in vivo experiment and exhibits promising in vitro inhibition of soybean lipoxygenase (IC(50)<1microM).
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antioxidants/chemical synthesis , Pyrazoles/chemical synthesis , Quinoxalines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antioxidants/therapeutic use , Edema/drug therapy , Pyrazoles/therapeutic use , Quinoxalines/therapeutic use , RatsABSTRACT
Las enfermedades olvidadas son un grupo de enfermedades infecciosas médicamentediversas entre las que se encuentran tuberculosis, malaria, leishmaniasisy la enfermedad de Chagas, que afectan a millares de personas en todo el mundopero, principalmente, a la gente pobre en países en vías de desarrollo. Son un retopara la Salud Pública Internacional ya que no existen vacunas parar controlarlasy los medicamentos existentes para su tratamiento no son adecuados. La necesidadde buscar nuevas terapias económicamente accesibles para la población afectadaes cada vez más urgente y palpable, lo que ha dado lugar a la puesta en marchade nuevas iniciativas internacionales que buscan la erradicación de estas enfermedades.A lo largo de los años, nuestro grupo de investigación ha llevado a cabo eldiseño 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 encontrarnuevos líderes para el tratamiento de algunas enfermedades olvidadas. Como resultadode varios proyectos de investigación, se han desarrollado nuevas estructurasactivas como agentes antituberculosos, antimaláricos, antichagas y, más recientemente,como agentes antileishmania. Este resumen presenta los resultadosmás importantes obtenidos en este campo, de los que se puede concluir que elnúcleo de 1,4-di-N-óxido de quinoxalina representa un posible avance en la búsquedade nuevos compuestos activos
Neglected diseases are diseases that affect thousands of people around theworld, but who do not have effective or suitable treatments. They are mainlyinfectious tropical diseases that fundamentally affect the poorest population; someexamples are tuberculosis, leishmaniasis, malaria and Chagas, which generate adevastating impact on humanity. This fact highlights the necessity to search fornew economically accessible therapies for the affected population. Throughout theyears our research group has carried out the design and synthesis of several quinoxaline1,4-di-N-oxide derivatives with the aim of finding new leaders for thetreatment of these types of diseases by means of simple, low cost synthetic methods.This work has resulted in the development of new active structures such asantitubercular, antimalarial and antichagas agents, and more recently, antileishmaniaagents. This summary displays the most important results obtained in thisfield, and it may be concluded that the quinoxaline 1,4-di-N-oxide nucleus representsa possible advance in the search of new active compounds