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1.
Molecules ; 19(2): 2166-80, 2014 Feb 18.
Article in English | MEDLINE | ID: mdl-24552985

ABSTRACT

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.


Subject(s)
Antimalarials/chemistry , Plasmodium falciparum/drug effects , Quinoxalines/chemistry , Structure-Activity Relationship , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Cell Line , Humans , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/pathogenicity , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology
2.
Exp Parasitol ; 127(4): 745-51, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21272583

ABSTRACT

Pyrazole and propenone quinoxaline derivatives were tested against intracellular forms of Leishmania peruviana and Trypanosoma cruzi. Both series were tested for toxicity against proliferative and non-proliferative cells. The pyrazole quinoxaline series was quite inactive against T. cruzi; however, the compound 2,6-dimethyl-3-f-quinoxaline 1,4-dioxide was found to inhibit 50% of Leishmania growth at 8.9 µM, with no impact against proliferative kidney cells and with low toxicity against THP-1 cells and murine macrophages. The compounds belonging to the propenone quinoxaline series were moderately active against T. cruzi. Among these compounds, two were particularly interesting, (2E)-1-(7-fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone and (2E)-3-(3,4,5-trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone. The former possessed selective activity against proliferative cells (cancer and parasites) and was inactive against murine peritoneal macrophages; the latter was active against Leishmania and inactive against the other tested cells. Furthermore, insilico studies showed that both series respected Lipinski's rules and that they confirmed a linear correlation between trypanocidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.


Subject(s)
Leishmania/drug effects , Quinoxalines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chlorocebus aethiops , Female , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/parasitology , Mice , Mice, Inbred BALB C , Molecular Structure , Quinoxalines/chemistry , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Vero Cells/parasitology
3.
Chem Biol Drug Des ; 77(4): 255-67, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21244639

ABSTRACT

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 , Rats
4.
Bioorg Med Chem ; 18(7): 2713-9, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20233660

ABSTRACT

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 Cells
5.
Molecules ; 14(6): 2256-72, 2009 Jun 22.
Article in English | MEDLINE | ID: mdl-19553897

ABSTRACT

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 effects
6.
Bioorg Med Chem ; 17(1): 385-9, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-19058970

ABSTRACT

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 Relationship
7.
Mem. Inst. Oswaldo Cruz ; 103(8): 778-780, Dec. 2008. tab
Article in English | LILACS | ID: lil-502297

ABSTRACT

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.


Subject(s)
Animals , Female , Mice , Antiprotozoal Agents/chemistry , Cyclic N-Oxides/chemistry , Leishmania mexicana/drug effects , Quinoxalines/chemistry , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/toxicity , Cyclic N-Oxides/pharmacology , Cyclic N-Oxides/toxicity , Mice, Inbred BALB C , Macrophages/drug effects , Parasitic Sensitivity Tests , Quinoxalines/pharmacology , Quinoxalines/toxicity , Structure-Activity Relationship
8.
Antimicrob Agents Chemother ; 52(9): 3321-6, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18625764

ABSTRACT

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.


Subject(s)
Antitubercular Agents , Cyclic N-Oxides , Disease Models, Animal , Mycobacterium tuberculosis/drug effects , Quinoxalines , Tuberculosis, Pulmonary/drug therapy , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/pharmacology , Cyclic N-Oxides/therapeutic use , Drug Resistance, Bacterial , Female , Humans , Lung/microbiology , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests/standards , Mycobacterium tuberculosis/isolation & purification , Quinoxalines/chemistry , Quinoxalines/pharmacology , Quinoxalines/therapeutic use , Specific Pathogen-Free Organisms , Spleen/microbiology , Structure-Activity Relationship , Treatment Outcome , Tuberculosis, Pulmonary/microbiology
9.
Molecules ; 13(1): 69-77, 2008 Jan 17.
Article in English | MEDLINE | ID: mdl-18259130

ABSTRACT

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/chemistry
10.
Molecules ; 13(1): 86-95, 2008 Jan 18.
Article in English | MEDLINE | ID: mdl-18259132

ABSTRACT

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/chemistry
11.
Eur J Med Chem ; 43(9): 1903-10, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18215443

ABSTRACT

As a continuation of our research and with the aim of obtaining new antimalarial agents, new series of 3-phenylquinoxaline 1,4-di-N-oxide derivatives have been synthesized following the classical Beirut reaction. Antiplasmodial activity was evaluated in vitro against Plasmodium falciparum by the incorporation of [3H]-hypoxanthine. Cytotoxicity was tested in KB cells by AlamarBlue assay. Twenty-one of the 60 compounds that were assayed against 3D7 (CQ-sensitive) showed enough activity to be also evaluated against K1 (CQ-resistant) strain. Ten of them were shown to be more active than chloroquine in the resistant strain. The most interesting compounds are 7-(methyl or methoxy)-3-(4'-fluoro or chloro)phenylquinoxaline-2-carbonitrile 1,4-di-N-oxides because of their low IC50 and their high SI shown for the K1 strain, making them valid new leads.


Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacokinetics , Quinoxalines/chemical synthesis , Quinoxalines/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/toxicity , Cattle , Cell Survival/drug effects , Drug Design , Humans , KB Cells , Plasmodium falciparum/drug effects , Quinoxalines/chemistry , Quinoxalines/toxicity , Structure-Activity Relationship
12.
Mem Inst Oswaldo Cruz ; 103(8): 778-80, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19148416

ABSTRACT

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.


Subject(s)
Antiprotozoal Agents/chemistry , Cyclic N-Oxides/chemistry , Leishmania mexicana/drug effects , Quinoxalines/chemistry , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/toxicity , Cyclic N-Oxides/pharmacology , Cyclic N-Oxides/toxicity , Female , Macrophages/drug effects , Mice , Mice, Inbred BALB C , Parasitic Sensitivity Tests , Quinoxalines/pharmacology , Quinoxalines/toxicity , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 17(23): 6439-43, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17942306

ABSTRACT

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 , Rats
14.
J Med Chem ; 50(22): 5485-92, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17910426

ABSTRACT

As a continuation of our research in the quinoxaline 1,4-di-N-oxide new series of 2-arylcarbonyl-3-trifluoromethylquinoxaline, 1,4-di-N-oxide derivatives have been synthesized and evaluated in a full panel of 60 human tumor cell lines. Selective reductions were carried out on two compounds which allowed us to determine the compound structures by comparison of the 1H NMR spectra. In general, all the di-N-oxidized compounds showed good cytotoxic parameters. The best activity was observed in derivatives with electron-withdrawing groups in position 6 or 7 on the quinoxaline ring and in the unsubstituted analogues, whereas loss of one or two oxygens reduced the cytotoxicity. The best five compounds were selected for evaluation for the in vivo hollow fiber assays. In vitro studies reveal that compound 5h efficiently generates reactive oxygen species via redox cycling in the presence of the NADPH/cytochrome P450 enzyme system, providing a plausible molecular mechanism for the observed aerobic cytotoxicity of these quinoxaline N-oxides.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclic N-Oxides/chemical synthesis , Quinoxalines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclic N-Oxides/chemistry , Cyclic N-Oxides/pharmacology , Cytochrome P-450 Enzyme System/metabolism , DNA Damage , Drug Screening Assays, Antitumor , Humans , NAD/metabolism , Oxidation-Reduction , Quinoxalines/chemistry , Quinoxalines/pharmacology , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
15.
An. R. Acad. Farm ; 73(4): 927-945, oct. 2007. ilus, tab
Article in Es | IBECS | ID: ibc-64412

ABSTRACT

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


Subject(s)
Quinoxalines/pharmacology , 4-Nitroquinoline-1-oxide/pharmacology , Communicable Diseases/chemically induced , Communicable Diseases/drug therapy , Quinoxalines/pharmacokinetics , Public Health/methods , Tuberculosis/drug therapy , Malaria/chemically induced , Malaria/drug therapy , Leishmaniasis/drug therapy , Chagas Disease/drug therapy , Public Health/education
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