Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

Torres, Enrique; Moreno‐Viguri, Elsa; Galiano, Silvia; Devarapally, Goutham; Crawford, Philip W.; Azqueta, Amaya; Arbillaga, Leire; Varela, Javier; Birriel, Estefanía; Maio, Rossanna Di; Cerecetto, Hugo; González, Mercedes; Aldana, Ignacio; Monge, Antonio; Pérez‐Silanes, Silvia

doi:10.1016/j.ejmech.2013.04.065

Cited by 50 publications

(43 citation statements)

References 67 publications

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“…41,42 In order to better understand the anti-T. cruzi mechanism of action of our compounds, we studied the effect of some selected QDO derivatives: compound 13 ( Figure 5) and compounds 41, 42 and 45 (Figure 11), on the mitochondrial dehydrogenase activity in comparison with the reference drug, Nfx. 40 The results show that Nfx. does not affect the mitochondrial dehydrogenase activity, while the quinoxaline derivatives (compound 13, 41, 42 and 45) produce a decrease in a timedependent manner (Figure 13).…”

Section: Effect On Mitochondrial Dehydrogenase Activitymentioning

confidence: 75%

“…The synthesized derivatives were modified at C-2 of the quinoxaline ring, possessing a methyl or ethyl ester group instead of the ketone moiety. 38,40 The new derivatives showed excellent in vitro biological activity against Tulahuen 2 strain of T. cruzi. Sixteen out of the eighteen compounds with CF 3 in C-3 were more potent than the reference drug Nfx.…”

Section: Ester Derivativesmentioning

confidence: 99%

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Quinoxaline 1,4-di-N-oxide Derivatives: Interest in the Treatment of Chagas Disease

Moreno‐Viguri¹,

Pérez‐Silanes²

2013

Revista Virtual De Química

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Resumo: Mais de 100 milhões de pessoas estão em risco de contrair a doença de Chagas. Estima-se que em 2008, mais de 10.000 pessoas morreram devido a esta patologia. Apesar de a doença ter sido descoberta há mais de 100 anos, ainda é preciso encontrar tratamento seguro e eficaz. Portanto, novos fármacos eficazes contra a doença de Chagas necessitam urgentemente serem descobertos. Derivados de quinoxalina apresentam interessantes propriedades biológicas (anti-infecciosa, citotóxica, anti-candida, anti-protozoário) e a avaliação de suas propriedades farmacológicas ainda está em andamento. Com respeito a isso, nós estamos há mais de uma década em busca de agentes anti-chagásicos. Nesta revisão mostramos nosso trabalho em andamento para identificação de novos agentes anti-T. cruzi com o padrão estrutural quinoxalina-di-N-óxido e apresentamos a relação estrutura-atividade observada entre as diferentes substituições nas posições C-2, C-3, C-6 e C-7 do anel da quinoxalina.Palavras-chave: Doença de Chagas; Trypanosoma cruzi; 1,4-di-N-óxido Quinoxalinas. AbstractsMore than 100 million people are at risk of contracting Chagas disease. It is estimated that in 2008, Chagas disease was responsible for the death of more than 10,000 people. Despite the fact that there are more than 100 years since the disease was discovered, safe and effective treatments still have to be found. Therefore, new drugs active against Chagas disease are urgently required. Quinoxaline derivatives show very interesting biological properties (antiinfective, cytotoxic, anticandida, antiprotozoal) and evaluation of their medicinal chemistry is still in progress. In this regard, we have spent more than a decade in the search for antiChagasic agents. In this review, we summarize our on-going work to identify new anti-T. cruzi agents with the quinoxaline-di-N-oxide scaffold. We present the structure-activity relationship observed among the different substitutions in C-2, C-3, C-6 and C-7 position of the quinoxaline ring.

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Section: Effect On Mitochondrial Dehydrogenase Activitymentioning

confidence: 75%

Section: Ester Derivativesmentioning

confidence: 99%

Quinoxaline 1,4-di-N-oxide Derivatives: Interest in the Treatment of Chagas Disease

Moreno‐Viguri¹,

Pérez‐Silanes²

2013

Revista Virtual De Química

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“…Recientemente, se han sintetizado y evaluado diversos compuestos con actividad antichagasica, incluyendo Benzofuroxanos, 15 N-óxidos de benzimidazol, 16 N-óxidos de imidazol 16,17 y N-óxidos de quinoxalina. 18,19 Particularmente, los derivados N-óxido de quinoxalina han mostrado ser promisorios debido a su excepcional actividad in vitro contra T. cruzi. Atendiendo a esto, Torres y colaboradores 18 sintetizaron una serie de compuestos 1,4-di-N-óxido de quinoxalina y evaluaron su actividad biológica in vitro contra Trypanosoma cruzi encontrando que la eficacia de estos compuestos está relacionada con la presencia de grupos extractores de electrones en el anillo de quinoxalina.…”

Section: Introduccionunclassified

“…18,19 Particularmente, los derivados N-óxido de quinoxalina han mostrado ser promisorios debido a su excepcional actividad in vitro contra T. cruzi. Atendiendo a esto, Torres y colaboradores 18 sintetizaron una serie de compuestos 1,4-di-N-óxido de quinoxalina y evaluaron su actividad biológica in vitro contra Trypanosoma cruzi encontrando que la eficacia de estos compuestos está relacionada con la presencia de grupos extractores de electrones en el anillo de quinoxalina. 18 El mecanismo de acción de este grupo de compuestos no se conoce por completo, sin embargo, estudios realizados por Benítez y colaboradores sugieren un mecanismo basado en la bio-reducción del grupo N-oxido (N-O, ver Figura 1) presente en los N-óxidos de quinoxalina con participación de la enzima deshidrogenasa mitocondrial.…”

Section: Introduccionunclassified

2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE

Guerra¹,

López²,

Figueredo³

et al. 2016

Química Nova

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publicado na web em 06/05/2016 2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE. In the present work was performed a quantitative structure-activity relationship (QSAR) for a set of derivatives of 1,4-quinoxaline N-oxides with antichagasic activity based on reactivity descriptors from the frame conceptual DFT. QSAR models showed a good statistical quality and capacity internal prediction with R 2 > 0.6 and Q 2 > 0.5 respectively. QSAR model suggest that antichagasic activity of the studied compounds depends largely from the reactive behavior of N-oxide group (N-O). Also, reactivity descriptors showed that the N-oxide group is a reactive site in theses derivatives with nucleophilic characteristics. The results QSAR shed light on the understanding of the mechanism of action and design of new drugs based on derivatives of 1,4-di-N-oxides quinoxaline.Keywords: QSAR; Antichagasic; N-oxide group; Nucleophilic. INTRODUCCIONLa enfermedad de Chagas fue descubierta en 1909 por el medico brasileño Carlos Chagas mientras diagnosticaba a una joven paciente de dos años que presentaba parásitos en el torrente sanguíneo.1 Esta enfermedad, producida por el parásito protozoario Trypanosoma cruzi (T. cruzi), afecta actualmente entre 6 y 8 millones de personas en el mundo, 2 siendo endémica en América latina. No obstante, su incidencia en el continente europeo y algunos países de Norteamérica ha aumentado en los últimos años debido a los patrones de migración que provocan la diseminación de la enfermedad. 3,4 Aunque el principal modo de transmisión de T. cruzi hacia el ser humano ocurre por contacto con las heces de algunos hematófagos triatominos, 5 existen otros modos de infección asociados a transfusiones sanguíneas, 6 trasplantes de órganos, 7,8 contacto entre madre e hijo durante el parto, 9 y por vía oral. 10Con respecto a las manifestaciones clínicas, existen dos etapas que caracterizan la enfermedad de Chagas. La primera etapa comienza justo después de la infección (fase aguda), y aunque es asintomática, se han reportado casos con síntomas similares a los de una infección febril, dificultando así su correcto diagnóstico. 11La segunda etapa (fase crónica), que puede tardar hasta 15 años en aparecer, se caracteriza por cardiomiopatía dilatada 12,13 y afecciones del tracto digestivo 14 que representan un alto riesgo comprometiendo la vida de los pacientes. Desde el punto de vista farmacológico, el tratamiento actual de la enfermedad de Chagas se basa principalmente en dos fármacos nitro-heterocíclicos llamados Nifurtimox (Nfx) y benznidazol (Bz), descubiertos empíricamente entre 1960 y 1970; mostrando una efectividad en casi el 60% de los casos que son tratados durante la fase aguda. Sin embargo, el uso de Nfx y Bz para el tratamiento de la enfermedad durante la frase crónica es controversial debido a que estos nitro-heterociclos solo son eficaces contra la forma extracelular de T. cruzi que se desarrolla durante la fase aguda. Por lo tanto, la búsqueda de nuevos fármacos más...

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“…Quinoxaline derivatives are of significant interest as they are noteworthy intermediates for the manufacturing of pharmaceuticals 409 and advanced materials. [410][411] Quinoxalines are very important compounds due to their wide spectrum of biological activities such as anticancer, [412][413] antibacterial 414 and activity as kinase inhibitors.…”

Section: Quinoxalinesmentioning

confidence: 99%

Ninhydrin in synthesis of heterocyclic compounds

Ziarani¹,

Lashgari²,

Azimian³

et al. 2015

Arkivoc

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Ninhydrin has been utilized in many heterocyclic preparations and considered as an important building block in organic synthesis. There is a wide range of reactions that include ninhydrin in the synthesis of heterocyclic compounds. This review highlights the advances in the use of ninhydrin as starting material in the synthesis of various organic compounds and drugs in a fully comprehensive way, from its first isolation in 1910 to the end of 2013. There is also a diversity of multi-component reactions of ninhydrin and we highlight the recent reports in this review.

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Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents

Cited by 50 publications

References 67 publications

Quinoxaline 1,4-di-N-oxide Derivatives: Interest in the Treatment of Chagas Disease

Quinoxaline 1,4-di-N-oxide Derivatives: Interest in the Treatment of Chagas Disease

2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE

Ninhydrin in synthesis of heterocyclic compounds

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