Challenges in Chagas Disease Drug Discovery: a review

Chagas disease or American trypanosomiasis is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Although the number of infected individuals has decreased, about 6-7 million people are infected worldwide. The chemotherapy drugs currently used are limited to benznidazole and nifurtimox. They are effective in acute phase, congenital transmission and children with chronic infection; however, recent clinical trials have shown limitations in adults with chronic infection, presenting drawbacks during the treatment. Thus, there is an urgent need for new effective, safe and affordable drugs to fight against this complex disease. There were high expectations for azole derivatives as they appeared to be the most promising drugs for the treatment of Chagas disease during the last decade; however, the disappointing results obtained so far in clinical trials evidenced the lack of correlation between preclinical and clinical development. Therefore, the feedback obtained from these studies should define the starting point for addressing a roadmap for the drug discovery process in the fight against this disease. To tackle this challenge, it is important to keep in mind the drug target profile, already defined by panels of experts, and the coordinated work involving multi-disciplinary networks focusing not only on the discovery of new drugs but also on the standardization of the protocols that would allow acceleration in the Chagas disease drug discovery process

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies

The combination of antagonism at histamine H3 receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H3 receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity. Compound 56, 1-(naphthalen-1-yl)-3-[(p-(3-pyrrolidin-1-ylpropoxy)benzene)]sulfonylurea exhibited the best H3 antagonism affinity. However, since all these derivatives failed to block KATP channels, the link of these two related moieties should not be considered a good pharmacophore for obtaining new dual H3 antagonists with insulinotropic activity, suggesting the necessity to propose a new chemical hybrid prototype

Quinoxaline 1,4-di-N-oxide derivatives: Interest in the treatment of Chagas disease

More 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 discove red, 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 (anti- infective, 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 anti-Chagasic 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. 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 daquinoxalin

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

Estudio in vivo de la oxidación mitocondrial en pacientes obesos tratados mediante restricción calórica

La restricción calórica es la terapia nutricional más frecuente en el tratamiento de la obesidad, cuya eficacia depende de la respuesta oxidativa del organismo para evitar la modificación del peso corporal. En este contexto, el objetivo del presente trabajo fue examinarin vivo la oxidación mitocondrial de voluntarios obesos, antes y después de adelgazar, utilizando el test en aliento con 2-ceto[1-13C]isocaproato. El estudio se realizó en 32 voluntarios de ambos sexos: 16 controles (índice de masa corporal: 19,0-27,0 kg/m2), y 16 obesos (índice de masa corporal: 30,0-41,6 kg/m2) que siguieron un período de restricción calórica (-500 kcal) durante 10 semanas. El test con 2-ceto[1-13C]isocaproato se realizó antes y después del tratamiento, a partir de la ingestión de 1 mg/kg de trazador y 20 mg/kg de L-leucina, disueltos en 200 mL de zumo de naranja. Antes y después de la ingestión (cada 10 minutos durante 2 horas), se tomaron muestras de aliento en las que se midió el enriquecimiento en13C mediante espectrometría de masas de relación isotópica. A partir de estas determinaciones se calculó el porcentaje de trazador oxidado en las mitocondrias (%13C). Los obesos tendieron a oxidar un porcentaje menor de trazador que los controles (25,1 ± 5,5% vs 27,5 ± 4,0% p = 0,175). Tras el período de intervención, la pérdida de peso medio fue -7,8 ± 3% (p < 0,001), y se acompañó de un aumento significativo en la oxidación del trazador (25,1 ± 5,5% vs 34,3 ± 5,2% p < 0,001). De hecho, el peso corporal y el porcentaje de 2-ceto[1-13C]isocaproato oxidado fueron inversamente proporcionales (r = -0,34, p = 0,018). Por tanto, el test en aliento con 2-ceto[113-C]isocaproato detectó in vivo la adaptación de la oxidación mitocondrial en obesos tratados mediante restricción calórica, ofreciendo una información complementaria sobre la pérdida de peso

Antiplasmodial and leishmanicidal activities of 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives.

Malaria and leishmaniasis are two of the World’s most important tropical parasitic diseases. Thirteen new 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives (CPCQs) were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against erythrocytic forms of Plasmodium falciparum and axenic forms of Leishmania infantum. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. None of the tested compounds was efficient against Plasmodium, but two of them showed good activity against Leishmania. Toxicity on VERO was correlated with leishmanicidal properties

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

Quinoxalinas como potenciales agentes Antimycobacterium tuberculosis: una revisión

La tuberculosis requiere nuevos tratamientos frente a su compleja resistencia como MDR-TB y XDR-TB. Las quinoxalinas presentan una amplia variedad de propiedades biológicas antichagásica, antimalarial,antileishmanial, antifungal, antimicobacteriana, antiviral, antitumoral, anticancerosa, analgésica, antiinflamatoria, antioxidante, antihipertensiva y antitrombótica. En esta revisión se muestra las propiedades y nuevas aproximaciones de derivados de 1,4-di-N-óxido de quinoxalina como potenciales agentes con actividad antimicobacterial. Tuberculosis requires of new treatments against their complex resistance as MDR-TB and XDR-TB. Quinoxalines present a wide variety of biological properties as antichagasic, antimalarial, antileishmanial, antifungal, antibacterial, antiviral, antitumor, anticancer, analgesic, antiinflammatory, antioxidant, antithrombotic and antihypertensive. This review shows the properties and new approaches for 1,4-di-N-oxide quinoxaline derivatives as potential antimycobacterial active agents

Design and synthesis of novel quinoxaline derivatives as potential candidates for treatment of multidrug-resistant and latent tuberculosis

Abstract Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-Glo microbial cell viability assay. Five compounds showed MIC values < 3.1 μM and IC50 values < 1.5 μM in primary screening and therefore, they were moved on for further evaluation. Compounds 21 and 18 stand out, showing MIC values of 1.6 μM and IC50 values of 0.5 and 1.0 μM respectively. Both compounds were the most potent against three evaluated drug-resistant strains. Moreover, they exhibited intracellular activity in infected macrophages, considering log-reduction and cellular viability. In addition, compounds 16 and 21 were potent against non-replicating M. Tb. and compound 21 was bactericidal. Therefore, quinoxaline derivatives could be considered for making further advances in the future development of antimycobacterial agents

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