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

Development, validation and application of a GC-MS method for the simultaneous detection and quantification of neutral lipid species in Trypanosoma cruzi

The development and validation of an analytical method for the simultaneous analysis of five neutral lipids in Trypanosoma cruzi epimastigotes by GC-MS is presented in this study. The validated method meets all validation parameters for all components and the chromatographic conditions have been optimized during its development. This analytical method has demonstrated good selectivity, accuracy, within-day precision, recovery and linearity in each of the established ranges. In addition, detection and quantification limits for squalene, cholesterol, ergosterol and lanosterol have been improved and it is worth highlighting the fact that this is the first time that squalene-2,3-epoxide validation data have been reported. The new validated method has been applied to epimastigotes treated with compounds with in vitro anti- T.cruzi activity. This new methodology is straightforward and constitutes a tool for screening possible sterol biosynthesis pathway inhibitors in Trypanosoma cruzi, one of the most studied targets in Chagas disease treatment. Therefore, it is an interesting and useful contribution to medicinal chemistry research

In vitro antileishmanial activity and iron superoxide dismutase inhibition of arylamine Mannich base derivatives

Leishmaniasis is one of the world’s most neglected diseases, and it has a worldwide prevalence of 12 million. There are no effective human vaccines for its prevention, and treatment is hampered by outdated drugs. Therefore, research aiming at the development of new therapeutic tools to fight Leishmaniasis remains a crucial goal today. With this purpose in mind, we present twenty arylaminoketone derivatives with a very interesting in vitro and in vivo efficacy against Trypanosoma cruzi that have now been studied against promastigote and amastigote forms of L. infantum, L. donovani and L. braziliensis strains. Six out of the twenty Mannich base-type derivatives showed Selectivity Index between 39 and 2337 times higher in the amastigote form than the reference drug glucantime. These six derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at a IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing a greater alteration in glucose catabolism and leading to greater levels of Fe-SOD (iron superoxide dismutase) inhibition. These molecules could be potential candidates for Leishmaniasis chemotherapy

A Comparative Study of Conventional and Microwave‐Assisted Synthesis of Quinoxaline 1,4‐di‐N‐oxide N‐acylhydrazones Derivatives Designed as Antitubercular Drug Candidates

Quinoxaline 1,4‐di‐N‐oxide (QdNO) and N‐acylhydrazone subunit are considered privileged scaffolds in medicinal chemistry because of its wide spectrum of biological activities, such as antibacterial, antitubercular, antiviral, anticancer, and antifungal. Beirut's reaction is the mostly commonly employed synthetic method to obtain QdNO; however, extended time, low yields, and byproduct formation are common features observed during the synthesis. Microwave‐assisted organic synthesis (MW) has gained popularity as an effective way to speed up chemical reactions, increasing yields and selectivity of a variety of reactions. Therefore, in an effort to synthesize compounds with potential to tuberculosis treatment, we reported herein the use of MW as a tool to obtain new QdNO derivatives containing the N‐acylhydrazone subunit. Four different synthetic routes were evaluated by using different benzofuroxan derivatives in the Beirut's reaction. The synthetic route D, which employed a dioxolan‐benzofuroxan derivative, has shown to be the best condition to obtain the desired hybrid quinoxaline. MW drastically reduces the reaction time to obtain all compounds compared to conventional heating. For compound 13, for example, the use of MW instead of conventional heating was able to reduce the reaction time in 192‐fold. In conclusion, the use of a benzofuroxan derivative without additional electrophilic sites besides N‐oxide nitrogen and the employment of the microwave‐assisted synthesis have proved to be the optimum condition to obtain quinoxaline 1,4‐di‐N‐oxide N‐acylhydrazone derivatives

In vitro and in vivo anti-Trypanosoma cruzi activity of new arylamine Mannich base-type derivatives

Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity and with a larger spectrum of action than that corresponding to the reference drug benznidazole. Indexes of high selectivity found in vitro formed the basis for later in vivo assays in BALB/c mice. Murine model results show that compounds 3, 4, 7 and 10 induced a remarkable decrease in parasitemia levels in acute phase and the parasitemia reactivation following immunosuppression, and curative rates were higher than with benznidazole. These high anti-parasitic activities encourage us to propose these compounds as promising molecules for developing an easy to synthesize anti-Chagas agent

Design, Synthesis and Characterization of N-oxide-containing Heterocycles with In vivo Sterilizing Antitubercular Activity

Tuberculosis, caused by the Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide- containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and non- replicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective leading to the reduction of the number of Mtb to undetected levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks the process of translation. Altogether, these results indicated benzofuroxan derivative 8 to be a promising lead compound for the development of a novel chemical class of antitubercular drugs

Diseño, síntesis y evaluación biológica de nuevos derivados de bases de Mannich de tipo arilamina como potenciales agentes tripanocidas y leishmanicidas

Chagas Disease (CD) and Leishmaniasis are two parasitic diseases transmitted by vectors and caused by protozoa from the Trypanosomatidae family. Both diseases are included within the neglected tropical diseases group and are caused by Trypanosoma cruzi and the Leishmania genus protozoa respectively. Chagas disease is endemic in 21 countries in the Americas and affects about 5 and 6 million people, causing 7,000 deaths annually. With regard to leishmaniasis, it is present in 98 countries of all continents, causing about 40,000 deaths annually. During its life cycle, T. cruzi and Leishmania spp acquire different development forms depending on the medium where they are. T. cruzi presents three stages: The trypomastigote form, highly infective for the mammalian host, epimastigote form, which is the replicative form in the insect vector and amastigote form, which is the reproductive form in mammalian cells. The genus Leishmania presents two evolutionary forms, the promastigote form, which is the infective form for humans and the amastigote form, which is the replicative form in mammalian cells. Regarding the treatment of CD and Leishmaniasis, despite its high prevalence and that they were discovered many years ago, there is still no fully an effective treatment from an activity, safety and cost point of view. In CD, only two drugs, Nifurtimox and Benznidazole, have an accepted clinical use. Both drugs have important limitations such as the multiple adverse reactions, their lower efficacy in the chronic phase of the disease, the complicated dosage, the long duration of the treatment and the resistant strains. With regard to leishmaniasis, the variety of available treatments is much wider than for CD. These treatments have a high efficacy, however, they have important limitations such as toxicity, adverse effects, high cost, the development of resistance, the long periods of treatment, the administration route and the need for hospitalization. Taking into account this situation of necessity in the acquisition and identification of new trypanocidal and leishmanicidal agents, after an extensive bibliographic review and considering the experience of the research group, a molecule repositioning strategy was applied as a starting point for the design of the presented arylaminoketone Mannich bases type derivatives. Sixty-two new derivatives were synthesized using two one-step and economically efficient synthetic methods. Fifty-eight were obtained by the Mannich reaction and four by an aliphatic nucleophilic substitution. The family of Mannich bases derivatives that has been published has shown great potential for the development of new agents against CD and Leishmaniasis. Compounds with excellent in vitro efficacy results have been identified against both kinetoplastids, with very low cytotoxicity against mammalian cells, a non-genotoxic profile and non-mutagenic. The leading compounds had a high in vivo activity against T. cruzi in the acute phase. In addition, no reactivation of parasitemia was observed in a immunosuppression murine model and they were very effectively in the presence prevention of the parasite in the target organs. In addition, the identified lead compounds had a high bioavailability. Because of this results we propose these compounds as a very promising molecules to continue their preclinical development as possible anti- kinetoplastids agentst

Diseño, síntesis y evaluación biológica de nuevos derivados de bases de Mannich de tipo arilamina como potenciales agentes tripanocidas y leishmanicidas

Chagas Disease (CD) and Leishmaniasis are two parasitic diseases transmitted by vectors and caused by protozoa from the Trypanosomatidae family. Both diseases are included within the neglected tropical diseases group and are caused by Trypanosoma cruzi and the Leishmania genus protozoa respectively. Chagas disease is endemic in 21 countries in the Americas and affects about 5 and 6 million people, causing 7,000 deaths annually. With regard to leishmaniasis, it is present in 98 countries of all continents, causing about 40,000 deaths annually. During its life cycle, T. cruzi and Leishmania spp acquire different development forms depending on the medium where they are. T. cruzi presents three stages: The trypomastigote form, highly infective for the mammalian host, epimastigote form, which is the replicative form in the insect vector and amastigote form, which is the reproductive form in mammalian cells. The genus Leishmania presents two evolutionary forms, the promastigote form, which is the infective form for humans and the amastigote form, which is the replicative form in mammalian cells. Regarding the treatment of CD and Leishmaniasis, despite its high prevalence and that they were discovered many years ago, there is still no fully an effective treatment from an activity, safety and cost point of view. In CD, only two drugs, Nifurtimox and Benznidazole, have an accepted clinical use. Both drugs have important limitations such as the multiple adverse reactions, their lower efficacy in the chronic phase of the disease, the complicated dosage, the long duration of the treatment and the resistant strains. With regard to leishmaniasis, the variety of available treatments is much wider than for CD. These treatments have a high efficacy, however, they have important limitations such as toxicity, adverse effects, high cost, the development of resistance, the long periods of treatment, the administration route and the need for hospitalization. Taking into account this situation of necessity in the acquisition and identification of new trypanocidal and leishmanicidal agents, after an extensive bibliographic review and considering the experience of the research group, a molecule repositioning strategy was applied as a starting point for the design of the presented arylaminoketone Mannich bases type derivatives. Sixty-two new derivatives were synthesized using two one-step and economically efficient synthetic methods. Fifty-eight were obtained by the Mannich reaction and four by an aliphatic nucleophilic substitution. The family of Mannich bases derivatives that has been published has shown great potential for the development of new agents against CD and Leishmaniasis. Compounds with excellent in vitro efficacy results have been identified against both kinetoplastids, with very low cytotoxicity against mammalian cells, a non-genotoxic profile and non-mutagenic. The leading compounds had a high in vivo activity against T. cruzi in the acute phase. In addition, no reactivation of parasitemia was observed in a immunosuppression murine model and they were very effectively in the presence prevention of the parasite in the target organs. In addition, the identified lead compounds had a high bioavailability. Because of this results we propose these compounds as a very promising molecules to continue their preclinical development as possible anti- kinetoplastids agentst

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