Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures

We describe the synthesis of 12 new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives on solid supports with room temperature and microwave-assisted solvent-free procedures. Results show that solid supports have good catalytic activity in the formation of quinoxaline 1,4-di-N-oxide derivatives. We found that florisil and montmorillonite KSF and K10 could be used as new, easily available, inexpensive alternatives of catalysts. Additionally, room temperature and microwave-irradiation solvent-free synthesis was more efficient than a conventional procedure (Beirut reaction), reducing reaction time and increasing yield

Esters of quinoxaline-7-carboxylate-1,4-di-N-oxide as Trichomonas vaginalis triosephosphate isomerase inhibitors

Trichomoniasis is a public health problem worldwide. Trichomoniasis treatment consists of the use of nitroimidazole derivatives; however, therapeutic ineffectiveness occurs in 5 to 20 % of the cases. Therefore, it is essential to propose new pharmacological agents against this disease. In this work, esters of quinoxaline-7-carboxylate-1,4-di-N-oxide (EQX-NO) were evaluated in in vitro assays as novel trichomonicidal agents. Additionally, an in vitro enzyme assay and molecular docking analysis against triosephosphate isomerase of Trichomonas vaginalis to confirm their mechanism of action were performed. Ethyl (compound 12) and n-propyl (compound 37) esters of quinoxaline-7-carboxylate-1,4-di-N-oxide derivatives showed trichomonicidal activity comparable to nitazoxanide, whereas five methyl (compounds 5, 15, 19, 20 and 22), four isopropyl (compounds 28, 29, 30 and 34), three ethyl (compound (4, 13 and 23) and one n-propyl (compound 35) ester derivatives displayed activity comparable to albendazole. Compounds 6 and 20 decreased 100 % of the enzyme activity of recombinant protein triosephosphate isomerase

Development of a Novel Ex-vivo 3D Model to Screen Amoebicidal Activity on Infected Tissue

Amoebiasis is a parasitic disease that causes thousands of deaths every year, its adverse effects and resistance to conventional treatments have led to the search of new treatment options, as well as the development of novel screening methods. In this work, we implemented a 3D model of intestine and liver slices from hamsters that were infected ex vivo with virulent E. histolytica trophozoites. Results show preserved histology in both uninfected tissues as well as ulcerations, destruction of the epithelial cells, and inflammatory reaction in intestine slices and formation of micro abscesses, and the presence of amoebae in the sinusoidal spaces and in the interior of central veins in liver slices. The three chemically synthetized compounds T-001, T-011, and T-016, which act as amoebicides in vitro, were active in both infected tissues, as they decreased the number of trophozoites, and provoked death by disintegration of the amoeba, similar to metronidazole. However, compound T-011 induced signs of cytotoxicity to liver slices. Our results suggest that ex vivo cultures of precision-cut intestinal and liver slices represent a reliable 3D approach to evaluate novel amoebicidal compounds, and to simultaneously detect their toxicity, while reducing the number of experimental animals commonly required by other model systems

Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures

We describe the synthesis of 12 new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives on solid supports with room temperature and microwave-assisted solvent-free procedures. Results show that solid supports have good catalytic activity in the formation of quinoxaline 1,4-di-N-oxide derivatives. We found that florisil and montmorillonite KSF and K10 could be used as new, easily available, inexpensive alternatives of catalysts. Additionally, room temperature and microwave-irradiation solvent-free synthesis was more efficient than a conventional procedure (Beirut reaction), reducing reaction time and increasing yield

Injertos óseos - Nueva alternativa. Fase III. Obtención, caracterización y evaluación de Hidroxiapatita Sintética y el compuesto de Hidroxiapatita Sintética porosa � Proteínas Morfogenéticas Óseas en un modelo experimental Lapino

El propósito de esta investigación fue obtener Hidroxiapatita (HA) sintética de porosidad inducida con características osteoconductivas y mezclarlas con Proteínas Morfogenéticas Óseas (PMO) de características osteoinductivas, para que actuaran sinérgicamente y formaran un material de injerto biocompatible capaz de inducir la diferenciación de células locales a células formadoras de hueso y al mismo tiempo proporcionar un andamio osteoconductivo que dirigiera la formación de nuevo hueso, inmovilizara la molécula inductiva en el sitio de implantación por un tiempo suficiente para influenciar las células de respuesta y actuara como una barrera mecánica inicial para el crecimiento de tejido fibroso o la interposición de músculo en el defecto, para lograr finalmente el crecimiento de nuevo hueso en un tiempo considerablemente reducido y el total reemplazo del injerto por hueso enteramente autólogo. Para evaluar las características de este material, se utilizaron un total de 20 conejos machos raza Blanca de Nueva Zelanda, con un peso promedio de 2.2 kg y 75 días de edad, a los cuales se les creó un defecto óseo de forma rectangular de 8 mm de longitud y de profundidad igual a la corteza, en las diáfisis de las tibias, cara medial. En un miembro se implantaron placas de hidroxiapatita de 8mm de longitud y 2 mm de grosor; en el miembro contrario se implantó el compuesto HA-PMO. Se distribuyeron en 4 grupos de evaluación, a las 3, 6, 9 y 12 semanas de evolución, para valorar las características del implante; se realizó inferencia estadística de los datos tomados en el experimento, con un diseño en parcelas divididas siguiendo como estructura básica de aleatorización un DCA (Diseño Completamente al Azar), aplicando el factor t (tiempo) a las parcelas principales (conejos), y el factor i (tipo de implante) a las subparcelas (miembros posteriores)

Essential Oil and Polyphenolic Compounds of Flourensia cernua Leaves: Chemical Profiling and Functional Properties

Flourensia cernua is a bush that grows in the semi-desert regions of Mexico. It has been used in traditional medicine due to its healing properties and currently represents an alternative source of bioactive molecules for different areas of the agri-food and health industries. The objective of this study was to extract and characterize the purified polyphenolic compounds (PPCs) and essential oils (EOs) of F. cernua leaves, determine the total flavonoid content, evaluate the antioxidant activity by three different assays, and determine, for the first time, its inhibitory effect against enzymes involved in the degradation of carbohydrates (α-amylase and α-glucosidase). In addition, the analysis of functional groups (by FTIR-ATR assay) and the identification of the chemical constituents present in both essential oils and phenolic compounds were carried out by GC/MS and UPLC-QToF/MS2, respectively. The results indicate that PPCs and EOs are rich in flavonoid-type compounds. In addition, they showed potential for free-radical scavenging and the inhibition of the lipid oxidation process. The analyzed EOs and PPCs had potential against α-amylase and α-glucosidase enzymes, which are related to high blood sugar levels. FTIR-ATR analysis allowed for the identification of functional groups characteristic of polyphenolic compounds and the chemical constituents of EOs. Finally, compounds such as caryophyllene, caryophyllene oxide, and germacrene-D were identified by GC/MS assay and luteolin 7-O-rutinoside and apigenin-6-C-glucosyl-8-C-arabinoside by UPLC/QToF-MS2. The results indicate that the PPCs and EOs of F. cernua have the potential to be used as antioxidant and enzyme inhibitor agents

Esters of quinoxaline-7-carboxylate-1,4-di-N-oxide as Trichomonas vaginalis triosephosphate isomerase inhibitors

Trichomoniasis is a public health problem worldwide. Trichomoniasis treatment consists of the use of nitroimidazole derivatives; however, therapeutic ineffectiveness occurs in 5 to 20 % of the cases. Therefore, it is essential to propose new pharmacological agents against this disease. In this work, esters of quinoxaline-7-carboxylate-1,4-di-N-oxide (EQX-NO) were evaluated in in vitro assays as novel trichomonicidal agents. Additionally, an in vitro enzyme assay and molecular docking analysis against triosephosphate isomerase of Trichomonas vaginalis to confirm their mechanism of action were performed. Ethyl (compound 12) and n-propyl (compound 37) esters of quinoxaline-7-carboxy-late-1,4-di-N-oxide derivatives showed trichomonicidal activity comparable to nitazoxanide, whereas five methyl (compounds 5, 15, 19, 20 and 22), four isopropyl (compounds 28, 29, 30 and 34), three ethyl (compounds 4, 13 and 23) and one npropyl (compound 35) ester derivatives displayed activity comparable to albendazole. Compounds 6 and 20 decreased 100 % of the enzyme activity of recombinant protein triosephosphate isomerase

Injertos óseos - Nueva alternativa. Fase II. Evaluación de las propiedades osteoinductoras de las proteínas morfogenéticas óseas parcialmente purificadas, implantadas en tejido subcutáneo de un modelo experimental lapino

El propósito de esta investigación fue evaluar las características osteoinductivas de las Proteínas Morfogenéticas Óseas (PMO) parcialmente purificadas de hueso bovino, mediante implantación subcutánea en un modelo experimental lapino, para ser utilizadas posteriormente como material de injerto óseo en combinación con un material osteoconductor. El procedimiento se llevó a cabo mediante la implantación subcutánea de ocho mg de PMO en la región dorsal a nivel de la escápula, en 21 conejos de Raza Blanca de Nueva Zelanda, los cuales se distribuyeron en 6 grupos de evaluación así: tres, seis, nueve, doce, veintiún días y ocho semanas de evolución, transcurridos estos tiempos se retiraron los implantes para ser evaluados histopatológicamente por microscopía óptica convencional y así caracterizar los diferentes elementos tisulares. Los resultados obtenidos se analizaron utilizando el método factorial de correspondencias múltiples con clasificación jerárquica, el cual mostró que las PMO estimulan la inducción de hueso en sitios ectópicos, teniendo actividad osteogénica ya que se observó presencia de trabéculas óseas en todas las muestras tomadas a partir del sexto día postimplante

Anti-mycobacterium tuberculosis activity of esters of quinoxaline 1,4-Di-N-Oxide

Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di-N-oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di-N-oxide derivatives in vitro against Mycobacterium tuberculosis (pansusceptible and monoresistant strains). Additionally, the inhibitory effect of esters of quinoxaline 1,4-di-N-oxide on M. tuberculosis gyrase supercoiling was examined, and a stability analysis by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was also carried out. Results showed that eight compounds (T-007, T-018, T-011, T-069, T-070, T-072, T-085 and T-088) had an activity similar to that of the reference drug isoniazid (minimum inhibitory concentration (MIC) = 0.12 µg/mL) with an effect on nonreplicative cells and drug monoresistant strains. Structural activity relationship analysis showed that the steric effect of an ester group at 7-position is key to enhancing its biological effects. Additionally, T-069 showed a high stability after 24 h in human plasma at 37 ◦C