Larvicidal activity of coumarin derivatives on Toxocara canis larvae, cytotoxicity analysis, and in silico bioavailability studies.

Human toxocariasis is a neglected anthropozoonosis with global distribution. Treatment is based on the administration of anthelmintics; however, their effectiveness at the tissue level is low to moderate, necessitating the discovery of new drug candidates. Several groups of synthetic compounds, including coumarin derivatives, have demonstrated bioactivity against fungi, bacteria, and even parasites, such as Dactylogyrus intermedius, Leishmania major, and Plasmodium falciparum. The aim of this study was to evaluate the effect of ten coumarin-derived compounds against Toxocara canis larvae using in vitro, cytotoxicity, and in silico tests for selecting new drug candidates for preclinical tests aimed at evaluating the treatment of visceral toxocariasis. The compounds were tested in vitro in duplicate at a concentration of 1 mg/mL, and compounds with larvicidal activity were serially diluted to obtain concentrations of 0.5 mg/mL; 0.25 mg/mL; 0.125 mg/mL; and 0.05 mg/mL. The tests were performed in a microculture plate containing 100 T. canis larvae in RPMI-1640 medium. One compound (COU 9) was selected for cytotoxicity analysis using J774.A1 murine macrophages and it was found to be non-cytotoxic at any concentration tested. The in silico analysis was performed using computational models; the compound presented adequate results of oral bioavailability. To confirm the non-viability of the larvae, the contents of the microplate wells of COU 9 were inoculated intraperitoneally (IP) into female Swiss mice at 7-8 weeks of age. This confirmed the larvicidal activity of this compound. These results show that COU 9 exhibited larvicidal activity against T. canis larvae, which, after exposure to the compound, were non-viable, and that COU 9 inhibited infection in a murine model. In addition, COU 9 did not exhibit cytotoxicity and presented adequate bioavailability in silico, similar to albendazole, an anthelmintic, which is the first choice for treatment of human toxocariasis, supporting the potential for future investigations and preclinical tests on COU 9.

4-Quinolinylhydrazone analogues kill Leishmania (Leishmania) amazonensis by inducing apoptosis and mitochondria-dependent pathway cell death.

Despite efforts, available alternatives for the treatment of leishmaniasis are still scarce. In this work we tested a class of 15 quinolinylhydrazone analogues and presented data that support the use of the most active compound in cutaneous leishmaniasis caused by Leishmania amazonensis. In general, the compounds showed activity at low concentrations for both parasitic forms (5.33-37.04 µM to promastigotes, and 14.31-61.98 µM to amastigotes). In addition, the best compound (MHZ15) is highly selective for the parasite. Biochemical studies indicate that the treatment of promastigotes with MHZ15 leads the loss of mitochondrial potential and increase in ROS levels as the primary effects, which triggers accumulation of lipid droplets, loss of plasma membrane integrity and apoptosis hallmarks, including DNA fragmentation and phosphatidylserine exposure. These effects were similar in the intracellular form of the parasite. However, in this parasitic form there is no change in plasma membrane integrity in the observed treatment time, which can be attributed to metabolic differences and the resilience of the amastigote. Also, ultrastructural changes such as vacuolization suggesting autophagy were observed. The in vivo effectiveness of MHZ15 in the experimental model of cutaneous leishmaniasis was carried out in mice of the BALB/c strain infected with L. amazonensis. The treatment by intralesional route showed that MHZ15 acted with great efficiency with significantly reduction in the parasite load in the injured paws and draining lymph nodes, without clinical signs of distress or compromise of animal welfare. In vivo toxicity was also evaluated and null alterations in the levels of hepatic enzymes aspartate aminotransferase, and alanine aminotransferase was observed. The data presented herein demonstrates that MHZ15 exhibits a range of favorable characteristics conducive to the development of an antileishmanial agent.

Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis.

Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed. Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against E. multilocularis in vitro and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against E. multilocularis metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1'681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against E. multilocularis. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.

Current leishmaniasis drug discovery.

Leishmaniasis is a complex protozoan infectious disease and, associated with malnutrition, poor health services and unavailability of prophylactic control measures, neglected populations are particularly affected. Current drug regimens are outdated and associated with some drawbacks, such as cytotoxicity and resistance, and the development of novel, efficacious and less toxic drug regimens is urgently required. In addition, leishmanial pathogenesis is not well established or understood, and a prophylactic vaccine is an unfulfilled goal. Human kinetoplastid protozoan infections, including leishmaniasis, have been neglected for many years, and in an attempt to overcome this situation, some new drug targets were recently identified, enabling the development of new drugs and vaccines. Compounds from new drug classes have also shown excellent antileishmanial activities, some of the most promising ones included in clinical trials, and could be a hope to control the disease burden of this endemic disease in the near future. In this review, we discuss the limitations of current control methods, explore the wide range of compounds that are being screened and identified as antileishmanial drug prototypes, summarize the advances in identifying new drug targets aiming at innovative treatments and explore the state-of-art vaccine development field, including immunomodulation strategies.

Selênio, um elemento essencial à vida humana

Introdução: O Selênio ao mesmo tempo em que é tóxico se ingerido em grandes quantidades, é, também, micronutriente essencial em diversos processos metabólicos de animais e humanos. A deficiência de selênio vem sendo relacionada à predisposição em desenvolver doenças como o câncer, a diabetes, doenças cardiovasculares, entre outras. Na química medicinal, o selênio vem ganhando importância a partir da descoberta do ebselen, do ethaselen e do disseleneto de difenila. Objetivo: Essa revisão tem como objetivo compilar as principais informações disponíveis na literatura sobre a importância do selênio para a vida humana, proporcionando ao leitor uma visão geral do papel biológico desse elemento, das principais doenças relacionadas à deficiência de selênio, e da química medicinal dos três principais compostos de organoselênio. Metodologia: Foram recuperados artigos e teses acadêmicas que contemplassem o papel do selênio na bioquímica e na química medicinal, publicados em português e inglês, utilizando-se as bases de dados SciFinder, PubMed e Google Acadêmico. Resultados: Até o momento, foram identificadas 25 selenoproteínas que desempenham funções biológicas essenciais em animais e humanos. Sabe-se que a deficiência de selênio está diretamente relacionada à predisposição no desenvolvimento de diversas doenças. No campo da química medicinal, foi provado que é possível desenvolver moléculas bioativas, com baixa toxidez, contendo átomos de selênio em sua estrutura. Conclusão: O selênio é um elemento essencial à vida, sendo o componente-chave das selenoproteínas. O entendimento dos processos bioquímicos modulados por elas é imperativo para que os químicos medicinais possam desenvolver fármacos potentes contendo átomos de selênio em sua estrutura.

SUMMARY Introduction: Selenium is, at the same time, toxic if ingested in great amounts and an essential micronutrient to several metabolic processes in both animals and humans. Selenium deficiency is being related to an increased chance to develop diseases such as cancer, diabetes, cardiovascular diseases, among others. In medicinal chemistry, selenium has gained in importance since the discovery of ebselen, ethaselen, and diphenyl disselenide. Objectives: This review aims to compile the main data avail-able on the literature on the importance of selenium to human life, providing an overview of its biological role, the main diseases related to its deficiency, as well as the medicinal chemistry of the three most prominent organoselenium compounds. Methodology: Articles and academic thesis, published in English and Portuguese, showing the role of selenium in biochemistry and medicinal chemistry were recov-ered from SciFinder, PubMed, and Google Scholar. Results: So far, 25 selenopro-teins that play a biological role in humans and animals were identified. It is known that selenium deficiency is directly related not only to a predisposition to developing some diseases but is also the main cause of illnesses such as Keshan and Kashin-Beck. In the medicinal chemistry field, the development of selenium-containing bioactive compounds with low toxicity was proved possible. Conclusion: Selenium is an essential element to life, being the core component of selenoproteins. The under-standing of the biochemical processes modulated by those proteins is mandatory to medicinal chemists willing to develop potent organoselenium drugs.

Introducción: El selenioa la par que tóxico si se ingiere en grandes cantidades, es también un micronutriente esencial en varios procesos metabólicos en animales y humanos. La deficiencia de selenio se ha relacionado con una predisposición a desarrollar enfermedades como cáncer, diabetes, enfermedades cardiovasculares, entre otras. Em química médica, el selenio ha ganado importancia desde el descubrimiento del ebselen, etaselen y difenil diselenide. Objetivo: Esta revisión tiene como objetivo recopilar los principales datos disponibles en la literatura sobre la importancia del selenio para la vida humana, y proporcionar al lector una descripción general del papel biológico de este elemento, las principales enfermedades relacionadas con la deficiencia de este elemento, así como los compuestos de organoselenio más destacados. Metodología: Se recuperaron artículos y tesis académicas que contemplaban el papel del selenio en la bioquímica y la química médica, publicados en portugués e inglés, utilizando las bases de datos SciFinder, PubMed y Google Scholar. Resultados: Hasta el momento, se han identificado 25 selenoproteínas que realizan funciones biológicas esenciales en animales y humanos. Se sabe que la deficiencia de selenio está directamente relacionada con la predisposición en el desarrollo de varias dolencias, y también es la principal causa de enfermedades como las de Keshan y Kashin-Beck. En el campo de la química médica se ha comprobado que es posible desarrollar moléculas bioactivas, de baja toxicidad, que contengan átomos de selenio en su estructura. Conclusión: El selenio es un elemento esencial en la vida, siendo un componente central de las selenoproteínas. Comprender los procesos bioquímicos modulados por ellos es imperativo para que los químicos médicos puedan desarrollar fármacos potentes que contengan átomos de selenio en su estructura.

In vitro and in silico trichomonacidal activity of 2,8-bis(trifluoromethyl) quinoline analogs against Trichomonas vaginalis.

Trichomoniasis is a great public health burden worldwide and the increase in treatment failures has led to a need for finding alternative molecules to treat this disease. In this study, we present in vitro and in silico analyses of two 2,8-bis(trifluoromethyl) quinolines (QDA-1 and QDA-2) against Trichomonas vaginalis. For in vitro trichomonacidal activity, up to seven different concentrations of these drugs were tested. Molecular docking, biochemical, and cytotoxicity analyses were performed to evaluate the selectivity profile. QDA-1 displayed a significant effect, completely reducing trophozoites viability at 160 µM, with an IC50 of 113.8 µM, while QDA-2 at the highest concentration reduced viability by 76.9%. QDA-1 completely inhibited T. vaginalis growth and increased reactive oxygen species production and lipid peroxidation after 24 h of treatment, but nitric oxide accumulation was not observed. In addition, molecular docking studies showed that QDA-1 has a favorable binding mode in the active site of the T. vaginalis enzymes purine nucleoside phosphorylase, lactate dehydrogenase, triosephosphate isomerase, and thioredoxin reductase. Moreover, QDA-1 presented a level of cytotoxicity by reducing 36.7% of Vero cells' viability at 200 µM with a CC50 of 247.4 µM and a modest selectivity index. In summary, the results revealed that QDA-1 had a significant anti-T. vaginalis activity. Although QDA-1 had detectable cytotoxicity, the concentration needed to eliminate T. vaginalis trophozoites is lower than the CC50 encouraging further studies of this compound as a trichomonacidal agent.

Camphor nitroimine: a key building block in unusual transformations and its applications in the synthesis of bioactive compounds.

The development of new drugs requires a lot of time and high financial investments. It involves a research network in which there is the participation of several researchers from different areas. For a new drug to reach the market, thousands of substances must be evaluated. There are several tools for this and the use of suitable building blocks can facilitate the process by allowing a lead compound to have suitable parameters. These compounds are key structures containing special functional groups that also permit adequate synthetic transformations, leading to several structures of interest in a short period of time. In this review, the use of camphor nitroimine as a potential key building block is explored. Derived from camphor, an abundant natural product present in various plant species, this nitroimine has proved to be quite versatile, allowing the access to substances with miscellaneous biological activities, ligands to asymmetric catalysis, asymmetric oxidants, O-N transfer agents and other applications. Its easy conversion to camphecene and other derivatives is described, as well as their applications in medicinal chemistry. Druglikeness analyses were performed on these studied agents as well as on their bioactive derivatives in order to assess their use in the development of potential drugs.

Moda e trabalho como prática de exclusão social: uma revisão das produções acadêmicas brasileiras / Fashion and Work as a practice of social exclusion: a review of brazilian academic literature / Moda y trabajo como práctica de exclusión social: una revisión de la literatura académica brasileña

A moda é uma construção social polissêmica que pode implicar exclusão social a diferentes atores sociais. Dessa forma, objetivou-se identificar os impactos da indústria da moda nas construções identitárias, contextos de trabalho e organização social, com o intuito de fomentar práticas psicossociais capazes de enfrentar a ocorrência de exclusão social nesses espaços. Foram identificados nove trabalhos sobre o tema por meio de busca na base de dados SciELO (Scientific Eletronic Library Online). Os resultados demonstraram que os estudos foram produzidos predominantemente por meio de método qualitativo com colaborações interdisciplinares entre ciências humanas e sociais aplicadas. De maneira geral, também evidenciaram a moda associada aos contextos laborais precarizados, permeados por anulação identitária de minorias como mulheres, indígenas e imigrantes, os quais tendem a ser submetidos às práticas psicossociais insatisfatórias que devem ser aprimoradas por meio da promoção de ideário equitativo e práticas inclusivas em múltiplos contextos.

Fashion is a polysemic social construction and may imply social exclusion to different social actors. For this reason, we aimed to identify the impacts of the fashion industry on personnel identity, work contexts and social organization, with the intention of fostering psychosocial practices capable of lowering the occurrence of social exclusion. We retrieved nine papers by the Scientific Electronic Library Online (SciELO) database. We found that the studies were produced predominantly through the qualitative method with interdisciplinary collaborations between the humanities and social sciences. In general, we also realized the fashion industry associated with precarious work contexts, permeated by the identity annihilation of minorities such as women, indigenous and immigrants, who tend to be subjected to unsatisfactory psychosocial practices that must be improved through the promotion of equitable ideas and inclusive practices in multiple contexts.

La moda es una construcción social polisémica que puede implicar exclusión social a diferentes actores sociales. De esta forma, se objetivó identificar los impactos de la industria de la moda en las construcciones identitarias, contextos de trabajo y organización social, con el propósito de fomentar prácticas psicosociales capaces de enfrentar la ocurrencia de exclusión social. Se identificaron nueve trabajos sobre el tema por medio de búsqueda en la base de datos SciELO (Scientific Eletronic Library Online). Los resultados demostraron que los estudios fueron producidos predominantemente por medio del método cualitativo con colaboraciones interdisciplinarias entre ciencias humanas y sociales aplicadas. De manera general, también evidenciaron la moda asociada a los contextos laborales precarizados, impregnados por anulación identitaria de minorías como mujeres, indígenas e inmigrantes, los cuales tienden a someterse a las prácticas psicosociales insatisfactorias que deben ser mejoradas por medio de la promoción de ideario equitativo y prácticas inclusivas en múltiples contextos.

Agreement Analysis between Sonographic Estimates and Birth Weight, by the WHO and Intergrowth-21st Tables, in Newborns of Diabetic Mothers.

OBJECTIVE: To analyze the agreement, in relation to the 90th percentile, of ultrasound measurements of abdominal circumference (AC) and estimated fetal weight (EFW), between the World Health Organization (WHO) and the International Fetal and Newborn Growth Consortium for the 21st Century (intergrowth-21st) tables, as well as regarding birth weight in fetuses/newborns of diabetic mothers. METHODS: Retrospective study with data from medical records of 171 diabetic pregnant women, single pregnancies, followed between January 2017 and June 2018. Abdominal circumference and EFW data at admission (from 22 weeks) and predelivery (up to 3 weeks) were analyzed. These measures were classified in relation to the 90th percentile. The Kappa coefficient was used to analyze the agreement of these ultrasound variables between the WHO and intergrowth-21st tables, as well as, by reference table, these measurements and birth weight. RESULTS: The WHO study reported 21.6% large-for-gestational-age (LGA) newborns while the intergrowth-21st reported 32.2%. Both tables had strong concordances in the assessment of initial AC, final AC, and initial EFW (Kappa = 0.66, 0.72 and 0.63, respectively) and almost perfect concordance in relation to final EFW (Kappa = 0.91). Regarding birth weight, the best concordances were found for initial AC (WHO: Kappa = 0.35; intergrowth-21st: Kappa = 0.42) and with the final EFW (WHO: Kappa = 0.33; intergrowth- 21st: Kappa = 0.35). CONCLUSION: The initial AC and final EFW were the parameters of best agreement regarding birth weight classification. The WHO and intergrowth-21st tables showed high agreement in the classification of ultrasound measurements in relation to the 90th percentile. Studies are needed to confirm whether any of these tables are superior in predicting short- and long-term negative outcomes in the LGA group.

OBJETIVO: Analisar a concordância, em relação ao percentil 90, das medidas ultrassonográficas da circunferência abdominal (CA) e peso fetal estimado (PFE), entre as tabelas da Organização Mundial de Saúde (OMS) e do International Fetal and Newborn Growth Consortium for the 21st Century integrowth-21st, bem como em relação ao peso ao nascer em fetos/recém-nascidos de mães diabéticas. MéTODOS: Estudo retrospectivo com dados de prontuários de 171 gestantes diabéticas, com gestações únicas, seguidas entre Janeiro de 2017 e Junho de 2018. Foram analisados dados da CA e do PFE na admissão (a partir de 22 semanas) e no pré-parto (até 3 semanas). Essas medidas foram classificadas em relação ao percentil 90. O coeficiente Kappa foi utilizado para analisar a concordância entre as tabelas da OMS e Intergrowth-21st, assim como, por tabela de referência, entre as medidas e o peso ao nascer. RESULTADOS: O estudo da OMS relatou 21,6% dos recém nascidos grandes para a idade gestacional (GIG) enquanto que o estudo do intergrowth-21st relatou 32,2%. Ambas as tabelas tiveram fortes concordâncias na avaliação da CA inicial e final e PFE inicial (Kappa = 0,66, 0,72 e 0,63, respectivamente) e concordância quase perfeita em relação ao PFE final (Kappa = 0,91). Em relação ao peso ao nascer, as melhores concordâncias foram encontradas para a CA inicial (OMS: Kappa = 0,35; intergrowth-21st: Kappa = 0,42) e com o PFE final (OMS: Kappa = 0,33; intergrowth-21st: Kappa = 0,35). CONCLUSãO: A CA inicial e o PFE final foram os parâmetros de melhor concordância em relação à classificação do peso ao nascer. As tabelas da OMS e intergrowth-21st mostraram alta concordância na classificação das medidas ultrassonográficas em relação ao percentil 90. Estudos são necessários para confirmar se alguma dessas tabelas é superior na previsão de resultados negativos a curto e longo prazo no grupo GIG.

Agreement analysis between sonographic estimates and birth weight, by the WHO and intergrowth-21st tables, in newborns of diabetic mothers / Análise de concordância entre estimativas ultrassonográficas e peso ao nascer, pelas tabelas da OMS e Intergrowth-21st, em recém-nascidos de mães diabéticas

Abstract Objective To analyze the agreement, in relation to the 90th percentile, of ultrasound measurements of abdominal circumference (AC) and estimated fetal weight (EFW), between the World Health Organization (WHO) and the International Fetal and Newborn Growth Consortium for the 21st Century (intergrowth-21st) tables, as well as regarding birth weight in fetuses/newborns of diabetic mothers. Methods Retrospective study with data from medical records of 171 diabetic pregnant women, single pregnancies, followed between January 2017 and June 2018. Abdominal circumference and EFW data at admission (from 22 weeks) and predelivery (up to 3 weeks) were analyzed. These measures were classified in relation to the 90th percentile. The Kappa coefficient was used to analyze the agreement of these ultrasound variables between the WHO and intergrowth-21st tables, as well as, by reference table, these measurements and birth weight. Results The WHO study reported 21.6% large-for-gestational-age (LGA) newborns while the intergrowth-21st reported 32.2%. Both tables had strong concordances in the assessment of initial AC, final AC, and initial EFW (Kappa = 0.66, 0.72 and 0.63, respectively) and almost perfect concordance in relation to final EFW (Kappa = 0.91). Regarding birth weight, the best concordances were found for initial AC (WHO: Kappa = 0.35; intergrowth-21st: Kappa= 0.42) and with the final EFW (WHO: Kappa = 0.33; intergrowth- 21st: Kappa = 0.35). Conclusion The initial AC and final EFW were the parameters of best agreement regarding birth weight classification. The WHO and intergrowth-21st tables showed high agreement in the classification of ultrasound measurements in relation to the 90th

Resumo Objetivo Analisar a concordância, em relação ao percentil 90, das medidas ultrassonográficas da circunferência abdominal (CA) e peso fetal estimado (PFE), entre as tabelas da Organização Mundial de Saúde (OMS) e do International Fetal and Newborn Growth Consortium for the 21st Century integrowth-21st, bem como em relação ao peso ao nascer em fetos/recém-nascidos de mães diabéticas. Métodos Estudo retrospectivo com dados de prontuários de 171 gestantes diabéticas, com gestações únicas, seguidas entre Janeiro de 2017 e Junho de 2018. Foram analisados dados da CA e do PFE na admissão (a partir de 22 semanas) e no pré-parto (até 3 semanas). Essas medidas foram classificadas em relação ao percentil 90. O coeficiente Kappa foi utilizado para analisar a concordância entre as tabelas da OMS e Intergrowth-21st, assim como, por tabela de referência, entre as medidas e o peso ao nascer. Resultados O estudo da OMS relatou 21,6% dos recém nascidos grandes para a idade gestacional (GIG) enquanto que o estudo do intergrowth-21st relatou 32,2%. Ambas as tabelas tiveram fortes concordâncias na avaliação da CA inicial e final e PFE inicial (Kappa= 0,66, 0,72 e 0,63, respectivamente) e concordância quase perfeita em relação ao PFE final (Kappa= 0,91).Emrelação ao peso ao nascer, asmelhores concordâncias foram encontradas para aCAinicial (OMS: Kappa= 0,35; intergrowth-21st: Kappa= 0,42) e como PFE final (OMS: Kappa = 0,33; intergrowth-21st: Kappa= 0,35). Conclusão A CA inicial e o PFE final foram os parâmetros de melhor concordância em relação à classificação do peso ao nascer. As tabelas da OMS e intergrowth-21st mostraram alta concordância na classificação das medidas ultrassonográficas em relação ao percentil 90. Estudos são necessários para confirmar se alguma dessas tabelas é superior na previsão de resultados negativos a curto e longo prazo no grupo GIG.

Antibacterial activity of new substituted 4-N-alkylated-2-trifluoromethyl-quinoline analogues against sensitive and resistant Mycobacterium tuberculosis strains.

OBJECTIVES: The emergence of resistant strain has aggravated the tuberculosis situation in the world, running out of control and hard to fight. We evaluate forty new quinoline analogues against sensitive and resistant Mycobacterium tuberculosis (Mtb). METHODS: The compounds were obtained via synthesis and evaluated against sensitive strain ATCC 27294. Selected compounds were evaluated against resistant strains SR 2571/0215 and T113/09, using the MABA method. The more active compounds were selected for their potential cytotoxic activity against human macrophage cells. RESULTS: Twenty-nine compounds displayed activity against sensitive strain, and thirteen were active against resistant strains. Against sensitive strain, the most promising compounds were 4c and 4d (MIC = 9 and 12 µM, respectively). Against resistant strains, the compounds 4a, 4d displayed the best results (MIC = 4 and 5 µM, respectively). The active compounds 4a, 4d, 6d, 7c, 8d, and 10d were non-cytotoxic to the host cells at concentrations near to the MIC. The non-cytotoxic compound 4d was the most potent against resistant and sensitive Mtb. CONCLUSION: These findings contribute to relevant information and perspectives in search of new bioactive compounds against sensitive and resistant TB. Resistant strains have turned tuberculosis a severe disease in the world.

Simultaneous separation of artesunate and mefloquine in fixed-dose combination tablets by CZE-UV.

A novel method was proposed for simultaneous determination of artesunate (ATS) and mefloquine (MFQ) in fixed-dose combination tablets by capillary zone electrophoresis with simultaneous direct and indirect detection by ultraviolet (CZE-UV). The background electrolyte, consisting of 30/15 mmol L-1 TRIS/3,5-dinitrobenzoic acid buffer at pH 8.2, a chromophore buffer, was selected taking into account a detailed study involving the effective mobility vs. pH curves of the analytes and electrolyte compounds in association with the very low molar absorptivity of ATS. Suitable separation conditions, considering voltage, temperature and buffer concentration as factors, were achieved through the 33 Box-Behnken design investigation. The optimum baseline separation conditions were: injection pressure of 30 mbar for 10 s, cartridge temperature of 22.5 °C and positive voltage of +30 kV. The method proved to be rapid (5 minutes), simple, selective, linear (r2 > 0.98), precise (relative standard deviation (RSD): ATS < 2.9% and MFQ < 2.2%) and accurate (recoveries: ATS 98.13-102.96% and MFQ 98.75-106.77%), proving to be suitable for routine quality control analysis.

Anti-Bronchospasmodic Effect of JME-173, a Novel Mexiletine Analog Endowed With Highly Attenuated Anesthetic Activity.

Local anesthetics (LAs), such as lidocaine and mexiletine, inhibit bronchoconstriction in asthmatics, but adverse effects limit their use for this specific clinical application. In this study, we describe the anti-spasmodic properties of the mexiletine analog 2-(2-aminopropoxy)-3,5-dimethyl, 4-Br-benzene (JME-173), which was synthesized and screened for inducing reduced activity on Na+ channels. The effectiveness of JME-173 was assessed using rat tracheal rings, a GH3 cell line and mouse cardiomyocytes to access changes in smooth muscle contraction, and Na+, and Ca++ionic currents, respectively. Bronchospasm and airway hyper-reactivity (AHR) were studied using whole-body barometric plethysmography in A/J mice. We observed that the potency of JME-173 was 653-fold lower than mexiletine in inhibiting Na+ currents, but 12-fold higher in inhibiting L-type Ca++ currents. JME-173 was also more potent than mexiletine in inhibiting tracheal contraction by carbachol, allergen, extracellular Ca++, or sodium orthovanadate provocations. The effect of JME-173 on carbachol-induced tracheal contraction remained unaltered under conditions of de-epithelized rings, ß2-receptor blockade or adenylate cyclase inhibition. When orally administered, JME-173 and theophylline inhibited methacholine-induced bronchospasm at time points of 1 and 3 h post-treatment, while only JME-173 remained active for at least 6 h. In addition, JME-173 also inhibited AHR in a mouse model of lipopolysaccharide (LPS)-induced lung inflammation. Thus, the mexiletine analog JME-173 shows highly attenuated activity on Na+ channels and optimized anti-spasmodic properties, in a mechanism that is at least in part mediated by regulation of Ca++ inflow toward the cytosol. Thus, JME-173 is a promising alternative for the treatment of clinical conditions marked by life-threatening bronchoconstriction.

The terpenic diamine GIB24 inhibits the growth of Trypanosoma cruzi epimastigotes and intracellular amastigotes, with proteomic analysis of drug-resistant epimastigotes.

The effect of N-geranyl-ethane-1,2-diamine dihydochloride (GIB24), a synthetic diamine, was assayed against different developmental forms of the parasitic protozoan Trypanosoma cruzi (strain Dm28c). The compound was effective against culture epimastigote forms (IC50/24h = 5.64 µM; SI = 16.4) and intracellular amastigotes (IC50/24h = 12.89 µM; SI = 7.18), as detected by the MTT methodology and by cell counting, respectively. Incubation of epimastigotes for 6h with 6 µM GIB24 (IC50/24h value) resulted in significant dissipation of the mitochondrial membrane potential, prior to permeabilization of the plasma membrane. Rounded epimastigotes with cell size reduction were observed by scanning electron microscopy. These morpho-physiological changes induced by GIB24 suggest an incidental death process. Treatment of infected Vero cells did not prevent the intracellular amastigotes from completing the intracellular cycle. However, there was a decrease in the number of released parasites, increasing the ratio amastigotes/trypomastigotes. Proteomic analysis of 15 µM GIB24 resistant epimastigotes indicated that the compound acts mainly on mitochondrial components involved in the Krebs cycle and in maintaining the oxidative homeostasis of the parasites. Our data suggest that GIB24 is active against the main morphological forms of T. cruzi.

Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels.

Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (Cmax), maximum time (Tmax), area under the blood concentration-time curve (AUC0-t) and area under the blood concentration-time curve from 0-Inf (AUC0-inf) of 163.3 ± 38.3 ng/mL, 1.2 ± 0.3 h, 729.4 ± 118.3 ng*h/ml and 868.9 ± 117.1 ng*h/ml (means ± S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.

Monocyclic ß-Lactam: A Review on Synthesis and Potential Biological Activities of a Multitarget Core.

A monocyclic ring in their structure characterizes monobactams, a subclass of ß-lactam antibiotics. Many of these compounds have a bactericidal mechanism of action and acts as penicillin and cephalosporins, interfering with bacterial cell wall biosynthesis. The synthesis of novel ß-lactams is an emerging area of organic synthesis research due to the problem of increasing bacterial resistance to existing ß -lactam antibiotics, and, in this way, new compounds have been presented with several structural modifications, aiming to improve biological activities. Among the biological activities studied, the most outstanding are antibacterial, antitubercular, anticholesterolemic, anticancer, antiinflammatory, antiviral, and anti-enzymatic, among others. This review explores the vast number of works related to monocyclic ß-lactams, compounds of great importance in scientific research.

Efficacy of the 7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline derivative against infection caused by Leishmania amazonensis.

INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.

Antiparasitic activity of furanyl N-acylhydrazone derivatives against Trichomonas vaginalis: in vitro and in silico analyses.

BACKGROUND: Trichomonas vaginalis is the causative agent of trichomoniasis, which is one of the most common sexually transmitted diseases worldwide. Trichomoniasis has a high incidence and prevalence and is associated with serious complications such as HIV transmission and acquisition, pelvic inflammatory disease and preterm birth. Although trichomoniasis is treated with oral metronidazole (MTZ), the number of strains resistant to this drug is increasing (2.5-9.6%), leading to treatment failure. Therefore, there is an urgent need to find alternative drugs to combat this disease. METHODS: Herein, we report the in vitro and in silico analysis of 12 furanyl N-acylhydrazone derivatives (PFUR 4, a-k) against Trichomonas vaginalis. Trichomonas vaginalis ATCC 30236 isolate was treated with seven concentrations of these compounds to determine the minimum inhibitory concentration (MIC) and 50% inhibitory concentration (IC50). In addition, compounds that displayed anti-T. vaginalis activity were analyzed using thiobarbituric acid reactive substances (TBARS) assay and molecular docking. Cytotoxicity analysis was also performed in CHO-K1 cells. RESULTS: The compounds PFUR 4a and 4b, at 6.25 µM, induced complete parasite death after 24 h of exposure with IC50 of 1.69 µM and 1.98 µM, respectively. The results showed that lipid peroxidation is not involved in parasite death. Molecular docking studies predicted strong interactions of PFUR 4a and 4b with T. vaginalis enzymes, purine nucleoside phosphorylase, and lactate dehydrogenase, while only PFUR 4b interacted in silico with thioredoxin reductase and methionine gamma-lyase. PFUR 4a and 4b led to a growth inhibition (< 20%) in CHO-K1 cells that was comparable to the drug of choice, with a promising selectivity index (> 7.4). CONCLUSIONS: Our results showed that PFUR 4a and 4b are promising molecules that can be used for the development of new trichomonacidal agents for T. vaginalis.

In vitro Assessment of Camphor Hydrazone Derivatives as an Agent Against Leishmania amazonensis.

PURPOSE: Due to serious problems with the treatment of leishmaniasis all around the world, here is an urgent need in the search for new drugs that are more effective and safer for the treatment of the various forms of leishmaniasis. Actual therapy is limited and lacks sufficient efficacy due to incomplete elimination of the parasites form of patients. In this sense, we decided to evaluate, by first-time, a series of seventeen camphor hydrazone derivatives (2a-2p) against Leishmania amazonensis. METHODS: The compounds previously synthesized from camphor, an abundant natural compound, were evaluated in vitro against the extra and intracellular forms of Leishmania amazonensis, and murine macrophages. RESULTS: The majority of compounds, fourteen, displayed activity against the intracellular form of the parasite (amastigote) with IC50 values ranging from 21.78 to 58.23 µM, being six compounds active for both forms of the parasite. The compound 2i exhibited higher activity against the amastigote form with the value of IC50 (21.78 µM) close to standard utilized miltefosine (12.74 µM) and selectivity index of at least 6.9. Six compounds displayed activity against promastigote form of Leishmania amazonensis 2g, 2j-2n (41.17-69.59 µM), with the compound 2m being the more active with IC50 = 41.17 µM, 1.9 times less active than the reference drug (IC50 = 21.39 µM). The compound 2m was the more selective to this form, with a selectivity index of at least 3.6. All the compounds were non-cytotoxic to macrophages. CONCLUSIONS: Most compounds showed activity against amastigote form of Leishmania amazonensis, being that they were not cytotoxic to macrophage at the maximum tested concentration, showing the selective property of these compounds. Since amastigotes are the parasite stages that cause the disease in humans, these results highlight the antileishmanial effect of the compounds. This study indicates the possible development of candidates to leishmanicidal drugs from an abundant natural compound of easy access.

Synthesis of PJOV56, a new quinoxalinyl-hydrazone derivative able to induce autophagy and apoptosis in colorectal cancer cells, and related compounds.

Quinoxaline derivatives are reported as antineoplastic agents against a variety of human cancer cell lines, with some compounds being submitted to clinical trials. In this work, we report the synthesis, characterization and cytotoxicity potential of a new series of quinoxalinyl-hydrazones. The most cytotoxic compound was (E)-2-[2-(2-pyridin-2-ylmethylene)hydrazinyl]quinoxaline (PJOV56) that presented a time-dependent effect against HCT-116 cells. After 48 h of incubation, PJOV56 was able to induce autophagy and apoptosis of HCT-116 cells, mediated by upregulation of Beclin 1, upregulation of LC3A/B II and activation of caspase 7. Apoptosis was induced along with G0/G1 cell cycle arrest at the highest concentration of PJOV56 (6.0 µM). Thus, PJOV56 showed a dose-dependent mode of action related to induction of autophagy and apoptosis in HCT-116 cells.