Naphth[1,2-d]imidazoles Bioactive from ß-Lapachone: Fluorescent Probes and Cytotoxic Agents to Cancer Cells.

Theranostics combines therapeutic and imaging diagnostic techniques that are extremely dependent on the action of imaging agent, transporter of therapeutic molecules, and specific target ligand, in which fluorescent probes can act as diagnostic agents. In particular, naphthoimidazoles are potential bioactive heterocycle compounds to be used in several biomedical applications. With this aim, a group of seven naphth[1,2-d]imidazole compounds were synthesized from ß-lapachone. Their optical properties and their cytotoxic activity against cancer cells and their compounds were evaluated and confirmed promising values for molar absorptivity coefficients (on the order of 103 to 104), intense fluorescence emissions in the blue region, and large Stokes shifts (20-103 nm). Furthermore, the probes were also selective for analyzed cancer cells (leukemic cells (HL-60). The naphth[1,2-d]imidazoles showed IC50 between 8.71 and 29.92 µM against HL-60 cells. For HCT-116 cells, values for IC50 between 21.12 and 62.11 µM were observed. The selective cytotoxicity towards cancer cells and the fluorescence of the synthesized naphth[1,2-d]imidazoles are promising responses that make possible the application of these components in antitumor theranostic systems.

Synthetic hydrazones: In silico studies and in vitro evaluation of the antileishmania potential.

Bioprospecting and synthesis of strategically designed molecules have been used in the search for drugs that can be in leishmaniasis. Hydrazones (HDZ) are promising compounds with extensive biological activities. The objective of this work was to perform in silico studies of hydrazones 1-5 and to evaluate their antileishmanial, cytotoxic and macrophage immunomodulatory potential in vitro. Hydrazones were subjected to prediction and molecular docking studies. Antileishmanial protocols on promastigotes and amastigotes of Leishmania amazonensis, cytotoxicity and macrophage immunomodulatory activity were performed. Hydrazones showed a good pharmacokinetic profile and hydrazone 3 and hydrazone 5 were classified as non-carcinogenic. Hydrazone 5 obtained the best conformation with trypanothione reductase. Hydrazone 1 and hydrazone 3 obtained the best mean inhibitory concentration (IC50) values for promastigotes, 4.4-61.96 µM and 8.0-58.75 µM, respectively. It also showed good activity on intramacrophagic amastigotes, with hydrazone 1 being the most active (IC50 = 6.79 µM) with selectivity index of 56. In cytotoxicity to macrophages hydrazone 3 was the most cytotoxic (CC50 = 256.3 ± 0,04 µM), while hydrazone 4 the least (CC50 = 1055.9 ± 0.03 µM). It can be concluded that the hydrazones revealed important pharmacokinetic and toxicological properties, in addition to antileishmania potential in reducing infection and infectivity in parasitized macrophages.

Antinociceptive and anti-inflammatory effects of hydrazone derivatives and their possible mechanism of action in mice.

Pain and inflammation are unpleasant experiences that usually occur as a result of tissue damage. Despite the number of existing analgesic drugs, side effects limit their use, stimulating the search for new therapeutic agents. In this sense, five hydrazone derivatives (H1, H2, H3, H4, and H5), with general structure R1R2C = NNR3R4, were synthesized with molecular modification strategies. In this paper, we describe the ability of hydrazone derivatives to attenuate nociceptive behavior and the inflammatory response in mice. Antinociceptive activity was evaluated through acetic acid-induced writhing and formalin-induced nociception tests. In both experimental models, the hydrazone with the greatest potency (H5) significantly (p < 0.05) reduced nociceptive behavior. Additionally, methods of acute and chronic inflammation induced by different chemicals (carrageenan and histamine) were performed to evaluate the anti-inflammatory effect of H5. Moreover, molecular docking analysis revealed that H5 can block the COX-2 enzyme, reducing arachidonic acid metabolism and consequently decreasing the production of prostaglandins, which are important inflammatory mediators. H5 also changes locomotor activity. In summary, H5 exhibited relevant antinociceptive and anti-inflammatory potential and acted on several targets, making it a candidate for a new multi-target oral anti-inflammatory drug.

Evaluation of eggshell membrane as an alternative biopolymeric matrix for delivery of nimesulide / Avaliação da membrana da casca do ovo como uma matriz biopolimérica alternativa para entrega de nimesulida / Evaluación de la membrana de la cáscara de huevo como una matriz de biopolímero alternativa para la administración de nimesulida

SUMMARY Introduction: Eggshell membrane (ESM) is a tissue found between the eggshell and the albumen of eggs that has attractive properties for use in drug delivery systems. Aim: To incorporate in ESM and used it as a model drug in release studies. The color change and FTIR analysis of the biopolymer proved the incorporation of nimesulide in ESM. Results: The drug uptake was 176.83 and 122.69 mg g-1 by natural and cross-linked ESM. Release studies were carried out using a spectrophotometric flow system in simulated intestinal fluid pH 7.4. The release profiles showed that after 60 minutes 54.55 and 42.58 % of the drug were released from natural and cross-linked ESM, respectively. Kinetics parameters indicated that drug release was better described by the Higuchi model and through a non-Fickian release. Conclusion: Considering these results is proved that ESM has the potential to become a polymeric matrix for drug release systems.

RESUMO Introdução: a membrana da casca do ovo (MCO) é um tecido encontrado entre a casca e o albúmen de ovos que possui propriedades atrativas para uso em sistemas de liberação de fármacos. Objetivo: incorporar à MCO e utilizá-la como fármaco modelo em estudos de liberação. Mudança de coloração e análises de FTIR do biopolímero comprovaram a incorporação da nimesulida na MCO. A incorporação do fármaco foi de 176,83 e 122,69 mg g-1 na MCO natural e reticulada, respectivamente. Resultados: os estudos de liberação foram realizados usando um sistema de fluxo espectrofotométrico em fluido intestinal simulado pH 7,4. Os perfis de liberação mostraram que após 60 minutos 54,55 e 42,58 % do medicamento foram liberados da MCO natural e reticulada, respectivamente. Os parâmetros cinéticos indicaram que a liberação do fármaco foi mais bem descrita pelo modelo de Higuchi e por meio de uma liberação não Fickiana. Conclusão: considerando estes resultados, fica comprovado que a MCO tem potencial para se tornar uma matriz polimérica para sistemas de liberação de fármacos.

RESUMEN Introducción: La membrana de cáscara de huevo (MCH) es un tejido que se encuentra entre la cáscara de huevo y la albúmina de los huevos que tiene propiedades atractivas para su uso en sistemas de administración de fármacos. Objetivo: Incorporar en MCH y utilizarla como fármaco modelo en estudios de liberación. El cambio de color y el análisis FTIR del biopolímero demostraron la incorporación de nimesulida en MCH. Resultados: La captación del fármaco fue de 176,83 y 122,69 mg g-1 por MCH natural y reticulado. Los estudios de liberación se llevaron a cabo utilizando un sistema de flujo espectrofotométrico en líquido intestinal simulado pH 7,4. Los perfiles de liberación mostraron que después de 60 minutos el 54,55 y el 42,58 % del fármaco se liberó de la MCH natural y reticulada, respectivamente. Los parámetros cinéticos indicaron que la liberación del fármaco se describió mejor mediante el modelo de Higuchi y mediante una liberación no Fickian. Conclusión: De acuerdo con estos resultados, el MCH tiene el potencial de convertirse en una matriz polimérica para sistemas de liberación de fármacos.

Naphthoquinone-based Hydrazone Hybrids: Synthesis and Potent Activity Against Cancer Cell Lines.

BACKGROUND: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, and the modification at their redox center is an interesting strategy to overcome such harmful activity. OBJECTIVE: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and ß- lapachones (α and ß, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. METHODS: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. RESULTS: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, compounds 3 and 4 being the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than ß-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90-12.40 µM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. CONCLUSION: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

Anti-biofilm Effect of ß-Lapachone and Lapachol Oxime Against Isolates of Staphylococcus aureus.

Antimicrobial resistance in bacteria, such as Staphylococcus aureus, has been the subject of many assistance studies of alternatives for the treatment of infections. These studies aim to solve this problem for bacteria, such as biofilm formation. Aiming to control the emergence of the problem or enhance antibiotic activity, the data sources are inserted into new therapeutic alternatives for the treatment of infections. ß-Lapachone and Lapachol Oxime are semi-synthetic derivatives of Lapachol with antimicrobial potential. Clinical isolates from human blood cultures were used in this study. Scanning electron microscopy (SEM) was performed following the glutaraldehyde fixation protocol. The presence of ß-Lapachone and Lapachol Oxima interfered in the biofilm formation state. In the MEV, the effect was observed in the reduction of the population of biofilm-forming cells. Therefore, it was possible to conclude the promising potential of the anti-biofilm of substances, justifying the nature of the natural products as agents of inspiration for the detection of new compounds with the biological function.

[Evaluation of the effect of pesticide use on the health of rural workers in irrigated fruit farming]. / Avaliação do efeito do uso de agrotóxicos sobre a saúde de trabalhadores rurais da fruticultura irrigada.

This study refers to the impact of the use of pesticides on human health in the São Francisco River Valley region, in which, through semi-structured interviews, the objective was to analyze the influence of social, cultural and economic determinants on the health-disease process of workers exposed to agrochemicals. For data collection, 339 rural workers from irrigated perimeters of the cities of Juazeiro, in the State of Bahia, and Petrolina, in the State of Pernambuco, were interviewed. All were male, of which 182 (53,7%) were rural owners and 157 (46,3%) were employees, predominantly between 40 and 59 years of age among owners and under 39 among workers. Over 50% have a low level of schooling and 55.2% of them have monthly incomes less than or equal to 2 minimum wages. Many of them know about the importance of wearing personal protective equipment (PPE) and the mandatory license for the use and purchase of agrochemicals. However, about 40% do not use PPE or use it inadequately and 28.9% do not have a license to purchase. More than 9% of participants reported cases of intoxication, however, less than 7% sought specialized care. Workers are aware of the risks that the use of agrochemicals expose them to risk situations, but this does not encourage them to change their worksite behavior.

O presente estudo refere-se ao impacto do uso de agrotóxicos sobre a saúde humana no Submédio do Vale do São Francisco. Por meio de entrevistas objetivou-se analisar a influência dos condicionantes sociais, culturais e econômicos no processo saúde-doença dos trabalhadores expostos a agrotóxicos. Para a coleta de dados foram entrevistados 339 trabalhadores rurais de perímetros irrigados dos municípios de Juazeiro-BA e Petrolina-PE. Todos do sexo masculino, sendo 182 (53,7%) proprietários rurais e 157 (46,3%) empregados, predominando indivíduos entre 40 e 59 anos entre os proprietários e abaixo de 39 anos entre os trabalhadores. Mais de 50% apresentou baixo nível de escolaridade e 55,2% tinha rendimentos mensais menor ou igual a 2 salários mínimos. Muitos sabem da importância do uso de EPIs e da obrigatoriedade do receituário agronômico para a utilização e a compra de agrotóxicos, entretanto cerca de 40% não usam EPIs ou fazem uso de forma incompleta e 28,9% não apresentam receituário durante a compra. Mais de 9% dos participantes relataram casos de intoxicação, no entanto, menos de 7% procuraram atendimento especializado. Os trabalhadores sabem que o uso de agrotóxicos nas lavouras os expõem a situações de risco, mas essa informação não é suficiente para alterar a conduta no exercício laboral.

Avaliação do efeito do uso de agrotóxicos sobre a saúde de trabalhadores rurais da fruticultura irrigada / Evaluation of the effect of pesticide use on the health of rural workers in irrigated fruit farming

Resumo O presente estudo refere-se ao impacto do uso de agrotóxicos sobre a saúde humana no Submédio do Vale do São Francisco. Por meio de entrevistas objetivou-se analisar a influência dos condicionantes sociais, culturais e econômicos no processo saúde-doença dos trabalhadores expostos a agrotóxicos. Para a coleta de dados foram entrevistados 339 trabalhadores rurais de perímetros irrigados dos municípios de Juazeiro-BA e Petrolina-PE. Todos do sexo masculino, sendo 182 (53,7%) proprietários rurais e 157 (46,3%) empregados, predominando indivíduos entre 40 e 59 anos entre os proprietários e abaixo de 39 anos entre os trabalhadores. Mais de 50% apresentou baixo nível de escolaridade e 55,2% tinha rendimentos mensais menor ou igual a 2 salários mínimos. Muitos sabem da importância do uso de EPIs e da obrigatoriedade do receituário agronômico para a utilização e a compra de agrotóxicos, entretanto cerca de 40% não usam EPIs ou fazem uso de forma incompleta e 28,9% não apresentam receituário durante a compra. Mais de 9% dos participantes relataram casos de intoxicação, no entanto, menos de 7% procuraram atendimento especializado. Os trabalhadores sabem que o uso de agrotóxicos nas lavouras os expõem a situações de risco, mas essa informação não é suficiente para alterar a conduta no exercício laboral.

Abstract This study refers to the impact of the use of pesticides on human health in the São Francisco River Valley region, in which, through semi-structured interviews, the objective was to analyze the influence of social, cultural and economic determinants on the health-disease process of workers exposed to agrochemicals. For data collection, 339 rural workers from irrigated perimeters of the cities of Juazeiro, in the State of Bahia, and Petrolina, in the State of Pernambuco, were interviewed. All were male, of which 182 (53,7%) were rural owners and 157 (46,3%) were employees, predominantly between 40 and 59 years of age among owners and under 39 among workers. Over 50% have a low level of schooling and 55.2% of them have monthly incomes less than or equal to 2 minimum wages. Many of them know about the importance of wearing personal protective equipment (PPE) and the mandatory license for the use and purchase of agrochemicals. However, about 40% do not use PPE or use it inadequately and 28.9% do not have a license to purchase. More than 9% of participants reported cases of intoxication, however, less than 7% sought specialized care. Workers are aware of the risks that the use of agrochemicals expose them to risk situations, but this does not encourage them to change their worksite behavior.