RESUMO
The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.
Assuntos
Antineoplásicos , Neoplasias da Mama , Naftoquinonas , Humanos , Feminino , Células MCF-7 , Espécies Reativas de Oxigênio/metabolismo , Triazóis/farmacologia , Naftoquinonas/farmacologia , Proteínas Quinases Ativadas por AMP , Proliferação de Células , Apoptose , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Global navigation satellite systems (GNSSs) became an integral part of all aspects of our lives, whether for positioning, navigation, or timing services. These systems are central to a range of applications including road, aviation, maritime, and location-based services, agriculture, and surveying. The Global Positioning System (GPS) Standard Position Service (SPS) provides position accuracy up to 10 m. However, some modern-day applications, such as precision agriculture (PA), smart farms, and Agriculture 4.0, have demanded navigation technologies able to provide more accurate positioning at a low cost, especially for vehicle guidance and variable rate technology purposes. The Society of Automotive Engineers (SAE), for instance, through its standard J2945 defines a maximum of 1.5 m of horizontal positioning error at 68% probability (1σ), aiming at terrestrial vehicle-to-vehicle (V2V) applications. GPS position accuracy may be improved by addressing the common-mode errors contained in its observables, and relative GNSS (RGNSS) is a well-known technique for overcoming this issue. This paper builds upon previous research conducted by the authors and investigates the sensitivity of the position estimation accuracy of low-cost receiver-equipped agricultural rovers as a function of two degradation factors that RGNSS is susceptible to: communication failures and baseline distances between GPS receivers. The extended Kalman filter (EKF) approach is used for position estimation, based on which we show that it is possible to achieve 1.5 m horizontal accuracy at 68% probability (1σ) for communication failures up to 3000 s and baseline separation of around 1500 km. Experimental data from the Brazilian Network for Continuous Monitoring of GNSS (RBMC) and a moving agricultural rover equipped with a low-cost GPS receiver are used to validate the analysis.
RESUMO
This paper revisits the stationary attitude initialization problem, i.e., the stationary alignment, of Attitude and Heading Reference Systems (AHRSs). A detailed and comprehensive error analysis is proposed for four of the most representative accelerometer- and magnetometer-based stationary attitude determination methods, namely, the Three-Axis Attitude Determination (TRIAD), the QUaternion ESTimator (QUEST), the Factored Quaternion Algorithm (FQA), and the Arc-TANgent (ATAN). For the purpose of the error analysis, constant biases in the accelerometer and magnetometer measurements are considered (encompassing, hence, the effect of hard-iron magnetism), in addition to systematic errors in the local gravity and Earth magnetic field models (flux density magnitude, declination angle, and inclination angle). The contributions of this paper are novel closed-form formulae for the residual errors (normality, orthogonality, and alignment errors) developed in the computed Direction Cosine Matrices (DCM). As a consequence, analytical insight is provided into the problem, allowing us to properly compare the performance of the investigated alignment formulations (in terms of ultimate accuracy), as well as to remove some misleading conclusions reported in previous works. The adequacy of the proposed error analysis is validated through simulation and experimental results.
Assuntos
Acelerometria/normas , Algoritmos , Gravitação , Magnetometria/normas , Simulação por Computador , HumanosRESUMO
Nitrogenated heterocyclic compounds are present in both natural and synthetic drugs, and hexahydropyrimidine derivatives may prove to be efficient in treating dermatomycosis causing fungi. This study evaluated the antifungal activity of four hexahydropyrimidine derivatives against the dermatomycosis causing fungi. These derivatives were synthesized, characterized, and assessed in terms of their activity against Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Trichophyton rubrum, Fusarium oxysporum, and Epidermophyton floccosum between concentrations 7.8 and 1,000 µg mL-1. Scanning electron micrographs were assessed for the active derivatives and reference drugs, and these micrographs revealed that new agents cause morphological changes in fungi. The derivatives HHP1, HHP3, and HHP4 revealed poor activity against the four fungal strains (MICs range 500-1000 µg mL-1). Compound HHP3 was found to be the best potential antifungal agent among those tested and was the most effective among all the active derivatives that caused morphological changes in the susceptible strains.
Assuntos
Antifúngicos/farmacologia , Dermatomicoses/microbiologia , Fungos/efeitos dos fármacos , Pirimidinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Dermatomicoses/tratamento farmacológico , Fungos/ultraestrutura , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/químicaRESUMO
In our previous work, we demonstrated the promising in vitro effect of VOSalophen, a vanadium complex with a stilbene derivative, against Leishmania amazonensis. Its antileishmanial activity has been associated with oxidative stress in L. amazonensis promastigotes and L. amazonensis-infected macrophages. In the present study, the mechanism involved in the death of parasites after treatment with VOSalophen, as well as in vivo effect in the murine model cutaneous leishmaniasis, has been investigated. Promastigotes of L. amazonensis treated with VOSalophen presented apoptotic cells features, such as cell volume decrease, phosphatidylserine externalization, and DNA fragmentation. An increase in autophagic vacuoles formation in treated promastigotes was also observed, showing that autophagy also may be involved in the death of these parasites. In intracellular amastigotes, DNA fragmentation was observed after treatment with VOSalophen, but this effect was not observed in host cells, highlighting the selective effect of this vanadium complex. In addition, VOSalophen showed activity in the murine model of cutaneous leishmaniasis, without hepatic and renal damages. The outcome described here points out that VOSalophen had promising antileishmanial properties and these data also contribute to the understanding of the mechanisms involved in the death of protozoa induced by metal complexes.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Estilbenos/química , Vanádio/química , Animais , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Leishmaniose Cutânea/genética , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organometálicos/uso terapêuticoRESUMO
The title compound, C14H11NO4, exists in the solid phase in the zwitterionic form, 2-{[(4-carboxy-3-hydroxyphenyl)iminiumyl]methyl}phenolate, with the H atom from the phenol group on the 2-hydroxybenzylidene ring transferred to the imine N atom, resulting in a strong intramolecular N-HâââO hydrogen bond between the iminium H atom and the phenolate O atom, forming a six-membered hydrogen-bonded ring. In addition, there is an intramolecular O-HâââO hydrogen bond between the carboxylic acid group and the adjacent hydroxy group of the other ring, and an intermolecular C-HâââO contact involving the phenol group and the C-H group adjacent to the imine bond, connecting the molecules into a two-dimensional network in the (103) plane. π-π stacking interactions result in a three-dimensional network. This study is important because it provides crystallographic evidence, supported by IR data, for the iminium zwitterionic form of Schiff bases.
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This paper describes the synthesis and in vitro biological activities of imidazolidine and hexahydropyrimidine derivatives against bacteria (Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) and Leishmania protozoa. Out of sixteen heterocyclic derivatives tested, none were cytotoxic against mammalian cells. The compounds showed significant bacterial effects and leishmanicidal activity. Compounds 4a and 4c were active against S. aureus and E. coli, respectively. Compounds 3a-3f, 4h and 4i presented promising results against M. tuberculosis, with MIC values ranging from 12.5 to 25.0 µg/mL, comparable to the "first and second line" drugs used to treat tuberculosis. Compounds 4a, 4c and 4e were active against L major. Three of them were structurally characterized by single-crystal X-ray diffraction.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antiparasitários , Bactérias/efeitos dos fármacos , Imidazolidinas , Leishmania/efeitos dos fármacos , Pirimidinas , Animais , Antibacterianos/química , Antiparasitários/síntese química , Antiparasitários/química , Antiparasitários/farmacologia , Células Cultivadas , Cristalografia por Raios X , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Imidazolidinas/farmacologia , Camundongos , Viabilidade Microbiana/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologiaRESUMO
The Schiff base N,N'-bis(salicylidene)-o-phenylenediamine (salophen) was prepared by the condensation of salicylaldehyde with o-phenylenediamine in ethanol solution. The compound was characterized by elemental analysis, infrared (IR), (1)H, (13)C and (1)H(15)N HMBC nuclear magnetic resonance (NMR) spectroscopic measurements, and also by X-ray diffraction. The tautomerism of salophen was also studied by calculations using density functional theory (DFT). Two of the three tautomers were shown to coexist. A comparison of the DFT data of the three tautomers has shown that the most stable one is salophen 1, which is in accordance with experimental X-ray crystallographic data.
Assuntos
Salicilatos/química , Aldeídos/química , Cristalografia por Raios X , Isomerismo , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Teoria Quântica , Bases de Schiff/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
This paper describes the preparation of N,N'-disubstituted ethylenediamine and imidazolidine derivatives and their in vitro biological activities against Leishmania species. Of the nine synthesized compounds, five displayed a good activity in both L. amazonensis and L. major promastigotes. The compounds 1,2-Bis(p-methoxybenzyl) ethylenediamine (4) and 1,3-Bis(p-methoxybenzyl)imidazolidines (5) showed the best activity on intracellular amastigotes, with IC50 values of 2.0 and 9.4 microgram/mL, respectively. In addition, none of compounds were cytotoxic against mammalian cells. The leishmanicidal activity can be related with inhibition of polyamine synthesis and cellular penetration within biological membranes.
Assuntos
Antiprotozoários/farmacologia , Etilenodiaminas/farmacologia , Imidazolidinas/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Etilenodiaminas/síntese química , Etilenodiaminas/química , Imidazolidinas/síntese química , Imidazolidinas/química , Leishmania/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Químicos , Estrutura MolecularRESUMO
We describe in this work the synthesis of nine new fluoroquinolone derivatives based on modifications at the C-7 position of the known fluoroquinolones cipro-, gati-, and moxifloxacin, as well as their antitubercular evaluation. The synthesis of these new analogues was improved using microwave irradiation, providing several advantages such as better yields and shorter reaction times, in comparison with classical reaction conditions. Derivatives 4, 5, and 7 exhibited promising antitubercular activities.
Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Carboidratos/química , Fluoroquinolonas/síntese química , Fluoroquinolonas/farmacologia , Antituberculosos/química , Compostos Aza/química , Compostos Aza/farmacologia , Ciprofloxacina/química , Ciprofloxacina/farmacologia , Fluoroquinolonas/química , Gatifloxacina , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Moxifloxacina , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologiaRESUMO
OBJETIVO: O objetivo deste trabalho foi relatar a morbimortalidade associada à técnica de reconstrução pancreática utilizando anastomose pancreato-jejunal tipo ducto-mucosa, sem cateter transanastomótico, em pâncreas de consistência mole e ducto de Wirsung menor que três mm. MÉTODOS: Analisamos consecutivamente os resultados de 16 pacientes submetidos à GDP com técnica de anastomose pancreato-jejunal tipo ducto-mucosa no Serviço de Cirurgia Abdômino-pélvica do INCA. Todos pacientes eram portadores de pâncreas de consistência mole e ducto pancreático fino (< 3mm). RESULTADOS: Dos 16 pacientes analisados, oito eram do sexo masculino e com mediana de idade de 55 anos. No período pós-operatório um paciente apresentou fístula pancreática e houve um caso que evoluiu para óbito. CONCLUSÃO: Acreditamos que é possível a realização de anastomose pancreática tipo ducto-mucosa, sem cateter transanastomótico, em pacientes com ducto pancreático menor que três mm sem aumento da morbimortalidade.
BACKGROUND: Our goal is to report the morbimortality associated to the pancreatic reconstruction technique using duct-to-mucosa nonstented pancreatojejunostomy in soft pancreas and Wirsung's duct less than 3 mm. METHODS: We analyzed 16 consecutive patients submitted to DP with duct-to-mucosa pancreatojejunostomy technique in the Service of Abdominal-pelvic Surgery of NCI-Brazil. All patients had soft pancreatic texture and small pancreatic duct (< 3mm). RESULTS: From those 16 patients, eight were males, with an mean age of 55 years old. In the post-operative period one patient developed pancreatic fistula. There had been one death. CONCLUSION: We believe that duct-to-mucosa nonstented pancreatojejunostomy is possible in patients with pancreatic duct less than three mm and soft texture pancreas without increased morbimortality.