RESUMEN
Currently, there are no licensed human vaccines or antivirals for treatment of or prevention from infection with encephalitic alphaviruses. Because epidemics are sporadic and unpredictable, and endemic disease is common but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we have continued development of ML336 to deliver a molecule with prophylactic and therapeutic potential that could be relevant for use in natural epidemics or deliberate release scenario for Venezuelan equine encephalitis virus (VEEV). We report findings from in vitro assessments of four analogs of ML336, and in vivo screening of three of these new derivatives, BDGR-4, BDGR-69 and BDGR-70. The optimal dosing for maximal protection was observed at 12.5â¯mg/kg/day, twice daily for 8 days. BDGR-4 was tested further for prophylactic and therapeutic efficacy in mice challenged with VEEV Trinidad Donkey (TrD). Mice challenged with VEEV TrD showed 100% and 90% protection from lethal disease when treated at 24 and 48â¯h post-infection, respectively. We also measured 90% protection for BDGR-4 in mice challenged with Eastern equine encephalitis virus. In additional assessments of BDGR-4 in mice alone, we observed no appreciable toxicity as evaluated by clinical chemistry indicators up to a dose of 25â¯mg/kg/day over 4 days. In these same mice, we observed no induction of interferon. Lastly, the resistance of VEEV to BDGR-4 was evaluated by next-generation sequencing which revealed specific mutations in nsP4, the viral polymerase.
Asunto(s)
Benzamidas , Benzamidinas , Farmacorresistencia Viral/genética , Virus de la Encefalitis Equina del Este/efectos de los fármacos , Virus de la Encefalitis Equina Venezolana/efectos de los fármacos , Piperazinas , Animales , Antivirales/síntesis química , Antivirales/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Benzamidinas/síntesis química , Benzamidinas/farmacología , Línea Celular , Encefalomielitis Equina Oriental/tratamiento farmacológico , Encefalomielitis Equina Oriental/prevención & control , Encefalomielitis Equina Venezolana/tratamiento farmacológico , Encefalomielitis Equina Venezolana/prevención & control , Genes Virales , Ratones , Mutación , Piperazinas/síntesis química , Piperazinas/farmacologíaRESUMEN
BACKGROUND: Moniliophthora perniciosa (Stahel) Aime & Phillips-Mora is the causal agent of witches' broom disease (WBD) of cocoa (Theobroma cacao L.) and a threat to the chocolate industry. The membrane-bound enzyme alternative oxidase (AOX) is critical for M. perniciosa virulence and resistance to fungicides, which has also been observed in other phytopathogens. Notably AOX is an escape mechanism from strobilurins and other respiration inhibitors, making AOX a promising target for controlling WBD and other fungal diseases. RESULTS: We present the first study aimed at developing novel fungal AOX inhibitors. N-Phenylbenzamide (NPD) derivatives were screened in the model yeast Pichia pastoris through oxygen consumption and growth measurements. The most promising AOX inhibitor (NPD 7j-41) was further characterized and displayed better activity than the classical AOX inhibitor SHAM in vitro against filamentous fugal phytopathogens, such as M. perniciosa, Sclerotinia sclerotiorum and Venturia pirina. We demonstrate that 7j-41 inhibits M. perniciosa spore germination and prevents WBD symptom appearance in infected plants. Finally, a structural model of P. pastoris AOX was created and used in ligand structure-activity relationships analyses. CONCLUSION: We present novel fungal AOX inhibitors with antifungal activity against relevant phytopathogens. We envisage the development of novel antifungal agents to secure food production. © 2018 Society of Chemical Industry.
Asunto(s)
Agaricales/efectos de los fármacos , Agaricales/fisiología , Benzamidas/síntesis química , Benzamidas/farmacología , Cacao/microbiología , Proteínas Mitocondriales/antagonistas & inhibidores , Oxidorreductasas/antagonistas & inhibidores , Enfermedades de las Plantas/microbiología , Proteínas de Plantas/antagonistas & inhibidores , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Benzamidas/química , Técnicas de Química Sintética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: NF-κB is a transcription factor involved in the transcriptional regulation of a large number of genes related to tumorigenesis in several cancer cell types, and its inhibition has been related to anticancer effect. DHMEQ (Dehydroxymethylepoxyquinomicin) is a compound that blocks the translocation of NF-κB from the cytoplasm to the nucleus, thus inhibiting its activity as a transcriptional activator. Several studies have shown the antineoplastic effects of DHMEQ in numerous tumor types, however, there are no surveys that tested their effects in MB. OBJECTIVES: The aim of the present study was to evaluate the effects of DHMEQ as NF-κB inhibitor in pediatric MB cell lines. METHOD: We used the UW402, UW473 and ONS-76 medulloblastoma (MB) cell lines to verify the effect of DHMEQ on proliferation, clonogenic capacity, apoptosis, cell invasion and migration, and evaluated the effect of the combination with other drugs and the potential as a radiosensitizator. RESULTS: A significant decrease in the cell growth, a strong inhibition of the clonogenic capacity, migration and cell invasion was observed after NF-κB inhibition in the three MB cell lines. Conversely, increased level of apoptosis rates were demonstrated. Additionally, treatments with DHMEQ combined with other chemotherapeutic agents were synergic in most points, and a strong radiosensitization by this compound was observed in the three MB cell lines. CONCLUSION: DHMEQ has potential antitumor effect on MB cells, and it may be considered a new therapeutic agent to improve treatment approaches in MB.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Ciclohexanonas/farmacología , Meduloblastoma/terapia , FN-kappa B/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzamidas/síntesis química , Benzamidas/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Meduloblastoma/metabolismo , Estructura Molecular , FN-kappa B/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
BACKGROUND: There are data indicating that several azonine-derivatives may exert effects on some biological systems; however, there is very low information on the biological activity induced by these compounds on left ventricular pressure. OBJECTIVE: The aim of this study was to synthesize and evaluate the biological activity of new triazoninederivative on left ventricular pressure. MATERIAL AND METHODS: The first stage involved: 1) preparation of two azepine-benzamide derivatives (Z or E) by reaction of the nitrobenzoyl azide with adrenosterone; and 2) reaction of (Z)-azepine-benzamide derivative with ethylenediamine to form the triazonine derivative. The structure of compounds was confirmed by spectroscopy and spectrometry data. The second stage involved the biologic activity on left ventricular pressure was evaluated in a model of rat heart isolated. In addition, some physicochemical parameters were evaluated to characterize the possible molecules involved in its effect. RESULTS: The results showed that only the triazonine increased left ventricular pressure via androgen receptor. CONCLUSIONS: In conclusion, this phenomenon is conditioned by the functional groups involved in the chemical structure of triazonine derivative and their interaction with residues of amino acids involved on the androgen receptor surface.
Asunto(s)
Azepinas/química , Azepinas/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Receptores Androgénicos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Presión Ventricular/efectos de los fármacos , Animales , Azepinas/síntesis química , Benzamidas/síntesis química , Benzamidas/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Humanos , Masculino , Simulación del Acoplamiento Molecular , Ratas WistarRESUMEN
A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S)-3-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (1f), N-{(2S)-1-[(4-bromophenyl)amino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g), and 4-chloro-N-{(2S)-1-[(3,4-dichlorophenyl)amino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (1h) was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL) and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count) after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h.
Asunto(s)
Antibacterianos/farmacología , Benzamidas/farmacología , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Antibacterianos/síntesis química , Antibacterianos/química , Benzamidas/síntesis química , Benzamidas/químicaRESUMEN
Tissue engineering encapsulated cells such as chondrocytes in the carrier matrix have been widely used to repair cartilage defects. However, chondrocyte phenotype is easily lost when chondrocytes are expanded in vitro by a process defined as “dedifferentiation”. To ensure successful therapy, an effective pro-chondrogenic agent is necessary to overcome the obstacle of limited cell numbers in the restoration process, and dedifferentiation is a prerequisite. Gallic acid (GA) has been used in the treatment of arthritis, but its biocompatibility is inferior to that of other compounds. In this study, we modified GA by incorporating sulfamonomethoxine sodium and synthesized a sulfonamido-based gallate, JJYMD-C, and evaluated its effect on chondrocyte metabolism. Our results showed that JJYMD-C could effectively increase the levels of the collagen II, Sox9, and aggrecan genes, promote chondrocyte growth, and enhance secretion and synthesis of cartilage extracellular matrix. On the other hand, expression of the collagen I gene was effectively down-regulated, demonstrating inhibition of chondrocyte dedifferentiation by JJYMD-C. Hypertrophy, as a characteristic of chondrocyte ossification, was undetectable in the JJYMD-C groups. We used JJYMD-C at doses of 0.125, 0.25, and 0.5 µg/mL, and the strongest response was observed with 0.25 µg/mL. This study provides a basis for further studies on a novel agent in the treatment of articular cartilage defects.
Asunto(s)
Animales , Conejos , Benzamidas/síntesis química , Desdiferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Fenotipo , Pirimidinas/síntesis química , Agrecanos/genética , Agrecanos/metabolismo , Antiinfecciosos/química , Antiinfecciosos/farmacología , Benzamidas/farmacología , Supervivencia Celular , Desdiferenciación Celular/inmunología , Condrocitos/citología , Condrocitos/metabolismo , Condrogénesis/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Glicosaminoglicanos/análisis , Inmunohistoquímica , Citometría de Barrido por Láser , Cultivo Primario de Células , Pirimidinas/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Ingeniería de TejidosRESUMEN
Tissue engineering encapsulated cells such as chondrocytes in the carrier matrix have been widely used to repair cartilage defects. However, chondrocyte phenotype is easily lost when chondrocytes are expanded in vitro by a process defined as "dedifferentiation". To ensure successful therapy, an effective pro-chondrogenic agent is necessary to overcome the obstacle of limited cell numbers in the restoration process, and dedifferentiation is a prerequisite. Gallic acid (GA) has been used in the treatment of arthritis, but its biocompatibility is inferior to that of other compounds. In this study, we modified GA by incorporating sulfamonomethoxine sodium and synthesized a sulfonamido-based gallate, JJYMD-C, and evaluated its effect on chondrocyte metabolism. Our results showed that JJYMD-C could effectively increase the levels of the collagen II, Sox9, and aggrecan genes, promote chondrocyte growth, and enhance secretion and synthesis of cartilage extracellular matrix. On the other hand, expression of the collagen I gene was effectively down-regulated, demonstrating inhibition of chondrocyte dedifferentiation by JJYMD-C. Hypertrophy, as a characteristic of chondrocyte ossification, was undetectable in the JJYMD-C groups. We used JJYMD-C at doses of 0.125, 0.25, and 0.5 µg/mL, and the strongest response was observed with 0.25 µg/mL. This study provides a basis for further studies on a novel agent in the treatment of articular cartilage defects.
Asunto(s)
Benzamidas/síntesis química , Desdiferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Fenotipo , Pirimidinas/síntesis química , Agrecanos/genética , Agrecanos/metabolismo , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Benzamidas/farmacología , Desdiferenciación Celular/inmunología , Supervivencia Celular , Condrocitos/citología , Condrocitos/metabolismo , Condrogénesis/efectos de los fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Glicosaminoglicanos/análisis , Inmunohistoquímica , Citometría de Barrido por Láser , Cultivo Primario de Células , Pirimidinas/farmacología , Conejos , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Ingeniería de TejidosRESUMEN
This study aimed to study the in vitro antioxidant activity and cytotoxicity on tumor cells lines of six synthetic substances derived from riparins. All the substances showed antioxidant activity and riparins C, D, E, F presented cell growth inhibition rates greater than 70%, suggesting that these molecules have antitumor properties. These substances also caused greater than 80% releases of cytoplasmic lactate dehydrogenase enzyme (LDH). Although the antioxidant and antitumor properties presented herein require further assessment, the outcomes indicate that these novel riparins are promising biologically active compounds.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antioxidantes/farmacología , Benzamidas/farmacología , Malondialdehído/antagonistas & inhibidores , Óxido Nítrico/antagonistas & inhibidores , Animales , Antioxidantes/síntesis química , Benzamidas/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Óxido Nítrico/biosíntesisRESUMEN
In this paper, we describe the synthesis of a novel class of pseudo-peptides derived from isomannide and several oxazolones as potential inhibitors of serine proteases as well as preliminary pharmacological assays for hepatitis C. Hepatitis C, dengue and West Nile fever are among the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes and are a primary target in the drug development field. Several pseudo-peptides were obtained in good yields from the reaction of isomannide and oxazolones, and their anti-HCV potential using the HCV replicon-based assay was shown.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Diseño de Fármacos , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Genes Reporteros , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatocitos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Oligopéptidos/química , Oxazoles/síntesis química , Oxazoles/química , Replicón , Inhibidores de Serina Proteinasa/químicaRESUMEN
In this study, the mutagenicity of the anti-inflammatory parsalmide [5-amino-N-butyl-2-(2-propynyloxy)-benzamide] analogues PA7 [5-amino-N-butyl-2-cyclohexyloxy-benzamide], PA10 [5-amino-N-butyl-2-phenoxy-benzamide] and PA31 [5-amino-N-butyl-2-(p-tolyloxy)-benzamide] was determined by an Ames Salmonella assay. The experiments were performed by preincubating the compounds in the absence and presence of a post-mitochondrial fraction (S9) of rat liver homogenate from phenobarbital/beta-naphtoflavone treated rats. No mutagenic effect was observed after direct testing (no S9 added) in Salmonella typhymurium strains TA98, TA100, TA102, TA1535 and TA1537. However, in the presence of S9, the test substances triggered mutagenic responses in strains TA100 and TA98. PA31 presented the strongest mutagenic potential. The reversion rates in the presence of PA31 were about 2-19 fold higher than spontaneous mutation rates. In the presence of PA7, the reversion increased 2-14-fold over spontaneous rates. While PA10 showed a relatively mild mutagenic potential, as the number of revertants did not exceed 2.5 times the number of spontaneous mutations. Mass spectrometric analysis of the in vitro biotransformation showed that S9 converted (%), regioselectively, PA7 (19%), PA10 (7%) and PA31 (12%) into hydroxy-derivatives.