RESUMEN
In the present study, sulfated polysaccharides were obtained by digestion of Sargassum horneri and preparation with enzyme-assisted extraction using three food-grade enzymes, and their anti- Alzheimer's activities were investigated. The results demonstrated that the crude sulfated polysaccharides extracted using AMGSP, CSP and VSP dose-dependently (25-100 µg·mL- 1) raised the spontaneous alternating manner (%) in the Y maze experiment of mice and reduced the escape latency time in Morris maze test. AMGSP, CSP and VSP also exhibited good anti-AChE and moderate anti-BuChE activities. CSP displayed the best inhibitory efficacy against AChE. with IC50 values of 9.77 µM. And, CSP also exhibited good inhibitory selectivity of AChE over BuChE. Next, CSP of the best active crude extract was separated by the preparation type high performance liquid phase to obtain the sulphated fucooligosaccharide section: SFcup (â3-α-L-fucp(2-SO3-)-1â4-α-L-fucp(2,3-SO3-)-1âsection), SFcup showed a best inhibitory efficacy against AChE with IC50 values of 4.03 µM. The kinetic research showed that SFcup inhibited AChE through dual binding sites. Moreover, the molecular docking of SFcup at the AChE active site was in accordance with the acquired pharmacological results.
Asunto(s)
Acetilcolinesterasa , Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Simulación del Acoplamiento Molecular , Oligosacáridos , Sargassum , Sargassum/química , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/uso terapéutico , Ratones , Acetilcolinesterasa/metabolismo , Oligosacáridos/farmacología , Oligosacáridos/química , Oligosacáridos/aislamiento & purificación , Masculino , Sulfatos/química , Sulfatos/farmacología , Butirilcolinesterasa/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Relación Dosis-Respuesta a DrogaRESUMEN
Traditional Chinese medicine (TCM)has played an important role in promoting the health of Chinese people. The TCM Psoralea corylifolia L. has been used in the treatment of various kinds of diseases including enuresis, vitiligo, and calvities. However, therapeutic effects of P. corylifolia L. have often influenced by the quality of plants. So, it is very important to control the quality of P. corylifolia L. In this study, analytical high-speed countercurrent chromatography (HSCCC) was successfully used to fingerprint P. corylifolia L. Samples of P. corylifolia L. were extracted by ultrasonic extraction. n-hexane-ethyl acetate-methanol-water at a ratio of 5:5.5:6.5:5 (v/v) was selected as a two-phase solvent system and the condition of HSCCC were optimized in order to good separation. And the method of HSCCC was verified (reproducibility, precision, and stability). HSCCC chromatograms exhibited six common peaks, which were selected as indicator compounds for the quality control of P. corylifolia L. Within 20 types of medicinal materials, chemical components are similar, but the levels of components are quite different in HSCCC fingerprint. The present results demonstrate that the HSCCC method provides a reliable basis for the quality control of P. corylifolia L. and can also be applied to confirm the authenticity of plant materials.
Asunto(s)
Distribución en Contracorriente , Psoralea/química , Control de Calidad , Acetatos/química , Hexanos/química , Humanos , Medicina Tradicional China , Metanol/química , Psoralea/crecimiento & desarrollo , Agua/químicaRESUMEN
In the present study, four new steroidal saponins, namely vernoniamyoside A-D (1-4), together with the two known steroidal saponins vernoamyoside D (5) and vernonioside B2 (6) were isolated from the ethanol extract of leaves of the African medicinal plant Vernonia amygdalina Del. (Asteraceae). Their structures were demonstrated by spectral analyses along with 1D and 2D nuclear magnetic resonance (NMR) techniques and mass spectrometry (MS). The cytotoxicity of the compounds was also tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method on the cell lines Hela, MCF-7, BT-549 and MDA-MB-231. Vernoniamyoside A, vernoniamyoside B, and vernonioside B2 showed cytotoxicity towards BT-549 cell lines. Vernoniamyoside C, vernoniamyoside D and vernoamyoside D showed different levels of cytotoxic activities.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Hojas de la Planta/química , Saponinas/aislamiento & purificación , Esteroides/aislamiento & purificación , Vernonia/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Células MCF-7 , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/química , Plantas Medicinales , Saponinas/química , Saponinas/farmacología , Esteroides/química , Esteroides/farmacologíaRESUMEN
A series of 4-(substituted-phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones (6a-x) with triazole and other heterocyclic substituents (7-14) were synthesized and the compounds were evaluated for their anticonvulsant activity and neurotoxicity by maximal electroshock (MES) and rotarod neurotoxicity tests. Among the compounds studied, 6o and 6q showed wide margins of safety with protective indices (PIs) that were much higher than those of currently used drugs (PI6o > 25.5, PI6q > 26.0). Compounds 6o and 6q showed significant oral activity against MES-induced seizures in mice, with ED50 values of 88.02 and 94.6 mg/kg, respectively. The two compounds were also found to have potent activity against seizures that were induced by pentylenetetrazole and bicuculline.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Diseño de Fármacos , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Convulsiones/prevención & control , Triazoles/síntesis química , Triazoles/farmacología , Animales , Anticonvulsivantes/toxicidad , Conducta Animal , Bicuculina , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Electrochoque , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Pentilenotetrazol , Quinazolinonas/toxicidad , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Relación Estructura-Actividad , Factores de Tiempo , Triazoles/toxicidadRESUMEN
Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ß receptor I (TßRI), to disrupt the interaction of TßRI-FK506 Binding Protein12 (FKBP12), which led to activation of TßRI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt TßRI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.
Asunto(s)
COVID-19 , Fibrosis Pulmonar , Animales , Ratones , COVID-19/complicaciones , Fibrosis , Proteínas de la Nucleocápside/uso terapéutico , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/tratamiento farmacológico , SARS-CoV-2RESUMEN
In this study, a molecular imprinted electrochemical sensor based on surface imprinting and boric acid affinity was prepared for the selective and sensitive detection of P-glycoprotein (P-gp) under physiological conditions. Several polymerization parameters were systematically investigated. Four electrochemical methods were used to characterize the sensors. It was proved that the glassy carbon electrode (GCE) was well modified by molecularly imprinted polymers (MIPs), and the electrochemical detection results were consistent with the theory. Methodological verification also showed that there were different linear relationships in the range of 1.0E-10-1.0E-1 µg/mL and 0.5-10 µg/mL with LOD = 2.233E-11 µg/mL and LOQ = 7.444E-11 µg/mL. The excellent selectivity and specificity of the sensor were demonstrated and the sensor could be stored in 1X PBS (0.01 M) at 4 °C for one week. Repeatability and intermediate precision were measured, and the RSD remained below 5%. In addition, the sensor could be reused up to three times without affecting the results of the measurements. The results of application showed that the sensor had a more accurate response value in 1% of plasma matrix. Compared with the detection results of ELISA kit method, the sensor had the advantages of wider detection range, shorter detection time, higher accuracy, simple operation and low cost, which indicated that the sensor had a certain practicability and clinical translational application capability. This study also provided a new idea and method for the detection of other high molecular weight biomarkers in complex biological samples.
Asunto(s)
Impresión Molecular , Subfamilia B de Transportador de Casetes de Unión a ATP , Ácidos Bóricos , Impresión Molecular/métodos , Polimerizacion , Polímeros/químicaRESUMEN
Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.
Asunto(s)
Caspasa 8 , Proteínas de Unión al ADN , Neoplasias , Piroptosis , Receptores del Factor de Necrosis Tumoral , Animales , Caspasa 1/metabolismo , Ácidos Cetoglutáricos , Ratones , Receptores de Muerte CelularRESUMEN
Structural optimization of multiple H-bonding region and structure-activity relationship of diarylalkyl amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent (45)Ca(2+) uptake inhibitions in rat DRG neuron with IC(50)s of 25, 32 and 28 nM, respectively.
Asunto(s)
Amidas/farmacología , Señalización del Calcio/efectos de los fármacos , Neuronas/efectos de los fármacos , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/metabolismo , Animales , Sitios de Unión , Calcio/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Concentración 50 Inhibidora , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
We have developed a new class of diarylalkyl amides as novel TRPV1 antagonists. They exhibited potent (45)Ca(2+) uptake inhibitions in rat DRG neuron. In particular, the amide 59 was identified as a potent antagonist with IC(50) of 57 nM. The synthesis and structure-activity relationship of the diarylalkyl amides are also described.
Asunto(s)
Amidas/síntesis química , Sulfonamidas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Amidas/química , Amidas/farmacología , Animales , Calcio/metabolismo , Células Cultivadas , Diseño de Fármacos , Concentración 50 Inhibidora , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Canales Catiónicos TRPV/metabolismo , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacologíaRESUMEN
Synthesis and structure-activity relationship of N-benzyl-3-phenylpropanamides as transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of substituents such as halide, ester, nitro, and alkyl groups at 2 or 3-position of 4-(methylsulfonylamino) benzyl unit were examined. These compounds exhibited potent 45Ca2+ uptake inhibition in rat DRG neuron via TRPV1 blockade. Especially compound 28c, has been identified as a potent antagonist with IC50 of 38 nM.
Asunto(s)
Amidas/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/farmacología , Animales , Calcio/metabolismo , Células Cultivadas , Diseño de Fármacos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
A series of novel 5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline derivatives was synthesized by the cyclization of 2-chloro-4-phenyl-1,2-dihydronaphthalene with formohydrazide. The starting material 2-chloro-4-phenyl-1,2-dihydronaphthalene was synthesized from ethyl-3-oxo-3-phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7-hexyloxy-5-phenyl-[1,2,4]-triazolo[4,3-a]quinoline 4f was found to be the most potent compound with an ED(50) value of 6.5 mg/kg and a protective index (PI = ED(50) / TD(50)) value of 35.1, which was much higher than the PI of the reference drug phenytoin.
Asunto(s)
Anticonvulsivantes/síntesis química , Quinolonas/síntesis química , Quinolonas/farmacología , Compuestos de Anilina/química , Animales , Anticonvulsivantes/farmacología , Ciclización , Electrochoque/efectos adversos , Ratones , Naftalenos/química , Quinolonas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Guided by bioisosterism and pharmacokinetic parameters, we designed and synthesized a series of novel benzamide derivatives. Preliminary in vitro studies indicated that compounds 10b and 10j show significant inhibitory bioactivity in HepG2 cells (IC50 values of 0.12 and 0.13 µM, respectively). Compounds 10b and 10j induced the expression of HIF-1α protein and downstream target gene p21, and upregulated the expression of cleaved caspase-3 to promote tumor cells apoptosis.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzamidas/síntesis química , Benzamidas/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 8-alkoxy-4,5-dihydro-[1,2,4]triazole[4,3-a]quinoline-1-one derivatives were synthesized using 7-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and the subcutaneous pentylenetetrazole test (sc-PTZ), and their neurotoxicities were measured by the rotarod neurotoxicity test (Tox). The tests demonstrated that 8-hexyloxy-4,5-dihydro-[1.2.4]triazole[4.3-a]quinoline-1-one (4e) and 8-heptyloxy-4,5-dihydro-[1,2,4] triazole[4,3-a]quinoline-1-one (4f) were the most potent anticonvulsants, with 4e having ED50 values of 17.17 mg/kg and 24.55 mg/kg and protective index (PI = TD50/ED50) values of 41.9 and 29.3 in the MES and sc-PTZ tests, respectively, and 4f having ED50 values of 19.7 mg/kg and 21.2 mg/kg and PI values of 36.5 and 33.9 in the MES and sc-PTZ tests, respectively. The PI values of 4e and 4f were many fold better than that of the marketed drugs phenytoin, carbamazepine, phenobarbital and valproate, which have PI values in the range of 1.6-8.1 in the MES test and < 0.22-5.2 in the sc-PTZ test. Structure-activity relationships were also discussed.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Animales , Anticonvulsivantes/toxicidad , Convulsivantes , Electrochoque , Epilepsia/inducido químicamente , Epilepsia/psicología , Femenino , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Pentilenotetrazol , Equilibrio Postural/efectos de los fármacos , Quinolonas/toxicidad , Espectrofotometría Infrarroja , Triazoles/toxicidadRESUMEN
To identify novel therapeutic agents to treat cancer, we synthesized a series of diaryl ether derivatives. Structure-activity relationship studies revealed that the presence of a chlorine or hydroxyl at the para-position on the phenyl ring (5h or 5k) significantly enhanced antitumor activity. Compound 5h had stronger growth inhibitory activity in HepG2, A549, and HT-29 cells than compound 5k, with IC50 values of 2.57, 5.48, and 30.04 µM, respectively. Compound 5h also inhibited the growth of other cells lines, including Hep3B, PLC/PRF5, SMMC-7721, HeLa, and A375, with IC50 values of 2.76, 4.26, 29.66, 18.86, and 10.21 µM, respectively. The antitumor activity of compound 5h was confirmed by a colony forming assay. Further, our results indicated that the antitumor activity of compound 5h may be mediated by enhancing expression of p21 and cl-caspase3, and leading to apoptosis of cancer cells.
Asunto(s)
Antineoplásicos/farmacología , Éteres/farmacología , Neoplasias/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Éteres/síntesis química , Éteres/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HT29 , Células HeLa , Humanos , Concentración 50 Inhibidora , Neoplasias/patología , Relación Estructura-ActividadRESUMEN
In this study, a series of novel N-(piperidine-4-yl)benzamide derivatives was designed, synthesized, and evaluated for antitumor activity. Some compounds were found to have potent antitumor activity. In particular, compound 47 showed the most potent biological activity against HepG2 cells, with an IC50 value of 0.25 µm. Western blot analysis demonstrated that compound 47 inhibited the expression of cyclin B1 and p-Rb and enhanced the expression of p21, p53, Rb, and phospho-adenosine monophosphate-activated protein kinase (p-AMPK). Further, cell cycle arrest was observed by flow cytometry (FCM). In summary, compound 47 was screened to have potential activity for the treatment of hepatocarcinoma via the induction of cell cycle arrest by a p53/p21-dependent pathway.
Asunto(s)
Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Piperidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzamidas/química , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/patología , Piperidinas/síntesis química , Piperidinas/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
A series of new purines containing triazole and other heterocycle substituents was synthesized and evaluated for their preliminary anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and rotarod neurotoxicity (TOX) tests. Among the compounds studied, 9-decyl-6-(1H-1,2,4-triazol-1-yl)-9H-purine (5e) was the most potent compound, with a median effective dose of 23.4 mg/kg and a high protective index of more than 25.6 after intraperitoneal administration in mice. Compound 5e showed significant oral activity against MES-induced seizures in mice, with an ED50 of 39.4 mg/kg and a PI above 31.6. These results demonstrate that compound 5e possesses better anticonvulsant activity and is safer than the commercially available drugs carbamazepine and valproate in MES, scPTZ and TOX models.
Asunto(s)
Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Purinas/farmacología , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/administración & dosificación , Modelos Animales de Enfermedad , Electrochoque , Ratones , Actividad Motora/efectos de los fármacos , Pentilenotetrazol/administración & dosificación , Purinas/administración & dosificación , Purinas/síntesis químicaRESUMEN
Design, synthesis and biological evaluation of B-region, known to be a dipolar interacting pharmacophore, modified diarylalkyl amide analogues for novel TRPV1 (transient receptor potential channel, vanilloid subfamily member 1) antagonists was described. A variety of moieties including guanidines, heterocyclic rings, cinnamides, and α-substituted acetamides were introduced at the B-region. TRPV1 antagonistic activities of these analogues were evaluated by (45)Ca(2+) uptake assay in rat DRG neuron. In particular, α,α-difluoroamide 53 exhibited 3-fold more potent TRPV1 antagonistic activity (IC50 = 0.058 µM) than the parent amide analogue 6.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Diseño de Fármacos , Canales Catiónicos TRPV/antagonistas & inhibidores , Animales , Calcio/metabolismo , Células Cultivadas , Ganglios Espinales/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A series of heterocycle-linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding modes of dibenzyl thiourea, benzylphenethyl amide, and furan-linked phenylbenzyl amide were examined by using the flexible docking study within the rTRPV1 homology model.
Asunto(s)
Amidas/química , Compuestos Heterocíclicos/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/farmacocinética , Amidas/uso terapéutico , Analgésicos/síntesis química , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Animales , Sitios de Unión , Furanos/química , Semivida , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Masculino , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Tiourea/químicaRESUMEN
Considerable interest has been focused on the triazole structure, which has been known to possess a broad spectrum of biological activities such as antitumor, anti-inflammatory, antimicrobial, antiviral, and anticonvulsant activities. Before this, several heterocyclic compounds containing triazole were synthesized that had shown considerable anticonvulsant activity. As part of our continuous research in this area, we have synthesized several new 7-substituted-5-phenyl-[1,2,4] triazolo[1,5-a] pyrimidines (compounds 3a-3i, 5a-5j) through incorporating triazole moiety into the pyrimidine ring, which are expected to have the synergistic effect in dealing with the epilepsy. Their anticonvulsant activities were measured through the Maximal electroshock (MES) test. Carbamazepine and valproate were considered as positive control drugs with anticonvulsant effects [ED50 = 11.8 and 272 mg/Kg]. Amongst the compounds tested, compound 3f, 7-(heptyloxy)-5-phenyl-[1,2,4] triazolo[1,5-a] pyrimidine, showed potent anticonvulsant activity with ED50 84.9 mg/Kg, which was weaker than carbamazepine, but better than valproate.
RESUMEN
A series of novel 10-alkoxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4]oxazepine derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). In the MES test, compound 10-Heptyloxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4]oxazepine (8f) was found to possess better anticonvulsant activity and higher safety than marketed drugs carbamazepine and phenytoin with an ED(50) value of 6.9 mg/kg a PI value of 9.5. To explain the possible mechanism of anticonvulsant activity, compound 8f was tested in pentylenetetrazole, isoniazid, thiosemicarbazide, 3-mercaptopropionic acid and Bicuculline induced seizures tests. The results suggest that compound 8f exerts anticonvulsant activity through GABA-mediated mechanism.