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Título : Potencial Antiepiléptico de Nuevos Derivados de 5-Bencilideno Pirimidinas
Autor : Guevara, Beatriz A
Lobo, Gricela
Rodriguez, Christan
Colman, Trina
Charris, Jaime
Palabras clave : 5-benzylidene-pirimidines, Maximal electroshock (MES), Pentylenetetrazole, Antiepileptic potential, Minimal neurotoxicity.
Fecha de publicación : 9-Nov-2014
Resumen : Three series of compounds 4,6-[(diamine)-5-benzylidene]-pyrimidine-2(5H)-thione (4a), (5E)-6-amine-5-[4-(dimethylamine)benzylidene]-pyrimidine-2,4(3H, 5H)-dione (5a), its analog: 4-fluoro (5b), and 4.6-[diamine-5-benzylidene] pyrimidine-2(5H)-one (3a) with its derivatives: 3,4-dichloro (3b), 2-methoxy (3c) and 4-dimethylamine (3d) substituted ring were synthesized in two reaction steps. In the first step key intermediates were synthesized by a condensation reaction between benzaldehyde and malononitrile. The intermediates of general structure were 1 benzylidene malononitrile and brokers of general structure 2 (2E)-2-cyano-3-methyl aril acrylate. The cyclization reaction between 1 and urea produced the benzylidene pyrimidine derivatives of general structure 3 4,6- [diamine-5-benzylidene] pyrimidine-2 (5H)-one. The cyclization of 1 with thiourea led to structure 4 benzylidene derivatives pyrimidines: 4,6-[diamine-5-benzylidene]pyrimidine-2(5H)-thione. Moreover, the cyclization of 2 with urea gave the benzylidene pyrimidine derivatives of general structure 5 (5E)-6- [amine-5-benzylidene]pyrimidine-2,4(3H,5H)-dione. The structures of the compounds were confirmed by IR, 1H-NMR, 13C NMR and MS. We evaluated the anticonvulsant activity and neurotoxicity of 5-benzylidene pyrimidine obtained from 3, 4 and 5, following of Development of Antiepileptic Drugs in Development Program (ADD), Program procedures (NIH, USA). This protocol states Maximal Electroshock Model (MES) and subcutaneous Penthylenetetrazole Model (scPTZ) as first step paramount tests. Albino mice from NMRI strain were used for all tests. Minimal neurotoxicity test was assessed using the rotarod test. The compounds were administered intraperitoneally (ip) 30 minutes to 4 hours before seizure stimuli. Analog compounds are 4a, 5a and 3a. Compounds 3b, 3c y 3d are 3a derivatives. Every compound but 3d did protect in MES and PTZsc models by preventing seizures at 30 min and 4 h in higher doses than phenobarbital (PBT). None of compounds could prevent seizures induced by 6 Hz model. Most toxic compounds were: 3a > 4a > 3c. 3d had the higher protection index (PI); even higher than PBT. Time to peak effect of 5a, 3b y 3c was 30 min, while 4a, 3a, 5b y 3d was at 4h. Altogether let as conclude that 4,6-diamino-5-(4-dimehylamino-2-benzylidene)pyrimidine-2(5H)-one (3d) had the highest performance among all compounds evaluated and even higher than the control drug PB
Descripción : Tres series de los compuestos 4,6-[(diamino)-5-benciliden]pirimidina-2(5H)-tiona (4a), (5E)-6-amino-5-[4-(dimetilamino)benciliden]pirimidina-2, 4(3H,5H)-diona (5a), su análogo: 4-fluoro (5b); y el 4,6-[diamino-5-benciliden]pirimidina-2(5H)-ona (3a) con los derivados: 3,4 -dicloro (3b), 2-metoxi (3c) y 4-dimetil amina (3d) de anillo sustituido fueron sintetizados. Se evaluó la actividad anticonvulsivante y la neurotoxicidad de las 5-bencilideno pirimidinas obtenidas de 3, 4 y 5, y siguiendo las pautas indicadas en el Programa de Desarrollo de Fármacos Antiepilépticos en Desarrollo (ADD) del Departamento de Salud, de USA, que establece como modelos primarios de actividad anticonvulsivante la técnica de electroshock máximo (MES) y la prueba de Pentilenetetrazol subcutáneo (scPTZ.
URI : http://saber.ucv.ve/jspui/handle/123456789/7591
ISSN : 1316-9688.
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