RESUMEN
In this study, oxime and oxime ether derivatives of anticonvulsant nafimidone [1-(2-naphthyl)-2-(imidozole-1-yl)ethanone] were prepared as potential anticonvulsant compounds. Nafimidone oxime was synthesized by the reaction of nafimidone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) tests in mice and rats according to procedures of the Antiepileptic Drug Development (ADD) program of the National Institutes of Health (NIH). In addition to anticonvulsant evaluation, compounds were also screened for possible antibacterial and antifungal activities because of the structural resemblance to the azole antifungals, especially to oxiconazole. All compounds were evaluated against three human pathogenic fungi and four bacteria using the microdilution method. Most of the compounds exhibited both anticonvulsant and antimicrobial activities; the O-alkyl substituted compounds (2, 3, 4 and 5) were found to be more active than the O-arylalkyl substituted compounds in both screening paradigms.
Asunto(s)
Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacología , Éteres/síntesis química , Nafazolina/síntesis química , Oximas/síntesis química , Animales , Antibacterianos , Antiinfecciosos/efectos adversos , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Bacterias/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Electrochoque , Éteres/efectos adversos , Éteres/farmacología , Éteres/uso terapéutico , Hongos/efectos de los fármacos , Humanos , Isomerismo , Ratones , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Nafazolina/efectos adversos , Nafazolina/análogos & derivados , Nafazolina/farmacología , Nafazolina/uso terapéutico , Oximas/efectos adversos , Oximas/farmacología , Oximas/uso terapéutico , Pentilenotetrazol/farmacología , Ratas , Reflejo/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
The synthesis of (R)-(+)-4-methyl-2-(1-naphthylmethyl)imidazoline hydrochloride (2) and (S)-(-)-4-methyl-2-(1-naphthylmethyl)imidazoline hydrochloride (3) is presented. The synthesis involves the preparation of (R)-(+)- and (S)-(-)-1,2-diaminopropane dihydrochloride and then allowing the appropriate diaminopropane to react with ethyl 1-naphthyliminoacetate hydrochloride in the presence of triethylamine. The parent compound, naphazoline, is a potent alpha-adrenoreceptor agonist (-log ED50 = 7.22), whereas the methylated derivatives, 2 and 3, were moderately potent antagonists (pA2 = 5.6 and 5.8, respectively) of the alpha-adrenoreceptor. Compounds 2 and 3 also produced blockade of the response to histamine on the rabbit aorta, but at concentrations approximately 20 times higher than necessary to produce equal blockade of the alpha-adrenoreceptor.