RESUMEN
Some novel derivatives of 2-alkyl 6-substituted pyridazin-3(2H)-ones were synthesized by condensation of 3,6-dichloropyridazine with the sodium salt of benzyl cyanide, followed by hydrolysis and coupling with alkyl halides. The synthesized compounds were screened as cyclooxygenase (COX)-1/COX-2 inhibitors and as analgesic and anti-inflammatory agents. Among the synthesized compounds, 6-benzyl-2-methylpyridazin-3(2H)-one (4a), 6-benzoyl-2-propylpyridazin-3(2H)-one (8b), and 6-(hydroxy(phenyl)methyl)-2-methylpyridazin-3(2H)-one (9a) displayed the highest COX-2 selectivity indices of 96, 99, and 98, respectively, and analgesic efficacies of 47%, 46%, and 45% protection, respectively. Also, compounds 4a, 8b, and 9a showed anti-inflammatory activities of 65%, 60%, and 62% inhibition of edema, respectively, at a dose of 10 mg/kg, which is higher than that of diclofenac (58% inhibition of edema).
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Conducta Animal/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Edema/tratamiento farmacológico , Piridazinas/farmacología , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Ratas , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
1-Substiuted 6-(3-cyanobenzoyl) and [(3-cyanophenyl)fluoromethyl]-5-ethyl-uracils were synthesized and evaluated in cell-based assays against HIV-1 wild-type and its clinically relevant non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants. Some of the synthesized compounds showed activity against HIV-1 wild-type in the same range as Emivirine (MKC-442). 3-{[3-(Allyloxymethyl)-5-ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]fluoromethyl}-benzonitrile 11b showed moderate activity against the Y181C HIV-1 mutant strain.