RESUMO
A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Tiofenos/química , Tiofenos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Células CACO-2 , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Modelos Químicos , Estrutura Terciária de Proteína , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Insights gained from a crystal structure of scytalone dehydratase led to the design of carboxamide inhibitors with a phenoxypropyl group substituted on the nitrogen atom Potent enzyme inhibitors were synthesized around this motif, the best of which provided excellent control of rice blast disease in greenhouse assays and outdoor field trials.
Assuntos
Antifúngicos/síntese química , Hidroliases/antagonistas & inibidores , Cristalografia por Raios X , Ciclopropanos/química , Desenho de Fármacos , Cinética , Modelos Químicos , Modelos Moleculares , Doenças das Plantas , Tirfostinas/químicaRESUMO
The strength of hydralazine hydrochloride (I) 10 mg tablets, containing starch as an excipient, decreases significantly with time. An investigation to determine the basis for the drop in strength showed that starch exposed to the drug exhibited fluorescence at 414 nm. As model compounds IIIa and V, which contain a triazolophthalazinyl moiety, also fluoresce at about 414 nm, it is proposed that the emission is due to a triazolophthalazine derivative (IIIc) resulting from hydralazine hydrochloride and starch. Degradation of IIIc generates s-triazolo[3,4-a]phthalazine (IIIb), and a small amount of IIIb is detected in aged tablets. IIIc in aged tablets can be converted to IIIb by acid-catalyzed hydrolysis. The quantity of IIIb determined by HPLC amounts to most of the "missing" hydralazine hydrochloride. The reaction between hydralazine hydrochloride and starch is believed to cause the unexpected drop in the strength of hydralazine hydrochloride tablets.
Assuntos
Hidralazina/química , Preparações Farmacêuticas/química , Amido/química , Cromatografia Líquida de Alta Pressão , FluorescênciaRESUMO
C9H12O3, Mr = 168.2, triclinic, P1, a = 5.5385 (6), b = 8.543 (1), c = 10.373 (1) A, alpha = 113.329 (9), beta = 100.78 (1), gamma = 99.82 (1) degree, V = 426.2 (2) A3, Dx = 1.31 g cm-3, Z = 2, Cu K alpha (lambda = 1.54178 A, graphite monochromator), mu = 8.2 cm-1, F(000) = 180, T = 293 K. Final R = 0.036, wR = 0.081 for 1559 reflections with I greater than 3 sigma(I). The relative configurations at the two chiral centers are (S,R). The dihedral angle between the five- and six-membered rings (O1--C4--C5--O3) is 69.9 (1) degree. The tetrahydropyran is in a chair conformation with the furanone ring equatorial.
