RESUMEN
We describe a novel 7-aminopyrazolo[1,5-a]pyrimidine (7-APP) derivative as a potent hepatitis C virus (HCV) inhibitor. A series of 7-APPs was synthesized and evaluated for inhibitory activity against HCV in different cell culture systems. The synthesis and preliminary structure-activity relationship study of 7-APP are reported.
Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Antivirales/química , Antivirales/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/química , Pirazoles/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The quaternary king: Azithromycin (1), which has improved pharmacological profiles compared with erythromycins, was the target of an enantioselective synthesis. All the stereogenic quaternary carbon centers were elaborated by a desymmetrization of 2-substituted glycerols using a chiral imine/CuCl(2) catalyst.
Asunto(s)
Antibacterianos/síntesis química , Azitromicina/síntesis química , Antibacterianos/química , Azitromicina/química , Catálisis , Cobre/química , Eritromicina/química , Iminas/química , EstereoisomerismoRESUMEN
We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.