RESUMEN
Carvedilol is a chiral drug with potent antihypertensive and antianginal activities. Although it is clinically used as a racemic mixture, its enantiomers show different pharmacokinetic and pharmacodynamic profiles. Here, the direct chiral separation of racemic drug by high performance liquid chromatography using two immobilized-type amylose-based chiral stationary phases is presented. Some chromatographic parameters, such as retention and selectivity, were determined under multimodal eluent conditions and different temperatures. A temperature-dependent inversion of the elution order of enantiomers was observed in the operative temperature range of chiral chromatographic support. Finally, an effective direct enantioselective method was successfully applied to the separation of the enantiomers of carvedilol on a semipreparative scale.
RESUMEN
Conformational restriction applied to dihydrobenzylpyrimidin-4-(3 H)-ones (DABOs) by the intoduction of a methyl group at the α-benzylic position is known to massively improve the anti-HIV-1 activity of these compounds. Here, we report the effects of methoxy substitution at the α-benzylic position in S-, NH-, and N, N-DABOs carrying 2,6-difluoro, 2-chloro-6-fluoro, or 2,6-dichloro substituted benzyl moieties. The various α-methoxy DABO series (12-14) present different SAR at the dihalo benzyl substitution, with the most potent compounds (12d,e and 13c) showing similar (picomolar/nanomolar) anti-HIV-1 potency as the corresponding α-methyl analogues against wt HIV-1, and 10-100-fold increased potency (up to low nanomolar) against clinically relevant K103N, Y181C, Y188L, IRLL98, and K103N+Y181C HIV-1 mutant strains, highlighting the importance of the α-methoxy substitution to provide highly efficient DABOs as "second generation" NNRTIs. HPLC enantioseparation of three of the most potent derivatives (12d, 13c, and 14c) provided single enantiomers with significant enantioselectivity in HIV-1 inhibition. Computational studies allowed to correlate the best antiviral activity with the ( R) absolute configuration at the α-methoxy stereogenic center.
Asunto(s)
Fármacos Anti-VIH/química , Pirimidinonas/química , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Sitios de Unión , Línea Celular , Farmacorresistencia Viral/efectos de los fármacos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Simulación del Acoplamiento Molecular , Mutación , Estructura Terciaria de Proteína , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Carvedilol is a chiral drug with potent antihypertensive and antianginal activities. Although it is clinically used as a racemic mixture, its enantiomers show different pharmacokinetic and pharmacodynamic profiles. Here, the direct chiral separation of racemic drug by high performance liquid chromatography using two immobilized-type amylose-based chiral stationary phases is presented. Some chromato-graphic parameters, such as retention and selectivity, were determined under multimodal eluent con-ditions and different temperatures. A temperature-dependent inversion of the elution order of enantiomers was observed in the operative temperature range of chiral chromatographic support. Finally, an effective direct enantioselective method was successfully applied to the separation of the enantiomers of carvedilol on a semipreparative scale.