RESUMEN

This paper reports the synthesis and the antiviral activities of a series of 6-arylmethyl-1-(allyloxymethyl)-5-alkyluracil derivatives, which can be viewed as analogues of the anti-HIV-1 drug emivirine (formerly MKC-442) from which they differ in the replacement of the ethoxymethyl group with variously allyloxymethyl moieties. The most active compounds N-1 allyloxymethyl- and N-1 3-methylbut-2-enyl substituted 5-ethyl-6-(3,5-dimethylbenzyl)uracils (12 and 13) showed activity against HIV-1 wild-type in the picomolar range with selective index of greater than 5 x 10(6) and activity in the submicromolar range against the clinically important Y181C and K103N mutant strains known to be resistant to emivirine. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the substitution pattern of the N-1 allyloxymethyl group.

Asunto(s)

Fármacos Anti-VIH/síntesis química , VIH-1/efectos de los fármacos , Uracilo/análogos & derivados , Uracilo/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Línea Celular , VIH-1/genética , Humanos , Espectroscopía de Resonancia Magnética , Mutación , Estereoisomerismo , Relación Estructura-Actividad , Uracilo/química , Uracilo/farmacología , Replicación Viral/efectos de los fármacos