Synthesis of Novel N-1 (Allyloxymethyl) Analogues of 6-Benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, Emivirine) with Improved Activity Against HIV-1 and Its Mutants

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 (<BO>12</BO> and <BO>13</BO>) showed activity against HIV-1 wild-type in the picomolar range with selective index of greater than 5 × 10⁶ 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.