1-(Ethoxymethyl)-6-(Phenylselenenyl)Pyrimidines with Activity against Human Immunodeficiency Virus Types 1 and 2

Abstract

The reaction of chloromethyl ethyl ether with bis(trimethylsilyl)uracil derivatives yield 1-(ethoxymethyl)pyrimidines 1a–d in good yield. Lithiation of 1a–d with lithium diisopropylamide at −78°C, followed by reaction with diphenyl diselenide as an electrophile, gave 1-(ethoxymethyl)-6-(phenylselenenyl)ura-cils 2a–d in 70–80% yield. The 6-phenylselenenyl acyclic pyrimidines 2b and 2d exhibited selective in vitro activity against HIV-1 and HIV-2 in primary human lymphocytes. The most potent compound was 1-(ethoxymethyl)-6-(phenylselenenyl)-5-ethyluracil 2d with a median effective concentration of 17 nM in primary human lymphocytes and no discernable cytotoxicity in these cells or rapidly dividing CEM and Vero cells. Well characterized AZT-resistant virus was modestly (3 to 12-fold increase) cross-resistant to compounds 2b and 2d.