Alkoxyalkyl Esters of ( S )-9-[3-Hydroxy-2-(Phosphonomethoxy)Propyl]Adenine Are Potent Inhibitors of the Replication of Wild-Type and Drug-Resistant Human Immunodeficiency Virus Type 1 In Vitro

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Abstract
( S )-9-[3-Hydroxy-2-(phosphonomethoxy)propyl]adenine [( S )-HPMPA], is an effective broad-spectrum antiviral against many DNA viruses but has been reported to be inactive against human immunodeficiency virus (HIV). We synthesized several alkoxyalkyl esters of ( S )-HPMPA and now report that hexadecyloxypropyl-( S )-HPMPA [HDP-( S )-HPMPA] and octadecyloxyethyl-( S )-HPMPA [ODE-( S )-HPMPA]had 50% effective concentrations of 0.4 to 7.0 nanomolar and were nearly fully active against HIV variants having reverse transcriptase mutations M184V and K103N and against a zidovudine-resistant variant with mutations D67N, K70R, T215Y, and K219Q. Resistance to HDP-( S )-HPMPA and ODE-( S )-HPMPA was noted for a mutant with mutation K65R. HDP-( S )-HPMPA is also active against herpes simplex virus type 1, human cytomegalovirus, hepatitis B virus, adenoviruses, and orthopoxviruses and is worthy of further evaluation as a possibly therapy for HIV infection.

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