HIV-1 protease inhibitors containing an N-hydroxyamino acid core structure

Two series of peptidomimetics containing an N-hydroxyamino acid core structure were prepared by mixed solution solid-phase synthesis and tested for inhibitory activity against the human immunodeficiency virus (HIV-1) protease (Pr) and the virus in cell culture. In general, N-hydroxy Gly containing pseudopeptides displayed modest HIV Pr inhibition (IC50≥930 nM). In the N-hydroxy Phe derivatives, Fmoc-Phe-ψ[CO–N(OH)]-Phe-Pro-NHtBu was the best inhibitor of the series (IC50=144 nM) showing satisfactory inhibition of HIV replication in cell culture (ED50=98 nM) and remarkable stability against cell culture and plasma enzymes.