A series of N-benzyl pseudopeptides was designed, synthesized and tested as HIV-1 protease inhibitors. The ability of the new compounds containing N-benzyl hydroxyalkylamino acid core structure to inhibit HIV replication in cell culture is comparable to their capacity to inhibit the isolated enzyme, a result compatible with good pharmacokinetic properties of these derivatives. The pseudotripeptide Fmoc-Leu-N(Bzl)Hse-Met-NH-tBu was the best inhibitor of the series (IC50=170 nM) showing promising inhibition of viral replication (ED50=52 nM). All new compounds exhibit high enzymatic resistance and stability against cell cultures and plasma enzymes.
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Financial support of this work by University of Ferrara and by Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST) is gratefully acknowledged.