Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors Containing a Stereochemically Unique Peptide Isostere

Article abstract of DOI:10.1021/jm00073a012

A series of HIV-1 proteinase inhibitors was synthesized based upon a single penicillin derived thiazolidine moiety.Reaction of the C-4 carboxyl group with (R)-phenylalaninol gave amide 10 which was a moderately potent inhibitor of HIV-1 proteinase (IC50=0.15 μM).Further modifications based on molecular modeling studies led to compound 48 which contained a stereochemically unique statine-based isostere.This was a potent competitive inhibitor (K_i=0.25 nM) with antiviral activity against HIV-1 in vitro (5 μM).Neither modification to the benzyl group in an attempt to improve interaction with the S'₂ pocket, nor introduction of a hydrogen bond donating group to interact with residue Gly48' resulted in improved inhibitory or antiviral activity.