We report here the synthesis and biological evaluation of
phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease
inhibitors and their functional effect on enzyme inhibition and antiviral
activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand
and phenylcarboxylic acids and carboxamide as the P2' ligands, showed
very potent HIV-1 protease inhibitory activity. However, carboxylic acid
containing inhibitors showed very poor antiviral activity compared to
carboxamide-derived inhibitors which showed good antiviral IC50 value.
Boronic acid-derived inhibitor with bis-THF as the P2 ligand showed very
potent enzyme inhibitory activity, but it showed relatively reduced antiviral
activity compared to darunavir in the same assay. Boronic acidcontaining
inhibitor with a P2-Crn-THF ligand also showed potent
enzyme Ki but significantly reduced antiviral activity. We have evaluated
antiviral activity against a panel of highly drug-resistant HIV-1 variants.
One of the inhibitors maintained good antiviral activity against HIVDRVRP20
and HIVDRVRP30 viruses. We have determined high resolution X-ray
structures of two synthetic inhibitors bound to HIV-1 protease and
obtained molecular insight into the ligand-binding site interactions.