AbstractWe report 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 relative 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 lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2‐Crn‐THF ligand also showed potent enzyme Ki but significantly decreased 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.