LAUSR

The structure‐based design, synthesis, and biological evaluation of a series of nonpeptidic HIV‐1 protease inhibitors with rationally designed P2′ ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2′ subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2′ ligands was set by asymmetric reduction of the corresponding ketone using (R,R)‐ or (S,S)‐Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme Ki values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir‐resistant HIV‐1 variants. An X‐ray structure of inhibitor 3g in complex with HIV‐1 protease revealed key interactions in the S2′ subsite.