Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1'phenyl substituents: X-ray crystal structure assisted design

Article abstract of DOI:10.1021/jm00088a003

By tethering of a polar hydrophilic group to the P₁ or P₁' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.