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

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 angstrom verifies the modeling predictions.