Nonpeptidic HIV Protease Inhibitors: 3-(S-benzyl Substituted)-4-hydroxy-6-(phenyl Substituted)-2H-pyran-2-one with an Inverse Mode of Binding

Systematic substitutions on 6-phenyl and 3-SCH2Ph rings of inhibitor 1, were carried out to optimize the inhibitory activity against HIV PR. These studies lead to 3-Sbenzyl esters with enhanced potency. The X-ray crystal structure of 32 bound to HIV PR revealed that the 3-SCH2phenyl group is occupying the P2′ pocket, which is contrary to the binding mode of 1 (derivative lacking ortho isopropyl ester group). In the latter case, benzyl group occupies the P1′ pocket.