A new structural theme in C2-symmetric HIV-1 protease inhibitors: ortho-Substituted P1/P1′ side chains

In this report, the rapid syntheses of 24 novel C2-symmetric HIV-1 protease inhibitors are described. Two ortho-iodobenzyloxy containing C-terminal duplicated inhibitors served as starting materials for microwave-enhanced palladium(0)-catalyzed carbon–carbon bond forming reactions (Suzuki, Sonogashira, Heck, and Negishi). Highly potent inhibitors equipped with ortho-functionalized P1/P1′ side chains as the structural theme were identified. Computational efforts were applied to study the binding mode of this class of inhibitors and to establish structure–activity relationships. The overall orientation of the inhibitors in the active site was reproduced by docking which suggested three possible conformations of the P1/P1′ groups of which two seem more plausible.

The syntheses of 24 novel HIV-1 protease inhibitors are presented. Computational methods were applied to rationalize the SAR.Figure optionsDownload as PowerPoint slide