A new structural theme in C2-symmetric HIV-1 protease inhibitors: ortho-substituted P1/P1' side chains |
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Authors: | Wannberg Johan Sabnis Yogesh A Vrang Lotta Samuelsson Bertil Karlén Anders Hallberg Anders Larhed Mats |
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Institution: | Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden. |
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Abstract: | 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. |
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