81 research outputs found
Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer)
Asymmetric Syntheses and Absolute Stereochemistry of 5,6-Dihydro-α-pyrones, A New Class of Potent HIV Protease Inhibitors
The generation of C-glycosides through the enolate Claisen rearrangement
The [3,3]-sigmatropic rearrangements of silyl ketene acetals obtained from aliphatic esters of furanoid and pyranoid glycals is described. The heterocyclic γ,δ-unsaturated carboxylic acids II are produced in good yields. A new preparation of furanoid and pyranoid glycals is described
Structure-Based Design of Nonpeptidic HIV Protease Inhibitors: The Sulfonamide-Substituted Cyclooctylpyranones
Synthesis and Antifungal Activity of Rhodopeptin Analogues. 2. Modification of the West Amino Acid Moiety
An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and spread of infection.
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