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In this work, we have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar tomore » those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.« less

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Furthermore, two high resolutionmore » X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.« less

A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1' pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1' ligand and a bis-THF P2 ligand, proved to be the most potent of the series. Lastly, the cLogP value of inhibitor 15d is improved compared to inhibitor 2more » with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor–protein interaction.« less

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand–binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolutionmore » X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand–binding site interactions are possibly responsible for their potent activity.« less