Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.

J Med Chem 2017 05 18;60(10):4267-4278. Epub 2017 Apr 18.

Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556, Japan.

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. Two high resolution 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.

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http://dx.doi.org/10.1021/acs.jmedchem.7b00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605781PMC
May 2017
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