Structure-Based Design of Highly Potent HIV‑1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X‑ray Structural Studies

We describe here design, synthesis, and biological evaluation of a series of highly potent HIV-1 protease inhibitors containing stereochemically defined and unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with a variety of sulfonamide derivatives as P2′ ligands. These in...

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Veröffentlicht in:J. Med. Chem 2020-05, Vol.63 (9), p.4867-4879
Hauptverfasser: Ghosh, Arun K, Kovela, Satish, Osswald, Heather L, Amano, Masayuki, Aoki, Manabu, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T, Mitsuya, Hiroaki
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Sprache:eng
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Zusammenfassung:We describe here design, synthesis, and biological evaluation of a series of highly potent HIV-1 protease inhibitors containing stereochemically defined and unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with a variety of sulfonamide derivatives as P2′ ligands. These inhibitors were designed to enhance the ligand-backbone binding and van der Waals interactions in the protease active site. A number of inhibitors containing the new P2 ligand, an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl as the P1 ligand, displayed very potent enzyme inhibitory potency and also showed excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The tricyclic P2 ligand has been synthesized efficiently in an optically active form using enzymatic desymmetrization of meso-1,2-(dihydroxymethyl)­cyclohex-4-ene as the key step. We determined high-resolution X-ray structures of inhibitor-bound HIV-1 protease. These structures revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insights into the binding properties of these new inhibitors.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00202