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Design, Synthesis, and X‑ray Studies of Potent HIV‑1 Protease Inhibitors with P2-Carboxamide Functionalities

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journal contribution
posted on 03.03.2020, 18:36 by Arun K. Ghosh, Alessandro Grillo, Jakka Raghavaiah, Satish Kovela, Megan E. Johnson, Daniel W. Kneller, Yuan-Fang Wang, Shin-ichiro Hattori, Nobuyo Higashi-Kuwata, Irene T. Weber, Hiroaki Mitsuya
The design, synthesis, biological evaluation, and X-ray structural studies are reported for a series of highly potent HIV-1 protease inhibitors. The inhibitors incorporated stereochemically defined amide-based bicyclic and tricyclic ether derivatives as the P2 ligands with (R)-hydroxyethylaminesulfonamide transition-state isosteres. A number of inhibitors showed excellent HIV-1 protease inhibitory and antiviral activity; however, ligand combination is critical for potency. Inhibitor 4h with a difluorophenylmethyl as the P1 ligand, crown-THF-derived acetamide as the P2 ligand, and a cyclopropylaminobenzothiazole P2′-ligand displayed very potent antiviral activity and maintained excellent antiviral activity against selected multidrug-resistant HIV-1 variants. A high resolution X-ray structure of inhibitor 4h-bound HIV-1 protease provided molecular insight into the binding properties of the new inhibitor.