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Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X-ray Studies

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Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, United States
§ Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States
*E-mail: [email protected]; Phone: (765)-494-5323; Fax: (765)-496-1612.
Cite this: J. Med. Chem. 2013, 56, 17, 6792–6802
Publication Date (Web):August 15, 2013
Copyright © 2013 American Chemical Society
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Abstract Image

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles.

Supporting Information

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HPLC and HRMS data for inhibitors 16a16i. Crystallographic data collection and refinement statistics for inhibitor 16a. This material is available free of charge via the Internet at

Accession Codes

The PDB accession code for 16a-bound HIV-1 protease X-ray structure is 4KB9.

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