Design of HIV‑1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein–Ligand X‑ray Studies

• Published in: Journal of medicinal chemistry Vol. 58; no. 17; pp. 6994 - 7006
• Main Authors: Ghosh, Arun K., Martyr, Cuthbert D., Osswald, Heather L., Sheri, Venkat Reddy, Kassekert, Luke A., Chen, Shujing, Agniswamy, Johnson, Wang, Yuan-Fang, Hayashi, Hironori, Aoki, Manabu, Weber, Irene T., Mitsuya, Hiroaki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.09.2015; Amer Chemical Soc
• Subjects: Binding Sites; Chemistry, Medicinal; Crystallography, X-Ray; Drug Resistance, Multiple, Viral; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - genetics; Hydrogen Bonding; Life Sciences & Biomedicine; Ligands; Models, Molecular; Pharmacology & Pharmacy; Protein Binding; Science & Technology; Stereoisomerism; MORTALITY; IN-VITRO; DARUNAVIR; RESOLUTION CRYSTAL-STRUCTURES; REPLICATION; THERAPY; 2,3 WITTIG REARRANGEMENT; DRUG-RESISTANT MUTANTS; ASYMMETRIC INDUCTION; BARRIER
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00900

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 resolution 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.