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Design,Synthesis and X-Ray Structural Studies of Potent HIV-1 Protease Inhibitors Containing C-4 Substituted Tricyclic Hexahydro-Furofuran Derivatives as P2 Ligands |
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| Authors: | Prof. Arun K. Ghosh Dr. Satish Kovela Dr. Ashish Sharma Dr. Dana Shahabi Ajay K. Ghosh Denver R. Hopkins Monika Yadav Megan E. Johnson Dr. Johnson Agniswamy Yuan-Fang Wang Dr. Shin-Ichiro Hattori Dr. Nobuyo Higashi-Kuwata Dr. Manabu Aoki Dr. Masayuki Amano Prof. Irene T. Weber Dr. Hiroaki Mitsuya |
| Affiliation: | 1. Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 USA;2. Departments of Biology and Chemistry, Molecular Basis of Disease, Georgia State University, Atlanta, GA 30303 USA;3. Department of Refractory Viral Infections, National Center for Global Health & Medicine Research Institute, Shinjuku, Tokyo 162-8655 Japan;4. Departments of Hematology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto, 860-8556 Japan;5. Departments of Hematology and Infectious Diseases, School of Medicine, Kumamoto University, Kumamoto, 860-8556 Japan Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD 20892 USA Center for Clinical Sciences, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan Department of Refractory Viral Infections, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655 Japan |
| Abstract: | The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2′ ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2′ ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted. |
| Keywords: | antiviral agents backbone binding HIV-1 protease inhibitors multidrug-resistance |