Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands
Journal Article
·
· Bioorganic and Medicinal Chemistry Letters
- Purdue Univ., West Lafayette, IN (United States)
- Georgia State Univ., Atlanta, GA (United States)
- Kumamoto Univ. of Medicine (Japan)
- Kumamoto Univ. of Medicine (Japan); National Inst. of Health (NIH), Bethesda, MD (United States); National Center for Global Health and Medicine, Tokyo (Japan)
Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. Lastly, these compounds showed excellent HIV-1 protease inhibitory (Ki = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- National Inst. of Health
- Grant/Contract Number:
- GM53386; GM62920
- OSTI ID:
- 1409115
- Journal Information:
- Bioorganic and Medicinal Chemistry Letters, Vol. 27, Issue 21; ISSN 0960-894X
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Cited by: 6 works
Citation information provided by
Web of Science
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