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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
 [1];  [1];  [1];  [1];  [2];  [2];  [3];  [3];  [2];  [4]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. of Medicine (Japan)
  4. Kumamoto Univ. of Medicine (Japan); National Inst. of Health (NIH), Bethesda, MD (United States); National Center for Global Health and Medicine, Tokyo (Japan)
+ Show Author Affiliations
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
OSTI ID:
1409115
Journal Information:
Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: 21 Vol. 27; ISSN 0960-894X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Diversity-Oriented Synthesis of Diol-Based Peptidomimetics as Potential HIV Protease Inhibitors and Antitumor Agents journal July 2018
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60 APPLIED LIFE SCIENCES
HIV protease
P1′-P2′ ligands
drug resistance
macrocyclic inhibitors
structure-based design