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Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Dec 10; Vol. 52 (23), pp. 7689-705. - Publication Year :
- 2009
-
Abstract
- The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
Cell Line
Crystallography, X-Ray
Drug Design
HIV Protease genetics
HIV Protease metabolism
HIV Protease Inhibitors chemical synthesis
HIV-1 drug effects
HIV-1 genetics
Humans
Ligands
Macrocyclic Compounds chemical synthesis
Models, Molecular
Molecular Conformation
Mutation
Drug Resistance, Viral drug effects
HIV Protease chemistry
HIV Protease Inhibitors chemistry
HIV Protease Inhibitors pharmacology
HIV-1 enzymology
Macrocyclic Compounds chemistry
Macrocyclic Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19746963
- Full Text :
- https://doi.org/10.1021/jm900695w