Abstract
To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 μM, respectively.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alcohols / chemistry*
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Chemistry Techniques, Synthetic
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Crystallography, X-Ray
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Drug Design*
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HIV Protease / chemistry
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HIV Protease / metabolism*
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HIV Protease Inhibitors / chemical synthesis*
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HIV Protease Inhibitors / chemistry
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HIV Protease Inhibitors / pharmacology*
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Macrocyclic Compounds / chemical synthesis*
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Models, Molecular
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Protein Conformation
Substances
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Alcohols
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HIV Protease Inhibitors
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Macrocyclic Compounds
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HIV Protease
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p16 protease, Human immunodeficiency virus 1