ArticleChemMedChem2015
Design of gem-difluoro-bis-tetrahydrofuran as P2 ligand for HIV-1 protease inhibitors to improve brain penetration: synthesis, X-ray studies, and biological evaluation.
Article in ChemMedChem, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Recent Advances in Heterocyclic HIV Protease Inhibitors.International journal of molecular sciences · 2025Review
- Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.Chemical communications (Cambridge, England) · 2022Review
- Fluorine Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier Penetration Property of Novel Central Nervous System-Targeting HIV-1 Protease InhibitorsAntimicrobial agents and chemotherapy · 2022Article
- Management of Antiretroviral Therapy with Boosted Protease Inhibitors-Darunavir/Ritonavir or Darunavir/Cobicistat.Biomedicines · 2021Review
- Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20.Biochemical and biophysical research communications · 2019Article
- Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications.Antimicrobial agents and chemotherapy · 2019Article
- Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease.ACS omega · 2018Article
- Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors.Asian journal of organic chemistry · 2018Article
- Article
- HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain-Penetrating Protease Inhibitors for Antiretroviral Treatment.Medical research archives · 2017Article
- A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413.Antimicrobial agents and chemotherapy · 2016Article
- Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.Journal of medicinal chemistry · 2016Review
- Conformational variation of an extreme drug resistant mutant of HIV protease.Journal of molecular graphics & modelling · 2015Article
- Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies.Journal of medicinal chemistry · 2015Article
- Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20.Journal of medicinal chemistry · 2015Article
- Highly resistant HIV-1 proteases and strategies for their inhibition.Future medicinal chemistry · 2015Review
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11 authors.
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Abstract
The structure-based design, synthesis, biological evaluation, and X-ray structural studies of fluorine-containing HIV-1 protease inhibitors are described. The synthesis of both enantiomers of the gem-difluoro-bis-THF ligands was carried out in a stereoselective manner using a Reformatskii-Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl) carbamate (3) and (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-aminophenyl)sulfonamido)phenylbutan-2-yl) carbamate (4), exhibited HIV-1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV-1LAI . The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood-brain barrier permeability in an in vitro model. A high-resolution X-ray structure of inhibitor 4 in complex with HIV-1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV-1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis-THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.
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