title: 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.
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.
authors.affiliation: Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907 (USA). akghosh@purdue.edu.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Sofiya
authors.initials: S
authors.lastname: Yashchuk
authors.forename: Akira
authors.initials: A
authors.lastname: Mizuno
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Chakraborty
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.forename: Pedro Miguel Salcedo
authors.initials: PM
authors.lastname: Gomez
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005838:Genotype; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism
chemical_list: D005663:Furans; D017320:HIV Protease Inhibitors; D008024:Ligands; C018674:tetrahydrofuran; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1
keywords: HIV-1 protease; antiviral agents; blood-brain barrier; inhibitors; ligands; multidrug resistance