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Design of substituted bis-Tetrahydrofuran (bis-THF)-derived Potent HIV-1 Protease Inhibitors, Protein-ligand X-ray Structure, and Convenient Syntheses of bis-THF and Substituted bis-THF Ligands.

ABSTRACT: We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (K(i) = 2.9 pM; IC(50) = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC3325757 | BioStudies | 2011-01-01

REPOSITORIES: biostudies

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Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors.

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2014-01-01 | S-EPMC4068604 | BioStudies

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Project description: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.

2015-01-01 | S-EPMC4419590 | BioStudies

Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies.

Project description:Structure-based design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidinone and methyl oxazolidinone as the P1'-ligands. These ligands are designed to interact with Gly-27' carbonyl and Arg-8 side chain in the S1'-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with a (R)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. This inhibitor maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b-bound HIV-1 protease revealed that the P1'-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1' and S2 subsites of HIV-1 protease.

2009-01-01 | S-EPMC2745609 | BioStudies

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