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. 2015 Jan;10(1):107-15.
doi: 10.1002/cmdc.201402358. Epub 2014 Oct 21.

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

Arun K Ghosh  1 , Sofiya Yashchuk, Akira Mizuno, Nilanjana Chakraborty, Johnson Agniswamy, Yuan-Fang Wang, Manabu Aoki, Pedro Miguel Salcedo Gomez, Masayuki Amano, Irene T Weber, Hiroaki Mitsuya
Affiliations

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

Arun K Ghosh et al. ChemMedChem. 2015 Jan.

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.

Keywords: HIV-1 protease; antiviral agents; blood-brain barrier; inhibitors; ligands; multidrug resistance.

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Figures

Figure 1
Figure 1
Structure of darunavir (1) and PIs 2–4.
Figure 2
Figure 2. A. GRL-05010A
-bound X-ray structure of HIV-1 protease. The major orientation of the inhibitor is shown. The inhibitor carbon atoms are shown in green, water molecules are red spheres, and the hydrogen bonds are indicated by dotted lines. B. Nonbonded interactions of gem-difluorides with the carbonyl of Gly48 in the protease flap region are shown. These interactions are indicated with respective distances.
Scheme 1
Scheme 1
Reformatskii-Claisen route to gem-difluoro derivatives 9a,b.
Scheme 2
Scheme 2
Synthesis of gem-difluoro bis-THF derivatives 12 and ent-12.
Scheme 3
Scheme 3
Synthesis of inhibitors 3, 4,19, 20and 21 with gem-difluorides.
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