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. 2011 Apr 14;2(4):298-302.
doi: 10.1021/ml100289m.

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

Arun K Ghosh  1 , Cuthbert D Martyr, Melinda Steffey, Yuan-Fang Wang, Johnson Agniswamy, Masayuki Amano, Irene T Weber, Hiroaki Mitsuya
Affiliations

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

Arun K Ghosh et al. ACS Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
Structures of protease inhibitors 1−3.
Scheme 1
Scheme 1. Synthesis of Bis-THF Ligand 11
Scheme 2
Scheme 2. Syntheses of Substituted Bis-THF Ligands
Scheme 3
Scheme 3. Syntheses of Protease Inhibitors
Figure 2
Figure 2
Stereoview of the X-ray structure of inhibitor 23c (green)-bound HIV-1 protease (pdb code: 3QAA). All strong hydrogen bonding interactions are shown as dotted lines.
See this image and copyright information in PMC

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