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. 2018 Dec 5:160:171-182.
doi: 10.1016/j.ejmech.2018.09.046. Epub 2018 Sep 18.

Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

Arun K Ghosh  1 , Ravindra D Jadhav  2 , Hannah Simpson  2 , Satish Kovela  2 , Heather Osswald  2 , Johnson Agniswamy  3 , Yuan-Fang Wang  3 , Shin-Ichiro Hattori  4 , Irene T Weber  3 , Hiroaki Mitsuya  5
Affiliations

Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

Arun K Ghosh et al. Eur J Med Chem. .

Abstract

We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.

Keywords: Design and synthesis; Drug resistance; HIV-1 protease inhibitors; P2 ligand; X-ray crystal structure.

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Figures

Figure 1.
Figure 1.
Structure of protease inhibitors 1-3, 4e.
Figure 2.
Figure 2.
Stereoview of the X-ray structure of inhibitor 4d (turquoise)-bound HIV-1 protease (PDB code: 6DV0). All strong active site hydrogen bonding interactions of inhibitor 4d with HIV-1 protease are shown as dotted lines.
Figure 3.
Figure 3.
Stereoview of the X-ray structure of inhibitor 4k (green)-bound HIV-1 protease (PDB code: 6DV4). All strong active site hydrogen bonding interactions of inhibitor 4k with HIV-1 protease are shown as dotted lines.
Scheme 1.
Scheme 1.
4-Aminothiochromane-6-carboxylic acid.
Scheme 2.
Scheme 2.
Synthesis of 8-amino-5-hydroxy-tetrahydronaphthalene-2-carboxylic acid.
Scheme 3.
Scheme 3.
Synthesis of protease inhibitors 4a-f.
Scheme 4.
Scheme 4.
Synthesis of protease inhibitors 4g-f.
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