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. 2013 Sep 12;56(17):6792-802.
doi: 10.1021/jm400768f. Epub 2013 Aug 15.

Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies

Arun K Ghosh  1 , Garth L Parham, Cuthbert D Martyr, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Yuan-Fang Wang, Masayuki Amano, Irene T Weber, Hiroaki Mitsuya
Affiliations

Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies

Arun K Ghosh et al. J Med Chem. .

Abstract

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.

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Figures

Figure 1
Figure 1
Structures of protease inhibitors 1–3.
Figure 2
Figure 2
Stereoview of the X-ray structure of inhibitor 16a-bound HIV-1 protease (PDB code: 4KB9). All strong hydrogen bonding interactions are shown as dotted lines.
Figure 3
Figure 3
Stereoview of the overlay X-ray structures of inhibitor 16a (green)-bound HIV-1 protease (PDB code: 4KB9) and 1 (magenta)-bound HIV-1 protease (PDB code: 3OK9). All strong hydrogen bonding interactions of inhibitor 1 are shown as dotted lines.
Scheme 1
Scheme 1
Synthesis of tricyclic ligands.
Scheme 2
Scheme 2
Synthesis of benzoate ester 12 and its structure in ORTEP diagram
Scheme 3
Scheme 3
Synthesis of heteroatom substituted tricyclic P2-ligands
Scheme 4
Scheme 4
ORTEP diagram of syn-anti-syn compound 13
Scheme 5
Scheme 5
Synthesis of inhibitors 16a–i
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