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. 2015 Jul 9;58(13):5334-43.
doi: 10.1021/acs.jmedchem.5b00676. Epub 2015 Jun 24.

Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies

Arun K Ghosh  1 , Xufen Yu  1 , Heather L Osswald  1 , Johnson Agniswamy  2 , Yuan-Fang Wang  2 , Masayuki Amano  3 , Irene T Weber  2 , Hiroaki Mitsuya  3   4   5
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Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies

Arun K Ghosh et al. J Med Chem. .

Abstract

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease.

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Figures

Figure 1
Figure 1
Structures of HIV-1 protease inhibitors 1–4.
Figure 2
Figure 2
Model of inhibitor 4 (green, X = H) created based upon the X-ray structure of inhibitor 2-bound HIV-1 protease active site (PDB code: 317E).
Figure 3
Figure 3
A. X-ray structure of inhibitor 17a -bound HIV-1 protease (PDB code:4ZLS). Hydrogen bonding interactions are shown as dotted lines. B. The main van der Waals interactions of the outer 3,5-dimethoxy-phenyl group interactions of with Gly49 Thr80′ and Pro81’are shown.
Scheme 1
Scheme 1
Synthetic strategy of inhibitors with biphenyl P1-ligands
Scheme 2
Scheme 2
Synthesis of Triflate 9
Scheme 3
Scheme 3
Synthesis of functionalized biphenyl by Suzuki-Miyaura cross-coupling
Scheme 4
Scheme 4
Synthesis of P2-Inhibitors 17, 20, and 21
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