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. 2009 Jul 9;52(13):3902-14.
doi: 10.1021/jm900303m.

Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies

Arun K Ghosh  1 , Sofiya Leshchenko-Yashchuk, David D Anderson, Abigail Baldridge, Marcus Noetzel, Heather B Miller, Yunfeng Tie, Yuan-Fang Wang, Yasuhiro Koh, Irene T Weber, Hiroaki Mitsuya
Affiliations

Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1'-ligands to enhance backbone-binding interactions with protease: synthesis, biological evaluation, and protein-ligand X-ray studies

Arun K Ghosh et al. J Med Chem. .

Abstract

Structure-based design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidinone and methyl oxazolidinone as the P1'-ligands. These ligands are designed to interact with Gly-27' carbonyl and Arg-8 side chain in the S1'-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with a (R)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. This inhibitor maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b-bound HIV-1 protease revealed that the P1'-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1' and S2 subsites of HIV-1 protease.

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Figures

Figure 1
Figure 1
Structures of inhibitors 1–4.
Figure 2
Figure 2
A stereoview of the major conformation of the X-ray structure of inhibitor 19b–bound HIV-1 protease.
Figure 3
Figure 3
Protease interactions with the two alternate conformations of the inhibitor pyrrolidine ring. The inhibitor is in green bonds with thick bonds for the major and thin bonds for the minor conformations of the pyrrolidine ring. Hydrogen bonds are shown in dotted lines. Distances between donor and acceptor atoms are shown in Å.
Scheme 1
Scheme 1
Synthesis of lactam containing sulfonamide isosteres
Scheme 2
Scheme 2
Synthesis of lactam containing PIs
Scheme 3
Scheme 3
Synthesis of sulfonamide isosteres with P1′-oxazolidinone
Scheme 4
Scheme 4
Synthesis of oxazolidinone-derived PIs.
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