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

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 an (S)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. Inhibitor 19b 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.

Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20

“…In the quest to identify promising inhibitors of PR20, we recently studied novel protease inhibitors with P1′-pyrrolidi-none (GRL-02031A) 28 and P2-tris-THF (GRL-0519A). 12 GRL-02031A has an enhanced P1′ group and GRL-0519A has a larger P2 group, which parallels the design strategy to fill the expanded S2 pocket of PR20.…”

“…Both these inhibitors showed added interactions with wild-type PR, together with excellent K i values and antiviral efficacy against both wild-type HIV-1 and other resistant variants. 12,28 However, GRL-02031A had weaker affinity for PR20, since the modified P1′ group forms poorer interactions with PR20 than with wild-type PR. 13 GRL-0519A with three THF rings in the P2 group fills the S2 pocket well, but its binding affinity for PR20 is essentially identical to that of darunavir.…”

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

“…The use of polar moieties at the P1’ position has also been investigated. 87, 88 Inhibitor 17 , containing a chiral methyl oxazolidinone as the P1’ ligand was synthesized. 87 Incorporation of the oxazolidinone in the P1’ position was carried out to interact with the backbone of Gly27’ and Arg8 in the S1’ pocket.…”

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1′-P2′ ligands

“…21 Early approaches of the work focused on the incorporation of 2-pyrrolidinone heterocycles with ( S )- and ( R )-configuration to promote hydrogen bonding interaction with Gly27 backbone amide NH. 27 Furthermore, we planned to incorporate N -methyl sulfonamide and alkyl ether functionalities to promote interactions with backbone atoms in the active site. The synthesis of the pyrrolidinone-containing macrocyclic inhibitors are described in Scheme 1.…”