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

Citations Over TimeTop 10% of 2009 papers

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.

Related Papers

• → Carbonic anhydrase inhibitors: topical sulfonamide antiglaucoma agents incorporating secondary amine moieties(2000)64 cited
• → Non-peptidic HIV protease inhibitors: C2-symmetry-based design of bis-sulfonamide dihydropyrones(1998)27 cited
• → Carbonic anhydrase inhibitors: Thioxolone versus sulfonamides for obtaining isozyme-selective inhibitors?(2008)37 cited
• → Synthesis of irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone as amide bond isosteres(1997)21 cited
• → Structures of Three Inhibitor Complexes of HIV-1 Protease(1991)