Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies

Abstract

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.

Figure 1

Structure of HIV-1 protease inhibitors 1–4 and 25j.

Figure 2

A. X-ray structure of inhibitor 25f-bound HIV-1 protease (PDB code: 5BRY). Hydrogen bonding interactions are shown as dotted lines. B. The main backbone interactions with Gly48 in the flap region and Asp29 and Asp30 in the S2 subsite are shown.

Scheme 1

Synthesis of azido bis-THF derivatives

Scheme 2

Synthesis of various C4-amino bis-THF derivatives

Scheme 3

Synthesis of various aminoalcohol derivatives

Scheme 4

Synthesis of active carbonates of bis-THF ligands

Scheme 5

Synthesis of HIV-1 protease inhibitors 25a–l