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

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.