Structure-Based Design of Potent HIV‑1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X‑ray Structural Studies

We
report the design, synthesis, X-ray structural studies, and biological
evaluation of a novel series of HIV-1 protease inhibitors. We designed
a variety of functionalized biphenyl derivatives to make enhanced
van der Waals interactions in the S1 subsite of HIV-1 protease. These
biphenyl derivatives were conveniently synthesized using a Suzuki–Miyaura
cross-coupling reaction as the key step. We examined the potential
of these functionalized biphenyl-derived P1 ligands in combination
with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl
urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1′-biphenyl
derivative as P1 ligand and bis-THF as the P2 ligand, displayed the
most potent enzyme inhibitory and antiviral activity. This inhibitor
also exhibited potent activity against a panel of multidrug-resistant
HIV-1 variants. A high resolution X-ray crystal structure of related
Boc-derivative 17a-bound HIV-1 protease provided important
molecular insight into the ligand-binding site interactions of the
biphenyl core in the S1 subsite of HIV-1 protease.