Structure-Based Design of Highly Potent HIV‑1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X‑ray Structural Studies

We describe here
design, synthesis, and biological evaluation of
a series of highly potent HIV-1 protease inhibitors containing stereochemically
defined and unprecedented tricyclic furanofuran derivatives as P2
ligands in combination with a variety of sulfonamide derivatives as
P2′ ligands. These inhibitors were designed to enhance the
ligand-backbone binding and van der Waals interactions in the protease
active site. A number of inhibitors containing the new P2 ligand,
an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl
as the P1 ligand, displayed very potent enzyme inhibitory potency
and also showed excellent antiviral activity against a panel of highly
multidrug-resistant HIV-1 variants. The tricyclic P2 ligand has been
synthesized efficiently in an optically active form using enzymatic
desymmetrization of meso-1,2-(dihydroxymethyl)­cyclohex-4-ene as the
key step. We determined high-resolution X-ray structures of inhibitor-bound
HIV-1 protease. These structures revealed extensive interactions with
the backbone atoms of HIV-1 protease and provided molecular insights
into the binding properties of these new inhibitors.