Design and synthesis of highly potent HIV-1 protease inhibitors and the development of synthetic methods for benzofused oxabicyclooctanes and nonanes

Substituted bis-THF containing protease inhibitors were designed to optimize ligand-enzyme interaction within the active site of the HIV protease. The [2,3]-sigmatropic rearrangement was used to gain access to the bis-THF ligand and C3-substituted bis-THF ligands. Incorporation of these ligands into the hydroxyethylamine isostere led to a series of highly potent HIV-1 protease inhibitors. Inhibitor 59f and 59g were the most potent among the O-substituted inhibitors. An X-ray structure of 59f -bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly48 amide NH in the S2-subsite. Evaluation of C4-amine bis-THF containing protease inhibitor 75c revealed the presence of a direct hydrogen bond interaction with the C3-NH and the carbonyl of Gly48. The [2,3]-sigmatropic rearrangement has been applied to the synthesis of tetrahydropyran-tetrahydrofuran (Tp-THF) and C3-substituted Tp-THF ligands. Tp-THF containing protease inhibitors were designed to optimize ligand-enzyme interaction within the enzyme active site of the HIV protease. Incorporation of these ligands led to a series of highly potent HIV-1 protease inhibitors. Presumably, the increased activity observed for these inhibitors results from an increased network of hydrogen bonds within the S 2-subsite of the enzyme active site. Inhibitor 105b, 105h displayed the most significant result when evaluated in enzymatic and cellular assays. C3 amine containing protease inhibitors 105n and 105o 105n had a Ki = 0.9 pM and 105o had a Ki=1.3 nM. Continuing our studies in probing the enzyme active site a convenient synthesis of substituted benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives were developed. The reaction involved a TiCl 4-mediated tandem carbonyl or imine addition followed by an intramolecular Friedel-Crafts cyclization to give these functionalized derivatives in good to excellent yields and high diastereoselectivity. The X-ray crystal structure of 144b provided valuable information about the relative stereochemistry of these compounds

TiCl₄-Promoted Tandem Carbonyl or Imine Addition and Friedel–Crafts Cyclization: Synthesis of Benzo-Fused Oxabicyclooctanes and Nonanes

A new and convenient synthesis of benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives are described. The reaction involved a TiCl₄-mediated tandem carbonyl or imine addition followed by a Friedel–Crafts cyclization to provide these functionalized derivatives in good to excellent yields and high diastereoselectivity

TiCl₄-Promoted Tandem Carbonyl or Imine Addition and Friedel–Crafts Cyclization: Synthesis of Benzo-Fused Oxabicyclooctanes and Nonanes

A new and convenient synthesis of benzo-fused 8-oxabicyclo[3.2.1]octane and 9-oxabicyclo[4.2.1]nonane derivatives are described. The reaction involved a TiCl₄-mediated tandem carbonyl or imine addition followed by a Friedel–Crafts cyclization to provide these functionalized derivatives in good to excellent yields and high diastereoselectivity

Highly Potent HIV‑1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X‑ray Studies

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors <b>16a</b> and <b>16f</b> showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors <b>16a</b> and <b>16f</b> maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of <b>16a</b>-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles

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 <b>25f</b>, <b>25i</b>, and <b>25j</b> 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 <b>25f</b>- and <b>25g</b>-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