Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis

The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand–backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson–Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.