Probing Multidrug‐Resistance and Protein–Ligand Interactions with Oxatricyclic Designed Ligands in HIV‐1 Protease Inhibitors

A healthier HAART: We report the design, synthesis, biological evaluation, and X-ray crystallographic analysis of a new class of HIV-1 protease inhibitors. Compound 4 proved to be an extremely potent inhibitor toward various multidrug-resistant HIV-1 variants, representing a near 10-fold improvement over darunavir (DRV). Compound 4 also blocked protease dimerization with at least 10-fold greater potency than DRV.