P1′ oxadiazole protease inhibitors with excellent activity against native and protease inhibitor-resistant HIV-1

HIV-1 protease inhibitors (PI’s) bearing 1,3,4-oxadiazoles at the P1′ position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1′ heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.