Microwave-Accelerated Synthesis of P1‘-Extended HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol in the Transition-State Mimicking Scaffold

Two series of P1‘-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting K i values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1‘ side chain. High cellular antiviral potencies were encountered when the P1‘ benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18−0.22 μM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.