Microwave-accelerated synthesis of P1′-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold

Article abstract of DOI:10.1021/jm051239z

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.