Synthesis and structure–activity relationship of α-keto amides as enterovirus 71 3C protease inhibitors

α-Keto amide derivatives as enterovirus 71 (EV71) 3C protease (3Cpro) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure–activity relationship (SAR) study indicated that small moieties were primarily tolerated at P1′ and the introduction of para-fluoro benzyl at P2 notably improved the potency of inhibitor. Inhibitors 8v, 8w and 8x exhibited satisfactory activity (IC50 = 1.32 ± 0.26 μM, 1.88 ± 0.35 μM and 1.52 ± 0.31 μM, respectively) and favorable CC50 values (CC50 > 100 μM). α-Keto amide may represent a good choice as a warhead for EV71 3Cpro inhibitor.