Discovery, total synthesis, HRV 3C-protease inhibitory activity, and structure–activity relationships of 2-methoxystypandrone and its analogues

2-Methoxystypandrone, a naphthoquinone, was isolated from a Chinese herb Polygonum cuspidatum by bioassay guided fractionation using HRV 3C-protease assay. It showed an IC 50 value of 4.6 μM and is moderately selective. A new 10-step, total synthesis of 2-methoxystypandrone was accomplished in 45% overall yield using a Diels–Alder approach. Several analogues of this compound were prepared. Isolation, synthesis and HRV 3C-protease structure–activity relationships of these compounds have been described. Discovery, a new total synthesis employing Diels–Alder method, HRV 3C-protease inhibitory activity, and SAR of methoxystypandrone has been described.