Directed scaffold evolution of chrysin for the development of potent carboxylesterase 2 inhibitors.

The direct modification of natural products to generate novel scaffolds can greatly enrich the diversity of natural products related chemical space. Herein, we revealed a directed scaffold evolution of natural products (DSENP) strategy, featuring the combination of molecular property prediction and synthetic methodology. Following this, an enantioselective [3 + 2] heterocyclization of chrysin with chloronitroalkenes was developed to evolve the scaffold of chrysin. The pharmacology studies of the corresponding derivatives towards carboxylesterase 2 identified compounds 3g and 3s as potent and selective CES2 inhibitors. Further in vitro and in vivo studies showed that 3g could inhibit the adipogenesis in cells greatly and ameliorates HFD-induced obesity and lipid metabolic disorder in mice. Moreover, the configuration of stereogenic centers played an important role and the nitro group also contributed significantly for the potent inhibitory activity. These results indicated that the DSENP should be a promising strategy for the discovery of lead compounds.