Synthesis of chalcone derivatives as AMPK activators

Abstract

Diabetes and diabetic nephropathy are two noticeable disorders in modern life. Chalcones are considered as a feasible candidate for these medication disorders due to the capability to activate AMPK relating to these two diseases. A series of chalcones with A-ring possessing 2'-hydroxy-, 3',4',5'-trimethoxyacetophenones or other types and B-ring decorated with mono-, di-, trisubstitution were accomplished by Claisen–Schmidt, etherification and hydrogenation reactions in almost moderate to high yield. 3-Methoxy group was found to be the best substituent for the activity in case of monosubstitution on B-ring. 3,4-Dimethoxy and 3,4-methylenedioxy groups on B-ring (63 and 65) enhanced the activity of disubstituted chalcones significantly, implying the important role of 3,4-disubstitution on B-ring for the activity. A-ring with 3',4',5'-trimethoxy group made chalcones less active than that with 2'-hydroxy group. Two dihydrochalcones (121 and 122) exhibited comparable potency to 63. Four chalcones (63, 65, 121 and 122) were selected to determine the concentration-response relationship and EC50 values. The chalcone 121, considered as the most potent candidate with the lowest EC50 and cytotoxicity, should be used for further studies.