α-Glucosidase inhibition of 6-hydroxyflavones. Part 3: Synthesis and evaluation of 2,3,4-trihydroxybenzoyl-containing flavonoid analogs and 6-aminoflavones as α-glucosidase inhibitors

Abstract The SAR studies suggested that the C-ring of baicalein ( 1 ) was not necessary for the activity, and validated the importance of 2,3,4-trihydroxybenzoyl structure of 1 . Thus, a series of 2,3,4-trihydroxybenzoyl-containing flavonoid analogs were investigated for the α-glucosidase inhibitory activity. The results indicated that 5,6,7-trihydroxy-2-phenyl-4-quinolone ( 2 ) and 5,6,7-trihydroxyflavanone ( 4 ) showed the comparable activity to 1 , while 3,5,6,7-tetrahydroxyflavone ( 7 ), 5,6,7-trihydroxyisoflavone ( 8 ), and 6-hydroxygenistein ( 9 ) showed moderate α-glucosidase inhibitory activity. In addition, it was found that 6-amino-5,7-dihydroxyflavone ( 16 ) was a more potent and specific rat intestinal α-glucosidase inhibitor than 1 , and showed the comparable activity to acarbose. This is the first report on mammalian intestinal α-glucosidase inhibitory activity of 6-aminoflavones. Kinetic studies revealed that 16 inhibited both sucrose- and maltose-hydrolyzing activities of rat intestinal α-glucosidase uncompetitively.