Prenylated Isoflavones Originating from East African Medicinal Plants Selectively Modulate the α-Glucosidase from...

Nine naturally occurring prenylated isoflavones and three nonnatural analogues were synthesized for the first time. The 12 newly synthesized and 11 previously synthesized isoflavones were tested for their activity as modulators of Saccharomyces cerevisiae α-glucosidase. Out of the 23 prenylated isoflavones tested in total, 4',7-dihydroxy-3',5'-diprenylisoflavone (26) and 8-prenyldaidzein (28), both secondary plant metabolites originally isolated from Psoralea corylifolia, were found to be the most potent inhibitors of S. cerevisiae α-glucosidase, with IC₅₀ values of 7.8 ± 2.3 μM and 14.6 ± 5.1 μM, respectively. Kinetic analysis revealed that 26 acts through a noncompetitive mechanism and 28 through an uncompetitive mechanism of inhibition. Surprisingly, a few of the compounds tested, in particular isoflavones with a 6,7- and 3',4'-dioxy substitution pattern, were found to be activators of S. cerevisiae α-glucosidase. The most notable effects in this regard were observed for predurallone (21c), a secondary plant metabolite originally isolated from Millettia dura, and its nonnatural analogue 7-methylpredurallone (22c). At a concentration of 50 μM, both compounds enhanced the activity of S. cerevisiae α-glucosidase by 53.7 ± 8.8% and 41.5 ± 8.2%, respectively. To the best of our knowledge, these are the first examples of small molecule activators of this enzyme.