Furofuran lignans as a new series of antidiabetic agents exerting α-glucosidase inhibition and radical scarvenging: Semisynthesis, kinetic study and molecular modeling

A new series of furofuran lignans containing catechol moiety were prepared from the reactions between lignans and a variety of phenolics. All 22 products obtained were evaluated against three different alpha-glucosidases (maltase, sucrase and Baker's yeast glucosidase) and DPPH radical. Of furofuran lignans evaluated, beta-14, having two catechol moieties and one acetoxy group, was the most potent inhibitor against Baker's yeast, maltase, and sucrase with IC50 values of 5.3, 25.7, and 12.9 mu M, respectively. Of interest, its inhibitory potency toward Baker's yeast was 28 times greater than standard drug, acarbose and its DPPH radical scavenging (SC50, 11.2 mu M) was 130 times higher than commercial antioxidant BHT. Subsequent investigation on mechanism underlying the inhibitory effect of beta-14 revealed that it blocked Baker's yeast and sucrase functions by mixed-type inhibition while it exerted non-competitive inhibition toward maltase. Molecular dynamics simulation of the most potent furofuran lignans (4, alpha-8b, alpha-14, and beta-14) with the homology rat intestinal maltase at the binding site revealed that the hydrogen bond interactions from catechol, acetoxy, and quinone moieties of furofuran lignans were the key interaction to bind tightly to alpha-glucosidase. The results indicated that beta-14 possessed promising antidiabetic activity through simultaneously inhibiting alpha-glucosidases and free radicals.