α‐Glucosidase Inhibition by Usnic Acid Derivatives

This study investigated a set of new potential antidiabetes agents. Derivatives of usnic acid were designed and synthesized. These analogs and nineteen benzylidene analogs from a previous study were evaluated for enzyme inhibition of α‐glucosidase. Analogs synthesized using the Dakin oxidative method displayed stronger activity than the pristine usnic acid (IC 50 >200 μM). Methyl (2 E ,3 R )‐7‐acetyl‐4,6‐dihydroxy‐2‐(2‐methoxy‐2‐oxoethylidene)‐3,5‐dimethyl‐2,3‐dihydro‐1‐benzofuran‐3‐carboxylate ( 6b ) and 1,1′‐(2,4,6‐trihydroxy‐5‐methyl‐1,3‐phenylene)di(ethan‐1‐one) ( 6e ) were more potent than an acarbose positive control (IC 50 93.6±0.49 μM), with IC 50 values of 42.6±1.30 and 90.8±0.32 μM, respectively. Most of the compounds synthesized from the benzylidene series displayed promising activity. (9b R )‐2,6‐Bis[(2 E )‐3‐(2‐chlorophenyl)prop‐2‐enoyl]‐3,7,9‐trihydroxy‐8,9b‐dimethyldibenzo[ b , d ]furan‐1(9b H )‐one ( 1c ), (9b R )‐3,7,9‐trihydroxy‐8,9b‐dimethyl‐2,6‐bis[(2 E )‐3‐phenylprop‐2‐enoyl]dibenzo[ b , d ]furan‐1(9b H )‐one ( 1g ), (9b R )‐2‐acetyl‐6‐[(2 E )‐3‐(2‐chlorophenyl)prop‐2‐enoyl]‐3,7,9‐trihydroxy‐8,9b‐dimethyldibenzo[ b , d ]furan‐1(9b H )‐one ( 2d ), (9b R )‐2‐acetyl‐6‐[(2 E )‐3‐(3‐chlorophenyl)prop‐2‐enoyl]‐3,7,9‐trihydroxy‐8,9b‐dimethyldibenzo[ b , d ]furan‐1(9b H )‐one ( 2e ), (6b R )‐8‐acetyl‐3‐(4‐chlorophenyl)‐6,9‐dihydroxy‐5,6b‐dimethyl‐2,3‐dihydro‐1 H ‐[1]benzofuro[2,3‐ f ][1]benzopyran‐1,7(6b H )‐dione ( 3e ), (6b R )‐8‐acetyl‐6,9‐dihydroxy‐5,6b‐dimethyl‐3‐phenyl‐2,3‐dihydro‐1 H ‐[1]benzofuro[2,3‐ f ][1]benzopyran‐1,7(6b H )‐dione ( 3h ), (6b R )‐3‐(2‐chlorophenyl)‐8‐[(2 E )‐3‐(2‐chlorophenyl)prop‐2‐enoyl]‐6,9‐dihydroxy‐5,6b‐dimethyl‐2,3‐dihydro‐1 H ‐[1]benzofuro[2,3‐ f ][1]benzopyran‐1,7(6b H )‐dione ( 4b ), and (9b R )‐6‐acetyl‐3,7,9‐trihydroxy‐8,9b‐dimethyl‐2‐[(2 E )‐3‐phenylprop‐2‐enoyl]dibenzo[ b , d ]furan‐1(9b H )‐one ( 5c ) were the most potent α‐glucosidase enzyme inhibitors, with IC 50 values of 7.0±0.24, 15.5±0.49, 7.5±0.92, 10.9±0.56, 1.5±0.62, 15.3±0.54, 19.0±1.00, and 12.3±0.53 μM, respectively.