α-Glucosidase Inhibitors from <i>Brickellia cavanillesii</i>

An aqueous extract from the aerial parts of <i>Brickellia cavanillesii</i> attenuated postprandial hyperglycemia in diabetic mice during oral glucose and sucrose tolerance tests. Experimental type-II DM was achieved by treating mice with streptozotocin (100 mg/kg) and β-nicotinamide adenine dinucleotide (40 mg/kg). These pharmacological results demonstrated that <i>B. cavanillesii</i> is effective for controlling fasting and postprandial blood glucose levels in animal models. The same aqueous extract also showed potent inhibitory activity (IC₅₀ = 0.169 vs 1.12 mg/mL for acarbose) against yeast α-glucosidase. Bioassay-guided fractionation of the active extract using the α-glucosidase inhibitory assay led to the isolation of several compounds including two chromenes [6-acetyl-5-hydroxy-2,2-dimethyl-2<i>H</i>-chromene (<b>1</b>) and 6-hydroxyacetyl-5-hydroxy-2,2-dimethyl-2<i>H</i>-chromene (<b>2</b>)], two sesquiterpene lactones [caleins B (<b>3</b>) and C (<b>4</b>)], several flavonoids [acacetin (<b>5</b>), genkwanin (<b>6</b>), isorhamnetin (<b>7</b>), kaempferol (<b>8</b>), and quercetin (<b>9</b>)], and 3,5-di-<i>O</i>-caffeoylquinic acid (<b>10</b>). Chromene <b>2</b> is a new chemical entity. Compounds <b>2</b>, <b>4</b>, <b>7</b>, and <b>9</b> inhibited the activity of yeast α-glucosidase with IC₅₀ 0.42, 0.28, 0.16, and 0.53 mM, respectively, vs 1.7 mM for acarbose. Kinetic analysis revealed that compounds <b>4</b> and <b>7</b> behaved as mixed-type inhibitors with <i>K</i>_i values of 1.91 and 0.41 mM, respectively, while <b>2</b> was noncompetititive, with a <i>K</i>_i of 0.13 mM. Docking analysis predicted that these compounds, except <b>2</b>, bind to the enzyme at the catalytic site