EXPLORATION OF BIOACTIVE COMPOUNDS FOR DIABETES THERAPY FROM SELECTED EAST KALIMANTAN FLORA

Abstract

In search of α-glucosidase inhibitors for the treatment of type 2 diabetes mellitus and its complications, we examined the inhibitory effect of selected plants collected from East Kalimantan, Indonesia which included Leucaena leucocephala, Swietenia macrcophylla, Pycnarrhena tumefacta, Luvunga eleutherandra, Crescentia cujete, Ceriops tagal and Horsfieldia macrobotrys. On the basis of ethnopharmacological knowledge together with biological and chemical screenings, selected plants were further investigated to afford active compounds. The methanol extract from leaves of Ceriops tagal yielded three compounds classified as pentacyclic triterpenoids named lupeol (1), betulone (2) and betulin (3). Of isolated compounds, 3 showed highest inhibition against yeast α-glucosidase with IC50 value of 18.87 μM followed by 1 and 2, respectively. The kinetic study of 1-3 showed noncompetitive inhibition against baker’s yeast α-glucosidase. In addition, the methanol extract from Horsfieldia macrobotrys seed coats was investigated using an α-glucosidase and antioxidant-guided isolation. Two arylalkanones named 1-(2,4,6-trihydroxyphenyl)-9-phenylnonan-1-one (4) and malabaricone A (5) together with a flavanone named 7-hydroxyflavanone (6) were isolated. Arylalkanone 4 was the most potent inhibitor against free radical and baker’s yeast α-glucosidase with IC50 value of 2.6 mM and 10.8 μM, respectively. Interestingly, the methyl ether analogues 4a and 5a, prepared by methylation of 4 and 5 with MeI/K2CO3, showed dramatic drop in inhibition. This observation indicated the critical role of hydroxy groups (-OH) in exerting radical scavenging and α-glucosidase inhibition. The kinetic study of 4 indicated that baker’s yeast α-glucosidase was mixed manner. Since promising bioactivity of isolated arylalkanones from seed coats of H. macrobotrys, we further investigated other parts of this plant. Bioassay-guided isolation of stem bark extract resulted in two new arylalkanones named horsfieldone A (7) and maingayone D (8) together with a new flavanone-C-glycoside named 8-C-β-D-glucopyranosylpinocembrin (9). Maingayone D (8) displayed significantly more potent inhibition than 7 against α-glucosidase and free radical. Kinetic study of 7 and 8 indicated their mixed inhibition against α-glucosidase. The results of this study showed that ethnopharmacological knowledge from Dayak people in East Kalimantan together with biological and chemical screenings provided a successful strategy to discover potent antidiabetic agents.