Identification of highly potent α-glucosidase inhibitory and antioxidant constituents from Zizyphus rugosa bark: enzyme kinetic and molecular docking studies with active metabolites.
BACKGROUND
Previous studies have shown that extracts of Zizyphus rugosa Lam. (Rhamnaceae) bark contained phytoconstituents with antidiabetic potential to lower blood glucose levels in diabetic rats. However, there has been no report on the active compounds in this plant as potential antidiabetic inhibitors.


OBJECTIVE
We evaluated the α-glucosidase inhibitory and antioxidant activities of Z. rugosa extract. Moreover, the active phytochemical constituents were isolated and characterized.


METHODS
The α-glucosidase inhibition of crude ethanol extract obtained from the bark of Z. rugosa was assayed as well as the antioxidant activity. Active compounds (1-6) were isolated, the structures were determined, and derivatives (2a-2 l) were prepared. All compounds were tested for their α-glucosidase inhibitory (yeast and rat intestine) and antioxidant (DPPH) activities.


RESULTS
The active α-glucosidase inhibitors (1-6) were isolated from Z. rugosa bark and 12 derivatives (2a-2 l) were prepared. Compound 2 showed the most powerful yeast α-glucosidase inhibitory activity (IC5016.3 μM), while compounds 3 and 4 display only weak inhibition toward rat intestinal α-glucosidase. Moreover, compound 6 showed the most potent antioxidant activity (IC5042.8 μM). The molecular docking results highlighted the role of the carboxyl moiety of 2 for yeast α-glucosidase inhibition through H-bonding.


CONCLUSIONS
These results suggest the potential of Z. rugosa bark for future application in the treatment of diabetes and active compounds 1 and 2 have emerged as promising molecules for therapy.
a Natural Products Research Unit, Department of Chemistry, Faculty of Science , Chulalongkorn University , Bangkok , Thailand.
Jirapast
J
Sichaem
a Natural Products Research Unit, Department of Chemistry, Faculty of Science , Chulalongkorn University , Bangkok , Thailand.
Thammarat
T
Aree
b Program of Chemistry, Faculty of Science and Technology , Bansomdej Chaopraya Rajabhat University , Bangkok , Thailand.
Kiattisak
K
Lugsanangarm
a Natural Products Research Unit, Department of Chemistry, Faculty of Science , Chulalongkorn University , Bangkok , Thailand.
Santi
S
Tip-Pyang
D000975:Antioxidants / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry; D000431:Ethanol / Q000737:chemistry; D065089:Glycoside Hydrolase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007700:Kinetics; D062105:Molecular Docking Simulation; D008517:Phytotherapy; D010851:Picrates / Q000737:chemistry; D024301:Plant Bark / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D011485:Protein Binding; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D031957:Ziziphus / Q000737:chemistry*; D000520:alpha-Glucosidases / Q000737:chemistry / Q000378:metabolism*
D000975:Antioxidants; D001713:Biphenyl Compounds; D065089:Glycoside Hydrolase Inhibitors; D010851:Picrates; D010936:Plant Extracts; D029701:Saccharomyces cerevisiae Proteins; D012997:Solvents; D000431:Ethanol; C004931:1,1-diphenyl-2-picrylhydrazyl; D000520:alpha-Glucosidases
Lupane-type triterpenes; flavonoid glycosides; lignan glycosides