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Abstract
Thirty-five 9-O-berberrubine carboxylate derivatives were synthesized and evaluated for yeast α-glucosidase inhibitory activity. All compounds demonstrated better inhibitory activities than the parent compounds berberine (BBR) and berberrubine (BBRB), and a positive control, acarbose. The structure–activity correlation study indicated that most of the substituents on the benzoate moiety such as methoxy, hydroxy, methylenedioxy, benzyloxy, halogen, trifluoromethyl, nitro and alkyl can contribute to the activities except multi-methoxy, fluoro and cyano. In addition, replacing benzoate with naphthoate, cinnamate, piperate or diphenylacetate also led to an increase in inhibitory activities except with phenyl acetate. 9, 26, 27, 28 and 33 exhibited the most potent α-glucosidase inhibitory activities with the IC50 values in the range of 1.61–2.67 μM. Kinetic study revealed that 9, 26, 28 and 33 interacted with the enzyme via competitive mode. These four compounds were also proved to be not cytotoxic at their IC50 values. The competitive inhibition mechanism of these four compounds against yeast α-glucosidase was investigated using molecular docking and molecular dynamics simulations. The binding free energy calculations suggest that 26 exhibited the strongest binding affinity, and its binding stability is supported by hydrophobic interactions with D68, F157, F158 and F177. Therefore, 9, 26, 28 and 33 would be promising candidates for further studies of antidiabetic activity.
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1 Chulalongkorn University, Department of Chemistry, Faculty of Science, Center of Excellence in Natural Products Chemistry, Pathumwan, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
2 University of Tsukuba, Center for Computational Sciences, Tsukuba, Japan (GRID:grid.20515.33) (ISNI:0000 0001 2369 4728)
3 Chulalongkorn University, Department of Chemistry, Faculty of Science, Center of Excellence in Natural Products Chemistry, Pathumwan, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); Institut Teknologi Bandung, Organic Chemistry Division, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Bandung, Indonesia (GRID:grid.434933.a) (ISNI:0000 0004 1808 0563)
4 Chulalongkorn University, Department of Microbiology, Faculty of Medicine, Center of Excellence in Applied Medical Virology, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
5 Chulalongkorn University, Bioinformatics and Computational Biology Program, Graduated School, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875); Chulalongkorn University, Department of Biochemistry, Faculty of Science, Center of Excellence in Biocatalyst and Sustainable Biotechnology, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)