Novel oxazolxanthone derivatives as a new type of α-glucosidase inhibitor: synthesis, activities, inhibitory modes and synergetic effect. Issue 12 (23rd July 2018)

• Record Type: Journal Article
• Authors: Ding, Sen-Miao; Lan, Tian; Ye, Gao-Jie; Huang, Jia-Jun; Hu, You; Zhu, Yi-Ran; Wang, Bo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 12(2018)
• Page Start: 3370
• Page End: 3378
• Publication Date: 2018-07-23
• Subjects: Oxazolxanthones -- α-Glucosidase inhibitors -- Docking -- Synergetic effect -- Non-competitive and competitive; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.05.008
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A series of novel oxazolxanthones 4–21 were synthesized as α-glucosidase inhibitors. Most of the compounds showed excellent anti-α-glucosidase activity. Both competitive (compound 4 ) and non-competitive (compounds 15, 16 and 20 ) manners were observed. Compounds 15, 16 and 20 may function in the noncompetitive domain of the enzyme. Synergistic inhibition of compounds 16 and 20 was predicted by Molecular docking and confirmed by experiment. Abstract: Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4 –21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b . Among them, compounds 5 –21 (IC50 = 6.3 ± 0.4–38.5 ± 4.6 μM) were more active than 1-deoxynojirimycin (IC50 = 60.2 ± 6.2 μM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC50 value of 1.9 ± 0.7 μM, better than the IC50 value of 7.1 ± 0.9 μM for compound 16 and 8.6 ± 0.9 μM for compound 20 .