Multitarget Action of Xanthones from Garcinia mangostana against α-Amylase, α-Glucosidase and Pancreatic Lipase

Abstract

Digestive enzymes such α-amylase (AA), α-glucosidase (AG) and pancreatic lipase (PL), play an important role in the metabolism of carbohydrates and lipids, being attractive therapeutic targets for the treatment of type 2 diabetes and obesity. Garcinia mangostana is an interesting species because there have been identified xanthones with the potential to inhibit these enzymes. In this study, the multitarget inhibitory potential of xanthones from G. mangostana against AA, AG and PL was assessed. The methodology included the isolation and identification of bioactive xanthones, the synthesis of some derivatives and a molecular docking study. The chemical study allowed the isolation of five xanthones (1–5). Six derivatives (6–11) were synthesized from the major compound, highlighting the proposal of a new solvent-free methodology with microwave irradiation for obtaining aromatic compounds with tetrahydropyran cycle. Compounds with multitarget activity correspond to 2, 4, 5, 6 and 9, highlighting 6 with IC50 values of 33.3 µM on AA, 69.2 µM on AG and 164.4 µM on PL. Enzymatic kinetics and molecular docking studies showed that the bioactive xanthones are mainly competitive inhibitors on AA, mixed inhibitors on AG and non-competitive inhibitors on PL. The molecular coupling study established that the presence of methoxy, hydroxyl and carbonyl groups are important in the activity and interaction of polyfunctional xanthones, highlighting their importance depending on the mode of inhibition.

Synthesis and Molecular Docking Studies of Alkoxy- and Imidazole-Substituted Xanthones as α-Amylase and α-Glucosidase Inhibitors

“…For compound 9b , the allyl group at C-1 shows a π-alkyl hydrophobic interaction with Phe303, and the 4-bromobutoxy fragment at C-2 exhibits an alkyl hydrophobic interaction with Arg315 and a hydrophilic interaction with the halogen atom (Thr310) while forming a carbon–hydrogen bond with Glu411 and Arg315 residues. According to these results, 6c , 6e , and 9b bind to an allosteric site near the catalytic site of the enzyme since they docked with amino acids of the catalytic pocket, thus sterically blocking it and indicating that they act as mixed inhibitors [ 55 ]. Data of 10c are summarized in Tables S1 and Figure S89, Supplementary Materials .…”

Bio-guided isolation of alpha-glucosidase inhibitory compounds from Vietnamese Garcinia schomburgkiana fruits: in vitro and in silico studies

“…Xanthones 7–11 are well-known in the Garcinia plants, i.e. , G. mangostana , 24–26 G. fusca , 27 G. cylindrocarpa , 28 G. planchonii . 29 These compounds showed strong cytotoxicity against various cancer cell lines and potent alpha-glucosidase inhibition.…”

“…29 These compounds showed strong cytotoxicity against various cancer cell lines and potent alpha-glucosidase inhibition. 24–29…”

α‐Glucosidase Inhibitory Components from Garcinia pedunculata Fruits

“…The plants of the genus are mainly distributed in Asia and Africa, among which 19 species are mainly native to Yunnan and Guangxi in China. [4,5] The chemical components mainly consist of xanthones, benzophenones, triterpenoids, etc., [6][7][8] and have exhibited pharmacological activities such as anticancer, hypoglycemic, antiparasitic, anti-HIV, and neuroprotective effects. [9][10][11][12][13] Garcinia pedunculata Roxb.…”

“…To explore its hypoglycemic constituents, two new compounds (1 and 2), a new natural product (3), and four known compounds (4-7) were isolated from G. pedunculata fruits (Figure 1). And by the comparison of the NMR data with those reported in the kinds of literature, the known compounds were identified as p-hydroxyl phenyl propanol (4), [14] 4-hydroxy-3,5-dimethoxybenzoic acid (5), [15] p-methoxybenzoicacid (6) [16] and ligballinol (7). [17] Subsequently, the isolated compounds were tested for α-glucosidase inhibitory activity.…”