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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 May 27

PMID 37241920

Authors

Dolores G Aguila-Munoz

Gabriel Vazquez-Lira

Erika Sarmiento-Tlale

Maria C Cruz-Lopez

Fabiola E Jimenez-Montejo

Victor E Lopez Y Lopez

Carlos H Escalante

Dulce Andrade-Pavon

Omar Gomez-Garcia

Joaquin Tamariz

Aaron Mendieta-Moctezuma

Affiliations

Soon will be listed here.

Abstract

Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds , and promoted higher α-glucosidase inhibition (IC = 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC = 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC = 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives and showed higher α-amylase inhibition (IC = 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC = 232.7 and 145.2 µM, respectively). According to the structure-activity relationship, attaching 4-bromobutoxy or 4'-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-glucosidase inhibition and lower α-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that , , and are mainly mixed inhibitors on α-glucosidase and α-amylase. In addition, drug prediction and ADMET studies support that compounds , , and are candidates with antidiabetic potential.

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References

Murugesu S, Ibrahim Z, Ahmed Q, Fathamah Uzir B, Yusoff N, Perumal V . Identification of α-glucosidase inhibitors from leaf extract using liquid chromatography-mass spectrometry-based metabolomics and protein-ligand interaction with molecular docking. J Pharm Anal. 2019; 9(2):91-99. PMC: 6460329. DOI: 10.1016/j.jpha.2018.11.001. View

Sriyatep T, Siridechakorn I, Maneerat W, Pansanit A, Ritthiwigrom T, Andersen R . Bioactive prenylated xanthones from the young fruits and flowers of Garcinia cowa. J Nat Prod. 2015; 78(2):265-71. DOI: 10.1021/np5008476. View

Santoso M, Ong L, Aijijiyah N, Wati F, Azminah A, Annuur R . Synthesis, α-glucosidase inhibition, α-amylase inhibition, and molecular docking studies of 3,3-di(indolyl)indolin-2-ones. Heliyon. 2022; 8(3):e09045. PMC: 8917276. DOI: 10.1016/j.heliyon.2022.e09045. View

Ding S, Lan T, Ye G, Huang J, Hu Y, Zhu Y . Novel oxazolxanthone derivatives as a new type of α-glucosidase inhibitor: synthesis, activities, inhibitory modes and synergetic effect. Bioorg Med Chem. 2018; 26(12):3370-3378. DOI: 10.1016/j.bmc.2018.05.008. View

Yang L, Zhang D, Li J, Zhang X, Zhou N, Zhang W . Prenylated xanthones with α-glucosidase and α-amylase inhibitory effects from the pericarp of . J Asian Nat Prod Res. 2021; 24(7):624-633. DOI: 10.1080/10286020.2021.1967328. View

Vazquez J, Sobel J . Miconazole mucoadhesive tablets: a novel delivery system. Clin Infect Dis. 2012; 54(10):1480-4. DOI: 10.1093/cid/cis205. View

Chaudhry F, Naureen S, Ashraf M, Al-Rashida M, Jahan B, Munawar M . Imidazole-pyrazole hybrids: Synthesis, characterization and in-vitro bioevaluation against α-glucosidase enzyme with molecular docking studies. Bioorg Chem. 2018; 82:267-273. DOI: 10.1016/j.bioorg.2018.10.047. View

Chi X, Zi C, Li H, Yang L, Lv Y, Li J . Design, synthesis and structure-activity relationships of mangostin analogs as cytotoxic agents. RSC Adv. 2022; 8(72):41377-41388. PMC: 9091619. DOI: 10.1039/c8ra08409b. View

Cardozo-Munoz J, Cuca-Suarez L, Prieto-Rodriguez J, Lopez-Vallejo F, Patino-Ladino O . Multitarget Action of Xanthones from against α-Amylase, α-Glucosidase and Pancreatic Lipase. Molecules. 2022; 27(10). PMC: 9144329. DOI: 10.3390/molecules27103283. View

10.

Li Y, Zhang J, Xie H, Ge Y, Wang K, Song Z . Discovery of new 2-phenyl-1H-benzo[d]imidazole core-based potent α-glucosidase inhibitors: Synthesis, kinetic study, molecular docking, and in vivo anti-hyperglycemic evaluation. Bioorg Chem. 2021; 117:105423. DOI: 10.1016/j.bioorg.2021.105423. View

11.

Kalita D, Holm D, LaBarbera D, Petrash J, Jayanty S . Inhibition of α-glucosidase, α-amylase, and aldose reductase by potato polyphenolic compounds. PLoS One. 2018; 13(1):e0191025. PMC: 5784920. DOI: 10.1371/journal.pone.0191025. View

12.

Hakamata W, Kurihara M, Okuda H, Nishio T, Oku T . Design and screening strategies for alpha-glucosidase inhibitors based on enzymological information. Curr Top Med Chem. 2009; 9(1):3-12. DOI: 10.2174/156802609787354306. View

13.

Hou T, Xia K, Zhang W, Xu X . ADME evaluation in drug discovery. 4. Prediction of aqueous solubility based on atom contribution approach. J Chem Inf Comput Sci. 2004; 44(1):266-75. DOI: 10.1021/ci034184n. View

14.

Chaudhry F, Naureen S, Huma R, Shaukat A, Al-Rashida M, Asif N . In search of new α-glucosidase inhibitors: Imidazolylpyrazole derivatives. Bioorg Chem. 2017; 71:102-109. DOI: 10.1016/j.bioorg.2017.01.017. View

15.

Naureen S, Chaudhry F, Munawar M, Ashraf M, Hamid S, Khan M . Biological evaluation of new imidazole derivatives tethered with indole moiety as potent α-glucosidase inhibitors. Bioorg Chem. 2017; 76:365-369. DOI: 10.1016/j.bioorg.2017.12.014. View

16.

Dharmaratne H, Sakagami Y, Piyasena K, Thevanesam V . Antibacterial activity of xanthones from Garcinia mangostana (L.) and their structure-activity relationship studies. Nat Prod Res. 2012; 27(10):938-41. DOI: 10.1080/14786419.2012.678348. View

17.

Chokki M, Cudalbeanu M, Zongo C, Dah-Nouvlessounon D, Ghinea I, Furdui B . Exploring Antioxidant and Enzymes (A-Amylase and B-Glucosidase) Inhibitory Activity of and Leaves from Benin. Foods. 2020; 9(4). PMC: 7230926. DOI: 10.3390/foods9040434. View

18.

Noori M, Davoodi A, Iraji A, Dastyafteh N, Khalili M, Asadi M . Design, synthesis, and in silico studies of quinoline-based-benzo[d]imidazole bearing different acetamide derivatives as potent α-glucosidase inhibitors. Sci Rep. 2022; 12(1):14019. PMC: 9386204. DOI: 10.1038/s41598-022-18455-7. View

19.

Nawaz M, Taha M, Qureshi F, Ullah N, Selvaraj M, Shahzad S . Synthesis, α-amylase and α-glucosidase inhibition and molecular docking studies of indazole derivatives. J Biomol Struct Dyn. 2021; 40(21):10730-10740. DOI: 10.1080/07391102.2021.1947892. View

20.

Kerru N, Singh-Pillay A, Awolade P, Singh P . Current anti-diabetic agents and their molecular targets: A review. Eur J Med Chem. 2018; 152:436-488. DOI: 10.1016/j.ejmech.2018.04.061. View