Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors

Ameni Ghabi; Jihed Brahmi; Fahad Alminderej; Sabri Messaoudi; Sébastien Vidal; Adel Kadri; Kaïss Aouadi

doi:10.1016/j.bioorg.2020.103713

Multifunctional isoxazolidine derivatives as α-amylase and α-glucosidase inhibitors

Bioorg Chem. 2020 May:98:103713. doi: 10.1016/j.bioorg.2020.103713. Epub 2020 Mar 2.

Authors

Ameni Ghabi¹, Jihed Brahmi¹, Fahad Alminderej², Sabri Messaoudi³, Sébastien Vidal⁴, Adel Kadri⁵, Kaïss Aouadi⁶

Affiliations

¹ University of Monastir, Faculty of Sciences of Monastir, Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity, Avenue of the Environment, 5019 Monastir, Tunisia.
² Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia.
³ Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia; Carthage University, Faculty of Sciences of Bizerte, 7021 Jarzouna, Tunisia.
⁴ Université Claude Bernard Lyon 1, Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR CNRS 5246, Laboratoire de Chimie Organique 2-Glycochimie, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.
⁵ Faculty of Science of Sfax, Department of Chemistry, Sfax University, B.P. 1171, 3000 Sfax, Tunisia; College of Science and Arts in Baljurashi, Albaha University, P.O. Box (1988), Albaha, Saudi Arabia.
⁶ University of Monastir, Faculty of Sciences of Monastir, Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity, Avenue of the Environment, 5019 Monastir, Tunisia; Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi Arabia. Electronic address: Kaiss_aouadi@hotmail.com.

PMID: 32151966
DOI: 10.1016/j.bioorg.2020.103713

Abstract

A series of novel isoxazolidines based on benzaldehyde derivatives have been synthesized from the cycloaddition of chiral menthone-based nitrone and allyl phenyl ethers. All synthetic compounds were assessed for their in vitro PPA, HPA and HLAG inhibitory activity. The results revealed that all targets exhibited better inhibitory effect against PPA (12.3 ± 0.4 < IC₅₀ < 38.2 ± 0.9 μM), HPA (10.1 ± 0.4 < IC₅₀ < 26.8 ± 0.2 μM) and HLAG (65.4 ± 1.2 < IC₅₀ < 274.8 ± 1.1 μM) when compared with the reference inhibitor, acarbose (IC₅₀ = 284.6 ± 0.3 μM for PPA, 296.6 ± 0.8 μM for HPA, 780.4 ± 0.3 μM for HLAG) with the highest PPA inhibitory activity was ascribed to compound 3g against both PPA and HPA, and 3b against HLAG enzymes, respectively. Structural activity relationships (SARs) were also established for all synthesized compounds and the interaction modes of the most potent inhibitors (3g for PPA and HPA, 3b for HLAG) and the active site with residues of three enzymes were confirmed through molecular docking studies. Furthermore, a combination of molecular docking analysis with the in vitro activities can help to improve prediction success and encourages the uses of some of these molecules as potential alternatives toward the modulation of T2D.

Keywords: 1,3-dipolar cycloaddition; Isoxazolidine; Molecular docking; Nitrone; Porcine and human pancreatic α-amylase activity; α-glucosidase activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dose-Response Relationship, Drug
Glycoside Hydrolase Inhibitors / chemical synthesis
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology*
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Pancreas / enzymology
Structure-Activity Relationship
Swine
alpha-Amylases / antagonists & inhibitors*
alpha-Amylases / metabolism
alpha-Glucosidases / metabolism*

Substances

Glycoside Hydrolase Inhibitors
Isoxazoles
alpha-Amylases
alpha-Glucosidases