Abstract
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•Synthesis a novel class of isoxazolidines derivatives.•All synthetic compounds were assessed for their in vitro PPA, HPI and HLAG.•A significant inhibitory activity was found for all the examined compounds.•The benzaldehyde moiety contribute to the stabilization of the ligand by their orientations.•We note the presence of intramolecular interaction.
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.