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Preparation and In Vivo Use of an Activity-based Probe for N-acylethanolamine Acid Amidase
Published on: November 23, 2016
Novel sulfonylhydrazide anacardic acid derivatives as potent α-glucosidase inhibitors: Synthesis, crystal structure,
Van-Can Pham1, Thammarat Aree2, Aamir Aman3
1Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok, 10330, Thailand.
Abstract:
Inhibiting α-glucosidase (AG) enzyme is recognized as a key therapeutic approach for diabetes treatment. Nine saturated anacardic acid derivatives (2-10) were synthesized, well-characterized, and evaluated for their inhibitory activity against AG. All six sulfonylhydrazide saturated anacardic acid analogues (5-10) were disclosed as novel compounds, and their structures were endorsed by NMR spectroscopy, X-ray crystallography, and mass spectrometry. They exhibited strong inhibition against AG with IC50 in a range of 0.24-6.01 µM, significantly surpassing the reference antidiabetic drug acarbose (IC50 = 817.38 µM). Notably, 10 was found to be a potent α-glucosidase inhibitor with an IC50 of 0.24 µM. The strong inhibitory effect of the side chain against AG was demonstrated through a comparison between 10 and a structurally similar salicylic acid analogue. Kinetic studies revealed that 10 functioned as a competitive inhibitor, binding to the free enzyme with an equilibrium constant Ki = 0.96 µM. Molecular docking studies further strengthened that compound 10 predominantly binds to the orthosteric site of AG with strong binding affinity and multiple stabilizing interactions, supporting its superior inhibitory activity compared to its precursor, the saturated anacardic acid 2. These findings contribute to the development of potent therapeutic agents for diabetes treatment.
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