Synthesis of new halogenated flavonoid-based isoxazoles: in vitro and in silico evaluation of a-amylase inhibitory potential, a SAR analysis and DFT studies

Abstract

Carbohydrates are the main source of calories in most diets, and α-amylase is considered one of the main enzymes that initiate their digestion. The inhibition of α-amylase is therefore considered to be a therapeutic strategy for the treatment of disorders of glucose absorption, such as dental caries, periodontal disease, overweight, obesity and diabetes. On the other hand, flavonoids, isoxazoles and halogenated derivatives are of great interest in medicinal chemistry due to their considerable bioactivities. Therefore, this work describes the design, the synthesis and the α-amylase inhibitory potential of new halogenated flavonoid-based isoxazoles, and their biological properties. In fact, the condensation of a previously synthesized halogenated flavonol with different aryl nitrile oxides afford thirteen new hybrid cycloadducts (2a-m). Their structures were characterized by 1H NMR, 13C NMR and HRMS analysis. The physicochemical properties of these compounds (2a-m) were also evaluated. The newly synthesized cycloadducts were evaluated in vitro for their α-amylase inhibitory activity and excellent results were noted. The compound 2b (IC50 = 16.2 ± 0.3 µM) exhibited the highest anti-α-amylase activity comparable to that of the standard substance (Acarbose, IC50 = 15.7 ± 0.2 µM). The study of the Structure-Activity Relationship (SAR) was sufficiently discussed based on the Molecular Docking analysis and the Density Functional Theory (DFT) studies.