Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis, In Vitro α-Amylase Inhibitory Activity, Molecular Docking and Structure-Activity Relationship Analysis.

Faisal K Algethami,Hichem Ben Jannet,Amani Chrouda,Mohamed R Elamin,Ilyes Saidi,Hani Nasser Abdelhamid,Babiker Y Abdulkhair

doi:10.3390/molecules26175214

Abstract

Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by 1H NMR, 13C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 μM, and with IC50 values of 12.6 ± 0.2 μM–27.6 ± 1.1 μM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 μM), with a potency (IC50 = 12.6 ± 0.2 μM) similar to that of the positive control acarbose (IC50 = 12.4 ± 0.1 μM). The study of the structure–activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.

Highlights

Obesity and diabetes mellitus constitute major human health problems worldwide [1,2].diabetes mellitus is primarily typified by uncontrolled blood sugar
Α-amylase inhibition contributes in one way or another to controlling the digestion of carbohydrates [6,7]; it constitutes a partial pathway to regulate the enzymatic activity of α-amylase; it is an ideal therapy for the regulation of obesity and diabetes, as well as their related complications [4]
The preparation of a trifluoromethylated flavonol (1)—previously synthesized in our laboratory and showing interesting cytotoxic potential—was reported according to the procedure adopted by Znati et al (2019) [30]. 5-Chloro-2-hydroxyacetophenone was condensed with 4-(trifluoromethyl)benzaldehyde under reflux of methanol and in the presence of sodium hydroxide for 3 h to produce 5-chloro-4 -(trifluoromethyl)-2-hydroxychalcone; the pyranic ring (C) was cyclized and the C-3 carbon was oxidized by the addition of (H2O2, NaOH) for 2 h at room temperature (Scheme 1)

Summary

Introduction

Obesity and diabetes mellitus constitute major human health problems worldwide [1,2].diabetes mellitus is primarily typified by uncontrolled blood sugar. Α-amylase inhibition contributes in one way or another to controlling the digestion of carbohydrates [6,7]; it constitutes a partial pathway to regulate the enzymatic activity of α-amylase; it is an ideal therapy for the regulation of obesity and diabetes, as well as their related complications [4]. A competitive inhibitor binds to the active site of the target enzyme and, prevents the substrate from binding. In competitive inhibition, the inhibitor competes with the substrate for the active site. For a good inhibition of carbohydrate digestion—which can help control obesity, and even type 2 diabetes—we need a non-selective substance capable of inhibiting most of the digestive enzymes of sugars, namely salivary α-amylase, pancreatic α-amylase, and α-glucosidase [8,9]

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