Abstract
The 2-amino-5-(3/4-fluorostyryl)acetophenones were prepared and reacted with benzaldehyde derivatives to afford the corresponding 5-styryl-2-aminochalcone hybrids. The trans geometry of the styryl and α,β-unsaturated carbonyl arms, and the presence of NH…O intramolecular hydrogen bond were validated using 1H-NMR and X-ray data. The 2-amino-5-styrylacetophenones and their 5-styryl-2-aminochalcone derivatives were screened in vitro for their capability to inhibit α-glucosidase and/or α-amylase activities. Their antioxidant properties were evaluated in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays. Kinetic studies of the most active derivatives from each series against α-glucosidase and/or α-amylase activities have been performed supported by molecular docking studies to determine plausible protein–ligand interactions on a molecular level. The key aspects of the pharmacokinetics of these compounds, i.e., absorption, distribution, metabolism, and excretion have also been simulated at theoretical level. The most active compounds from each series, namely, 2a and 3e, were evaluated for cytotoxicity against the normal monkey kidney cells (Vero cells) and the adenocarcinomic human epithelial (A549) cell line to establish their safety profile at least in vitro.
Highlights
This metabolic disorder is characterized by an increased level of glucose in the blood known as post-prandial hyperglycemia (PPHG), which causes vascular complications leading to damage of vital organs [2,3]
Since an ideal antidiabetic drug should exhibit hypoglycemic properties and inhibit oxidative stress, we evaluated the test compounds for antioxidant potential through the 2,2-diphenyl1-picrylhydrazyl (DPPH) and nitric oxide (NO) free radical scavenging assays
The synthesis of the title compounds was achieved as outlined in Scheme 1 below via initial Suzuki–Miyaura cross-coupling of 2-amino-5-iodoacetophenone (1) with phenylboronic acid derivatives as coupling partners to afford the corresponding 2-amino-5styrylacetophenones 2a–d (Table 1 shows the designation of substituents)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Oxidative stress may result from the interaction of scavenger receptors, such as RAGE, with advanced glycoxidation end-prod of acids ucts (AGEs) formed from the non-enzymatic glycation of proteins, lipids and nucleic with reducing sugars and with the products of glucose metabolism and their oxidation products, a phenomenon which is fostered by chronic hyperglycemia [15]. Schmidt aldol condensation of the intermediate 2-amino-5-styrylacetophenones with 3/4fluorobenzaldehyde This rational design was inspired by the literature precedents that the electron-withdrawing inductive effect of fluorine atom could help the drug molecules in forming hydrogen and/or halogen bonding interactions with the protein targets, and enhance biological activity [28]. Kinetic assays (in vitro) and molecular docking (in silico) were performed on the most active compounds from each series against these carbohydrate hydrolyzing enzymes to determine plausible protein-drug interactions on a molecular level. The ADME (absorption, distribution, metabolism, and excretion) properties of the most active derivatives were predicted using in silico methods
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