Synthesis, Structure, Carbohydrate Enzyme Inhibition, Antioxidant Activity, In Silico Drug-Receptor Interactions and Drug-Like Profiling of the 5-Styryl-2-Aminochalcone Hybrids

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.

Synthesis, Structural and Biological Properties of the Ring-A Sulfonamido Substituted Chalcones: A Review

“…Significant inhibitory effect agaisnt α-glucosidase was observed for 8f (IC 50 = 3.2 ± 0.33 µM) substituted with the 4-fluorophenyl group on the styryl and chalcone arms. The activity of this compound was found to be higher than that of the isomer 8b (IC 50 = 5.4 ± 0.10 µM), and twice higher than that previously observed for the corresponding substrate 7b (IC 50 = 6.9 ± 0.37 µM) [ 39 ]. The docking pose of compound 8h revealed π-π stacking interactions with the side chain of α-glucosidase, and the hydrogen bond is envisaged to be mainly contributed by its carbonyl group.…”

“…The docking pose of compound 8h revealed π-π stacking interactions with the side chain of α-glucosidase, and the hydrogen bond is envisaged to be mainly contributed by its carbonyl group. The presence of sulfonamide group at the ortho [ 39 ], meta or para position of ring A [ 40 ] generally resulted in increased inhibitory effect against α-glucosidase compared to the corresponding aminochalcone precursors. The 5-styryl-2-(tolylsulfonamido)chalcone hybrids 8a – h were also evaluated for inhibitory effect in vitro against α-amylase ( Table 3 ) [ 26 ].…”

“…Replacement of the amino group of 7a – d with a sulfonamido group resulted in variable activity for derivatives 8a – d against α-amylase with IC 50 values in the range 4.8 ± 0.25–13.6 ± 0.15 µM. A combination of the 5-(3-fluorostyryl) and 4-chlorophenyl group on the chalcone wing of compound 8c resulted in significantly reuced inhibitory effect agaisnt this enzyme compared to substrate 7c [ 39 ] with IC 50 values of 13.6 ± 0.15 μM and 2.4 ± 0.10 μM, respectively. The other derivataves within this series exhibited comparable activity against α-glucosidase and α-amylase.…”

“…Both 8e and 8f exhibited reduced inhibitory effect against α-amylase compared to the isomeric 8a and 8b . The presence of the sulfonamido group in 8e also resulted in significantly reduced activity against α-amylase compared to substrate 7e (IC 50 = 1.6 ± 0.52 μM [ 39 ]) and the corresponding IC 50 value is 12.5 ± 0.18 μM. The 5-(4-chlorostyryl) 8g (IC 50 = 4.1 ± 0.61 μM) and the 5-(4-methoxystyryl) 8h (IC 50 = 2.1 ± 0.53 μM) substituted derivatives exhibited significant activity against α-amylase than the corresponding isomers 8c and 8d , respectively.…”

“…The 5-(4-chlorostyryl) 8g (IC 50 = 4.1 ± 0.61 μM) and the 5-(4-methoxystyryl) 8h (IC 50 = 2.1 ± 0.53 μM) substituted derivatives exhibited significant activity against α-amylase than the corresponding isomers 8c and 8d , respectively. Hitherto, the IC 50 values for the corresponding substrates 7g and 7h were found to be 1.7 ± 0.25 μM and 7.6 ± 0.20 μM, respectively [ 39 ]. The docking pose of 8h in the active site of α-amylase revealed Leu165 and Ile235 as the two command residues that made hydrophobic interactions with this compound [ 26 ].…”