An in vitro study of the 5-methyl- and 5-bromo/chloro substituted 2-hydroxy-3-nitrochalcones as alpha-glucosidase and/or alpha-amylase inhibitors with potential anti-inflammatory activity

Series of the 5-methyl-, 5-bromo- and 5-chloro substituted 2-hydroxy-3-nitrochalcones (2a-d), (2e-h) and (2i-l), respectively, have been synthesized and characterized using a combination of spectroscopic and single crystal X-ray diffraction techniques. The compounds were, in turn, evaluated through enzymatic assays in vitro for inhibitory effect against alpha-glucosidase and alpha-amylase activities. Most of the test compounds exhibited increased inhibitory activity against alpha-glucosidase compared to the anti-diabetic drug, acarbose. Chalcones 2a, 2c, 2d, and 2g-j exhibited dual inhibitory effect against both enzymes with minimal cytotoxicity against the Raw-264,7 macrophage (Murine) cells compared to the anticancer drug, curcumin. Derivatives 2e and 2k exhibited increased inhibitory activity and selectivity against alpha-amylase with significantly reduced cytotoxicity against the Raw-264,7 cells. Chalcones 2a, 2i, and 2j showed the capability to increase the phagocytic ability of Raw-264,7 cells in the presence of lipopolysaccharide (LPS) stimuli. Molecular docking has been performed on the most active derivatives to predict the hypothetical protein-ligand binding modes into the alpha-glucosidase and alpha-amylase binding sites. Selected compounds were also docked into the Toll-like receptor-myeloid differentiation factor 2 (TLR4-MD2) active sites to determine their binding energies at least at theoretical level. The key aspects of the pharmacokinetics of these compounds, namely, absorption, distribution, metabolism, and excretion have also been simulated.