Design, synthesis, and comprehensive evaluation of novel imidazole-chromone hybrids as potent cholinesterase and α-glucosidase inhibitors

Abstract

A series of new hybrid styrylchromone (3a-3h) molecules incorporating imidazole and chromone nuclei were synthesized and characterized. A Diels-Alder cycloaddition reaction was performed on these compounds, leading to the formation of a new series of tricyclic molecules (4a-4h). The evaluation of their biological activity revealed that the cyclization of the styrylchromones significantly enhances their bioactive potential, in particular their inhibitory capacity towards acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and alpha-glucosidase enzymes. Among the tested compounds, derivative 4c exhibited the most promising inhibitory activity against both AChE (3.93 mu M) and alpha-glucosidase (9.61 mu M), with an efficacy comparable to or even exceeding that of the standard inhibitors tacrine and acarbose. This compound also showed remarkable inhibition of BChE enzyme with an IC50 of 9.41 mu M. Furthermore, derivative 4a was identified as the most potent inhibitor of this enzyme, displaying an activity approximately two times greater than that of tacrine (IC50 10.01 vs 22.30 nM). In silico studies, including molecular docking and DFT calculations, were conducted to better understand the interaction modes between the synthesized molecules and their target enzymes, as well as the reaction mechanism underlying their synthesis. Overall, the results of this study highlight the therapeutic potential of the synthesized compounds, particularly the cyclized derivatives.