Synthesis, bioactivity and docking studies of chrysin derivatives as iNOS inhibitors

Endothelial dysfunction, mainly linked to ionic channel malfunctions, is a key mechanism in the pathogenesis of different vascular disorders including hypertension and atherosclerosis. Several studies confirm a strong correlation between endothelial dysfunction, inflammation and oxidative stress. Regular consumption of antioxidant polyphenol-rich foods has been linked to a reduction in cardiovascular morbidity and mortality. The flavone chrysin, a known Ca v 1.2 channel inhibitor, was selected in this work as lead compound to generate a library of its derivatives evaluated for their antioxidant and anti-inflammatory properties by means of vitro and cell-based assays. Among them, the best one resulted in the 8-nitrochrysin ( 1i ). Molecular docking revealed that the nitro group plays a critical role in enhancing the binding mode toward iNOS by facilitating the formation of additional polar interactions compared to chrysin. LogP values of chrysin derivatives were also experimentally determined via spectrophotometric method to evaluate the impact of the chemical modifications with respect to the parent compound.