Abstract
Background: Coumarins are secondary plant metabolites typically found in the species of Asteraceae, Rutaceae and Umbeliferae families which demonstrate several pharmacological properties, including antioxidant activity. As antioxidants, coumarins are known to influence the formation and uptake of Reactive Oxygen Species (ROS), to reduce the oxidative damage caused by free radicals and to prevent eicosanoid formation, being of interest for drug design. In this context, we designed the synthesis of 4-chloromethylcoumarins via Pechmann condensation with different substituents at the position 6 of the coumarin ring through Click chemistry reactions, aiming to improve their antioxidant activities.
Methods: The synthesis of the envisioned compounds started with Pechmann condensation using hydroquinone and ethyl 4-chloroaceacetate followed by functionalization of the phenolic hydroxyl with propargyl bromide via Williamsom ether synthesis. Subsequently, Click chemistry reactions were performed under microwave irradiation using previously synthesized organic azides, then yielding five 6-substituted-4-chloromethylcoumarin analogues. These compounds had their intrinsic toxicities estimated via cell viability assays using the NIH 3T3 Cell Line (mouse embryonic fibroblasts) by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. The antioxidant activities were then assayed using the DCFH-DA (2’,7’-diihydrochlorofluorescin diacetate) assay.
Result and Conclusion: Five novel coumarins were synthesized with low to moderate yields (11-61%), while four of these compounds displayed some degree of toxicity in the cell viability assay. However, the remaining coumarin, LaSOM 322, was nearly atoxic in all the assayed conditions and displayed the most relevant antioxidant properties, being a promising lead for subsequent optimization.
Keywords: Coumarins, antioxidants, reactive oxygen species, free radical scavenging, Click chemistry, Pechmann condensation.
Graphical Abstract
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