Fishing antioxidant 4-hydroxycoumarin derivatives: synthesis, characterization, and in vitro assessments

Abstract

Coumarins represent a diverse class of natural compounds whose importance in pharmaceutical and agri-food sectors has motivated multiple novel synthetic derivatives with broad applicability. The phenolic moiety in 4-hydroxycoumarins underscores their potential to modulate the equilibrium between free radicals and antioxidant species within biological systems. The aim of this work was to assess the antioxidant activity of 18 4-hydroxycoumarin coumarin derivatives, six of which are commercially available and the other 12 were synthesized and chemically characterized and described herein. The 4-hydroxycoumarins were prepared by a two steps synthetic strategy with satisfactory yields. Their antioxidant potential was evaluated through three in vitro methods, two free radical-scavenging assays (DPPH• and ABTS•+) and a metal chelating activity assay. Six synthetic coumarins (<b>4a</b>, <b>4g</b>, <b>4h</b>, <b>4i</b>, <b>4k</b>, <b>4l</b>) had a scavenging capacity of DPPH• higher than butylated hydroxytoluene (BHT) (IC₅₀ = 0.58 mmol/L) and compound <b>4a</b> (4-hydroxy-6-methoxy-2 H-chromen-2-one) with an IC₅₀ = 0.05 mmol/L outperformed both BHT and ascorbic acid (IC₅₀ = 0.06 mmol/L). Nine hydroxycoumarins had a scavenging capacity against ABTS•+ greater (<b>C3</b>, <b>4a</b>, <b>4c</b>) or comparable (<b>C1</b>, <b>C2</b>, <b>C4</b>, <b>C6</b>, <b>4g</b>, <b>4l</b>) to Trolox (IC₅₀ = 34.34 µmol/L). Meanwhile, the set had a modest ferrous chelation capacity, but most of them (<b>C2</b>, <b>C5</b>, <b>C6</b>, <b>4a</b>, <b>4b</b>, <b>4h</b>, <b>4i</b>, <b>4j</b>, <b>4k</b>, <b>4l</b>) reached up to more than 20% chelating ability percentage. Collectively, this research work provides valuable structural insights that may determine the scavenging and metal chelating activity of 4-hydroxycoumarins. Notably, substitutions at the C6 position appeared to enhance scavenging potential, while the introduction of electron-withdrawing groups showed promise in augmenting chelation efficiency.