Regioselectivity of aminomethylation in 3-acetyl-7-hydroxycoumarins: Mannich bases and Betti bases

Abstract

7-Hydroxycoumarin is a privileged structure for anti-inflammatory drug development. In this study, several new 3-acetyl-7-hydroxycoumarin derivatives were designed, synthesized and tested as anti-inflammatory agents. Interestingly, Mannich bases and Betti bases were separately obtained under acidic or neutral conditions. The regioselectivity of aminomethylation was studied based on the atomic electron density distribution by analysing the Voronoi deformation density (VDD) atomic charges, which reasonably explained the experimental outcome. Detection of nitric oxide (NO) and tumour necrosis factor alpha (TNF-α) release revealed that Mannich bases displayed stronger anti-inflammatory activity than the corresponding Betti bases.