Synthesis, antibacterial activity and molecular modeling of dicoumarols

Abstract

Dicoumarol and its nineteen derivatives containing the substituted benzene ring at the methylenebis position were synthesized from the condensation reaction between 4-hydroxycoumarin with interesting aromatic aldehydes. These well-characterized compounds were evaluated for their antibacterial activity against gram-positive bacteria: Staphylococcus aureus and Bacillus subtilis and gram-negative bacteria: Escherichia coli and Klebsiella sp. The synthesized dicoumarols exhibited antibacterial activity selectively against gram-positive bacteria. Most derivatives with the substitution of steric bulky group on the methylenebis position appear to decrease in the efficacy of antibacterial effect. This finding is roughly described by the poorer docked poses of the derivatives to a homology model of S. aureus flavoprotein. 3D-QSAR study highlighted structural features around the substituted benzene ring of dicoumarols as the antibacterial activity. CoMFA and CoMSIA contour maps support the idea that steric repulsion at the para position could diminish the antibacterial activity. Futhermore, drug-likeness properties of the synthesized compounds were fallen in citeriors for Lipinski rule. The results of this study provide a better understanding of the molecular basis for the antibacterial activity of dicoumarols.