Abstract
Dicoumarols and coumarin derivatives have shown a variety of pharmaceutical activities and have been found to be potent inhibitor for the NAD(P)H-dependent flavoproteins. In this report, dicoumarol and its derivatives containing the substituted benzene ring at the methylenebis position were synthesized and evaluated for their antibacterial activity against gram-positive bacteria: Staphylococcus aureus and Bacillus subtilis, and gram-negative bacteria: Escherichia coli and Klebsiella sp. The results showed that the synthesized dicoumarols affect cell growth but are selective against gram-positive over gram-negative bacterial cells. However, for most derivatives, the substitution of steric bulky benzene group on the methylenebis position appears to decrease in the efficacy of antibacterial effect. This finding is roughly described by the predicted poorer docked structure 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. The results of this study provide a better understanding of the molecular basis for the antibacterial activity of dicoumarols.
Highlights
Dicoumarol (3,3-methylene-bis-4-hydroxycoumarin) is a naturally coumarin-based compound which has long been used as an oral anticoagulant drug
We focused on the synthesis and the antibacterial activity of a series of dicoumarol derivatives containing 3,3-phenylmethylene-bis-4-hydroxycoumarins
Dicoumarol and nineteen dicoumarol derivatives were synthesized from the condensation reaction between two-mole equivalent of 4hydroxycoumarin and one-mole equivalent of corresponding aldehydes
Summary
Dicoumarol (3,3-methylene-bis-4-hydroxycoumarin) is a naturally coumarin-based compound which has long been used as an oral anticoagulant drug. It is metabolically produced from coumarin which was first isolated from both of the Tonka bean (Dipteryx odorata) and the sweet clover (Melilotus alba and Melilotus officinalis) [1]. Many dicoumarols and coumarin derivatives have shown a variety of pharmaceutical activities such as antiinflammatory, antibacterial, antiviral, anticancer, anti-HIV, and antiproliferative properties [3,4,5,6,7,8,9]. Dicoumarols have received much attention for medical and pharmaceutical applications
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