Antibacterial Activity and Molecular Docking Studies of a Selected Series of Hydroxy-3-arylcoumarins

Abstract

Antibiotic resistance is one of the main public health concerns of this century. This resistance is also associated with oxidative stress, which could contribute to the selection of resistant bacterial strains. Bearing this in mind, and considering that flavonoid compounds are well known for displaying both activities, we investigated a series of hydroxy-3-arylcoumarins with structural features of flavonoids for their antibacterial activity against different bacterial strains. Active compounds showed selectivity against the studied Gram-positive bacteria compared to Gram-negative bacteria. 5,7-Dihydroxy-3-phenylcoumarin (compound 8) displayed the best antibacterial activity against Staphylococcus aureus and Bacillus cereus with minimum inhibitory concentrations (MICs) of 11 g/mL, followed by Staphylococcus aureus (MRSA strain) and Listeria monocytogenes with MICs of 22 and 44 g/mL, respectively. Moreover, molecular docking studies performed on the most active compounds against Staphylococcus aureus tyrosyl-tRNA synthetase and topoisomerase II DNA gyrase revealed the potential binding mode of the ligands to the site of the appropriate targets. Preliminary structure-activity relationship studies showed that the antibacterial activity can be modulated by the presence of the 3-phenyl ring and by the position of the hydroxyl groups at the coumarin scaffold.

Keywords: Perkin–Oglialoro reaction; antibacterial activity; hydroxy-3-arylcoumarins; molecular docking.

Figure 1

Chemical structure of some flavonoids and a flavonoid analogue (3-arylcoumarin).

Scheme 1

Synthetic routes and chemical structures of compounds 1–10.

Figure 2

Interaction network between S. aureus tyrosyl-tRNA synthetase protein and the studied compounds. The negatively charged residues are shown in red, polar residues in cyan, and hydrophobic residues in parrot green. Hydrogen bond (H-bond) interactions are shown as pink arrow.

Figure 3

Interaction network between topoisomerase II DNA gyrase and the studied compounds. The protein residues with a negative charge are shown in red, positive charge in velvet, polar in cyan, and hydrophobic in parrot green. The DNA bases are shown in grey. The H-bond interactions are shown as pink arrow, pi–pi stacking as green line, and pi–cation as red line.