Unraveling the molecular drivers of antibacterial prenylated (iso)flavonoids and chalcones against Streptococcus mutans

Given the negative side effects and increased resistance associated with conventional oral antimicrobials, prenylated phenolics are promising alternatives to combat the oral pathogen Streptococcus mutans. A total of 40 prenylated phenolics were evaluated for their antibacterial activity against S. mutans. Eleven prenylated phenolics were purified from licorice (Glycyrrhiza spp.) spent, including the newly discovered double prenylated 2-arylbenzofuran, isokanzonol V. Twenty-eight compounds showed similar potency as chlorhexidine. Activity was correlated with structural properties and novel structure–activity relationships were established: (i) Hydrophobic volume was the main driver associated to activity (double prenylated phenolics were consistently more active than single prenylated phenolics); (ii) the conversion of flavanones to chalcones by C-ring opening increases molecular length and planarity as well as antibacterial activity, and (iii) active single prenylated isoflavones have balanced molecular hydrophilicity. Hence, double or single prenylated phenolics featuring planarity, an extended configuration, and balanced hydrophilicity hold promise for S. mutans control.