Dunnianol, a natural sesqui-neoligan derived from the leaves and stems of Illicium simonsii Maxim, has been found to possess moderate antibacterial activity. To improve the antibacterial activity and solubility of dunnianol, a series of dunnianol-based Mannich bases were prepared and evaluated for their antibacterial activities. The most promising compound, 5a', exhibited excellent antibacterial activity against Staphylococcus aureus and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 1 to 2 μg/mL. Structure-activity relationships indicated that the introduction of (dimethylamino)methyl at the ortho position of the phenolic hydroxyl group of dunnianol could obtain a more active compound. A mechanism study revealed that 5a' killed MRSA more rapidly than did vancomycin by disrupting the cell membrane. Moreover, 5a' was not susceptible to drug resistance development and also showed low toxicity and good antibacterial efficacy in vivo. These results indicate that the dunnianol-based Mannich base 5a' could be a promising antibiotic candidate for further research.
Keywords: Mannich base; antibacterial activity; bacterial resistance; dunnianol; methicillin-resistant Staphylococcus aureus.