Discovery, Synthesis, and Biological Evaluation of Dunnianol-Based Mannich Bases against Methicillin-Resistant <i>Staphylococcus aureus</i> (MRSA)

Abstract

Dunnianol, a natural sesqui-neoligan derived from the leaves and stems of <i>Illicium simonsii</i> 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, <b>5a'</b>, exhibited excellent antibacterial activity against <i>Staphylococcus aureus</i> and clinically isolated methicillin-resistant <i>Staphylococcus aureus</i> (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 <b>5a'</b> killed MRSA more rapidly than did vancomycin by disrupting the cell membrane. Moreover, <b>5a'</b> was not susceptible to drug resistance development and also showed low toxicity and good antibacterial efficacy <i>in vivo</i>. These results indicate that the dunnianol-based Mannich base <b>5a'</b> could be a promising antibiotic candidate for further research.