Synthesis and Antimicrobial Activity of Canthin-6-One Alkaloids

Canthin-6-one alkaloids have consistently attracted the interest of medicinal chemists due to their wide range of promising bioactivities, including antitumor, antifungal, antibacterial, and antiviral properties. However, their low natural abundance in plants has constrained the further exploration of their potential bioactivities. This study reports a comprehensive synthesis of canthin-6-one alkaloids, utilizing key Suzuki coupling and Cu-catalyzed amidation reactions to construct their core scaffold. Derivatives were synthesized with Koenig-Knorr glycosylation for the further modification of synthetic canthin-6-ones. The antimicrobial activities of the synthesized compounds were evaluated against <i>C. albicans</i>, <i>C. neoformans</i>, <i>S. aureus</i> and <i>E. coli</i> using the micro-dilution method. In total, 17 compounds were synthesized, including nine canthin-6-ones. Notably, alkaloids <b>4</b>, <b>5</b>, <b>7</b> and <b>12</b>-<b>13</b> were prepared for the first time, along with 8 new derivatives. Their structures were confirmed by NMR and MS analyses. At 50 µg/mL, the alkaloids <b>1</b>-<b>4</b> and <b>9</b> exhibited antimicrobial properties against <i>C. albicans</i>, <i>C. neoformans</i> and <i>S. aureus</i>. The antimicrobial activity of alkaloids <b>2</b>, <b>4</b>-<b>5</b> and <b>12</b>-<b>13</b> against these four microbial human pathogens is reported here for the first time. Overall, this research not only advances our understanding of canthin-6-one alkaloid synthesis, but also provides a foundation for developing novel compounds with pharmaceutical properties.