Morphing Natural Product Platensimycin via Heck, Sonogashira, and One-Pot Sonogashira/Cycloaddition Reactions to Produce Antibiotics with In Vivo Activity.

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against β -ketoacyl-[acyl carrier protein] synthase II (FabF) and β -ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further development. In this work, thirty-two PTM derivatives were rapidly prepared via Heck, Sonogashira, and one-pot Sonogashira/cycloaddition cascade reactions based on the Gram-scale synthesis of 6-iodo PTM ( 4 ). About half of the synthesized compounds were approximately equipotent to PTM against the tested Staphylococcus aureus strains. Among them, the representative compounds 4 , A4 , and B8 exhibited different plasma protein binding affinity or stability in the human hepatic microsome assay and showed improved in vivo efficacy over PTM in a mouse peritonitis model. In addition, A4 was also effective in an S. aureus -infected skin mouse model. Our study not only significantly expands the known PTM derivatives with improved antibacterial activities in vivo, but showcased that C-C cross-coupling reactions are useful tools to functionalize natural product drug leads.