Synthesis and antibacterial activity against Clostridium difficile of novel demethylvancomycin derivatives

To explore the structure–activity relationships (SAR) of demethylvancomycin (2) and find more effective new chemical entities than known glycopeptides for the treatment of Clostridium difficile (C. difficile), 17 novel N-substituted (N-arylmethylene or -aliphatic substituents) demethylvancomycin derivatives were prepared. These analogues have been evaluated in vitro for their antibacterial activities against C. difficile and Enterococcus faecium (E. faecium). Compounds 5d, 5h, and 5i with N-arylmethylene substituents, structurally similar to Oritavancin, showed more potent antibacterial activity against C. difficile than vancomycin (1) or demethylvancomycin (2). Meanwhile, compound 5k with an undecyl side chain showed the most potent antibacterial activity against E. faecium (vancomycin-resistant strain).

Graphical abstractSeventeen novel N-substituted demethylvancomycin derivatives were prepared and evaluated in vitro for their antibacterial activities against C. difficile and E. faecium. Compounds 5d, 5h, and 5i showed more potent antibacterial activity against C. difficile, while 5k showed the most potent antibacterial activity against E. faecium.Figure optionsDownload full-size imageDownload as PowerPoint slide