Synthesis and Biological Evaluation of Fingolimod Derivatives as Antibacterial Agents

We recently identified fingolimod as a potent antibiofilm compound by screening FDA-approved drugs. To study if the antibacterial activity of fingolimod could be further improved and to explore in-depth structure-activity relationships, we synthesized 28 novel fingolimod derivatives and evaluated their efficacy against Staphylococcus aureus grown in planktonic/single cell and biofilms. The most effective derivatives were tested on preformed S. aureus biofilms and against Gram-negative bacteria Acinetobacter baumannii and Pseudomonas aeruginosa , using fingolimod as the reference compound. Seven derivatives were more effective against S. aureus , while five other derivatives showed improved activity against P. aeruginosa and/or A. baumannii , with no apparent change in cytotoxicity on human cells. The most interesting derivatives, compounds 43 and 55 , displayed a broader spectrum of antibacterial activity, possibly exerted by the change of the para -hydrocarbon chain to a meta position for 43 and by an additional hydroxyl group for 55 .