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.