Novel fungicidal benzylsulfanyl-phenylguanidinesNovel fungicidal benzylsulfanyl-phenylguanidines
François, Isabelle E.J.A.
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Laboratory for Microbiology, Parasitology and Hygiene (LMPH)
Bioorganic and medicinal chemistry letters. - Oxford
21(2011):12, p. 3686-3692
University of Antwerp
A series of substituted benzylsulfanyl-phenylamines was synthesized, of which four substituted benzylsulfanyl-phenylguanidines (665, 666, 667 and 684) showed potent fungicidal activity (minimal fungicidal concentration, MFC less-than-or-equals, slant 10 μM for Candida albicans and Candida glabrata). A benzylsulfanyl-phenyl scaffold with an unsubstituted guanidine resulted in less active compounds (MFC = 50100 μM), whereas substitution with an unsubstituted amine group resulted in compounds without fungicidal activity. Compounds 665, 666, 667 and 684 also showed activity against single C. albicans biofilms and biofilms consisting of C. albicans and Staphylococcus epidermidis (minimal concentration resulting in 50% eradication of the biofilm, BEC50 less-than-or-equals, slant 121 μM for both biofilm setups). Compounds 665 and 666 combined potent fungicidal (MFC = 5 μM) and bactericidal activity (minimal bactericidal concentration, MBC for S. epidermidis less-than-or-equals, slant 4 μM). In an in vivo Caenorhabditis elegans model, compounds 665 and 667 exhibited less toxicity than 666 and 684. Moreover, addition of those compounds to Candida-infected C. elegans cultures resulted in increased survival of Candida-infected worms, demonstrating their in vivo efficacy in a mini-host model.