title: Novel fungicidal benzylsulfanyl-phenylguanidines.
abstract: 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 ≤ 10 μM for Candida albicans and Candida glabrata). A benzylsulfanyl-phenyl scaffold with an unsubstituted guanidine resulted in less active compounds (MFC=50-100 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 ≤ 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 ≤ 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.
authors.affiliation: Centre of Microbial and Plant Genetics (CMPG), Katholieke Universiteit Leuven, Heverlee, Belgium. karin.thevissen@biw.kuleuven.be
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.forename: Klaartje
authors.initials: K
authors.lastname: Pellens
authors.forename: Katrijn
authors.initials: K
authors.lastname: De Brucker
authors.forename: Isabelle E J A
authors.initials: IE
authors.lastname: François
authors.forename: Kwok K
authors.initials: KK
authors.lastname: Chow
authors.forename: Els M K
authors.initials: EM
authors.lastname: Meert
authors.forename: Wim
authors.initials: W
authors.lastname: Meert
authors.forename: Geert
authors.initials: G
authors.lastname: Van Minnebruggen
authors.forename: Marcel
authors.initials: M
authors.lastname: Borgers
authors.forename: Valérie
authors.initials: V
authors.lastname: Vroome
authors.forename: Jeremy
authors.initials: J
authors.lastname: Levin
authors.forename: Dirk
authors.initials: D
authors.lastname: De Vos
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects*; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D008954:Models, Biological; D015394:Molecular Structure; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000935:Antifungal Agents; D006146:Guanidines; D013440:Sulfides