Novel fungicidal benzylsulfanyl-phenylguanidines

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 12; pp. 3686 - 3692
• Main Authors: Thevissen, Karin, Pellens, Klaartje, De Brucker, Katrijn, François, Isabelle E.J.A., Chow, Kwok K., Meert, Els M.K., Meert, Wim, Van Minnebruggen, Geert, Borgers, Marcel, Vroome, Valérie, Levin, Jeremy, De Vos, Dirk, Maes, Louis, Cos, Paul, Cammue, Bruno P.A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-06-2011; Elsevier
• Subjects: Animals; antibacterial properties; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; antifungal properties; Benzylsulfanyl-phenylguanidines; Biofilm; Biological and medical sciences; Caenorhabditis elegans; Caenorhabditis elegans - drug effects; Candida albicans; Candida albicans - drug effects; Candida glabrata; Fungicidal; General aspects; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - pharmacology; Guanidines - toxicity; Medical sciences; minimum inhibitory concentration; Models, Biological; Molecular Structure; Pharmacology. Drug treatments; Staphylococcus epidermidis; Sulfides - chemical synthesis; Sulfides - chemistry; Sulfides - pharmacology; Sulfides - toxicity; toxicity; Candida albicans; BEC; Fungicidal; Biofilm; MFC; Benzylsulfanyl-phenylguanidines; MBC; Candida glabrata; Guanidines; Biological activity; Organic sulfide; Fungi; Antifungal agent; Staphylococcus epidermidis; Chlorine Organic compounds; Bacteria; Micrococcales; Benzenic compound; Micrococcaceae; Bromine Organic compounds; Fungi Imperfecti; Antibacterial agent; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.04.075

Benzylsulfanyl-phenylguanidines
665 and
667 combined potent fungicidal and bactericidal activity. These compounds exhibited minor toxicity in a
Caenorhabditis elegans model and showed in vivo efficacy in a
Candida-infected worm model.
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.