Novel fungicidal benzylsulfanyl-phenylguanidines

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 synthesiz...

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Bibliographic Details
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
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Summary:	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.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2011.04.075 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.04.075