Centre of Microbial and Plant Genetics (CMPG), Katholieke Universiteit Leuven, Heverlee, Belgium.
Bioorg Med Chem Lett. 2011 Jun 15;21(12):3686-92. doi: 10.1016/j.bmcl.2011.04.075. Epub 2011 Apr 24.
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.
合成了一系列取代的苄硫基-苯基胺，其中四个取代的苄硫基-苯基胍（665、666、667 和 684）表现出很强的杀菌活性（最小杀菌浓度，MFC≤10μM，用于白色念珠菌和光滑念珠菌）。具有未取代胍的苄硫基-苯基支架导致活性较低的化合物（MFC=50-100μM），而用未取代的胺基取代则导致没有杀菌活性的化合物。化合物 665、666、667 和 684 还对单一白色念珠菌生物膜和由白色念珠菌和表皮葡萄球菌组成的生物膜表现出活性（导致生物膜减少 50%的最小浓度，两种生物膜设置的 BEC50≤121μM）。化合物 665 和 666 结合了强大的杀菌（MFC=5μM）和杀菌活性（最小杀菌浓度，S. epidermidis 的 MBC≤4μM）。在体内秀丽隐杆线虫模型中，化合物 665 和 667 的毒性低于 666 和 684。此外，将这些化合物添加到感染白色念珠菌的秀丽隐杆线虫培养物中，导致感染白色念珠菌的线虫存活率增加，证明了它们在小型宿主模型中的体内功效。
