Journal of medicinal chemistry · 2015
2-(2-oxo-morpholin-3-yl)-acetamide derivatives as broad-spectrum antifungal agents.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Bardiot Dorothée, Thevissen Karin, De Brucker Katrijn, Peeters Annelies, Cos Paul, Taborda Carlos P, McNaughton Michael, Maes Louis, Chaltin Patrick, Cammue Bruno P A, Marchand Arnaud
Аннотация
From a fungicidal screen, we identified 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as fungicidal agents against Candida species, additionally characterized by antifungal activity against Aspergillus species. However, development of this series was hampered by low plasmatic stability. Introduction of a gem-dimethyl on the 6-position of the morpholin-2-one core led to considerable improvement in plasmatic stability while maintaining in vitro antifungal activity. Further optimization of the series resulted in the discovery of N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide (87), which, in addition to fungicidal activity against Candida species, shows promising and broad antifungal in vitro activity against various fungi species, such as molds and dermatophytes. In vivo efficacy was also demonstrated in a murine model of systemic Candida albicans infection with a significant fungal load reduction in kidneys.