title: 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as broad-spectrum antifungal agents.
abstract: 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.
authors.affiliation: Cistim Leuven vzw , Bioincubator 2, Gaston Geenslaan 2, 3001 Leuven, Belgium.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Bardiot
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.forename: Katrijn
authors.initials: K
authors.lastname: De Brucker
authors.forename: Annelies
authors.initials: A
authors.lastname: Peeters
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Taborda
authors.forename: Michael
authors.initials: M
authors.lastname: McNaughton
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaltin
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchand
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000081:Acetamides; D000935:Antifungal Agents; D009025:Morpholines; C000596771:N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide