title: Synthesis and antifungal activity of 2H-1,4-benzoxazin-3(4H)-one derivatives.
abstract: A series of 2-alkyl-2H-1,4-benzoxazin-3(4H)-ones (4a-l) was easily synthesized by two-step process involving O-alkylation of 2-nitrophenols with methyl 2-bromoalkanoates and next "green" catalytic reductive cyclization of the obtained 2-nitro ester intermediates (3a-l). Further, 6,7-dibromo (5a-c) and N-acetyl (6) derivatives were prepared by bromination and acetylation of unsubstituted 2-alkyl-2H-1,4-benzoxazin-3(4H)-ones (4a-c). The novel compounds (3a-l, 4d-l, 5a-c and 6) were fully characterized by spectroscopic methods (MS, (1)H and (13)C NMR). 2-Alkyl-2H-1,4-benzoxazin-3(4H)-ones (4a-l, 5a-c and 6) were screened for antifungal activity. Preliminary assays were performed using two methods: in vitro against seven phytopathogenic fungi-Botrytis cinerea, Phythophtora cactorum, Rhizoctonia solani, Phoma betae, Fusarium culmorum, Fusarium oxysporum and Alternaria alternata-and in vivo against barley powdery mildew Blumeria graminis. The tested compounds displayed moderate to good antifungal activity at high concentration (200 mg L(-1)). The most potent compounds were 2-ethyl-2H-1,4-benzoxazin-3(4H)-one (4a), 2-ethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (4g) and 4-acetyl-2-ethyl-2H-1,4-benzoxazin-3(4H)-one (6), which completely inhibited the mycelial growth of seven agricultural fungi at the concentration of 200 mg L(-1) in the in vitro tests. Moreover, 2-ethyl-2H-1,4-benzoxazin-3(4H)-one (4a) and 4-acetyl-2-ethyl-2H-1,4-benzoxazin-3(4H)-one (6) were also screened for antifungal activity at concentrations of 100 mg L(-1) and 20 mg L(-1). In the concentration of 100 mg L(-1), the N-acetyl derivative (6) completely inhibited the growth of three strains of fungi (F. culmorum, P. cactorum and R. solani), while 2-ethyl-2H-1,4-benzoxazin-3(4H)-one (4a) completely inhibited only R. solani strain. At the concentration of 20 mg L(-1), compound 6 showed good activity only against P. cactorum strain (72%).
authors.affiliation: a Institute of Chemical Organic Technology, West Pomeranian University of Technology , Szczecin , Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Śmist
authors.affiliation: a Institute of Chemical Organic Technology, West Pomeranian University of Technology , Szczecin , Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Kwiecień
authors.affiliation: b Department of Applications and Formulation of Pesticides , Institute of Industrial Organic Chemistry , Warsaw , Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Krawczyk
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D048588:Benzoxazines / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005658:Fungi / Q000187:drug effects / Q000472:pathogenicity; D005670:Fusarium / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010944:Plants / Q000382:microbiology*
chemical_list: D000935:Antifungal Agents; D048588:Benzoxazines
keywords: 1,4-Benzoxazin-3(4H)-ones; O-alkylation; fungicides; reductive cyclization