Synthesis and anti-fungal activity of simple β-lactams

A series of 4-aryloxy- and 4-arylthioazetidin-2-ones A and B were synthesized by reacting 4-acetoxyazetidin-2-one with phenols or thiophenols and subsequent alkylation at the nitrogen with alkylcarboxymethyl groups. Several compounds had anti-fungal activity in vitro against various strains of Microsporum, Trichophyton and a few also against Candida. A multiple regression analysis of the dependence of minimum inhibitory concentration on T. mentagrophytes from logP and Verloop's parameters L, B1, B4 and B5, although not very satisfactory, seems to indicate that steric parameters are the most important in determining the activity. The strong difference in activity between the enantiomers of 4-phenyl-thioazetidin-2-one lends support to the hypothesis of a possible correlation between the 4S configuration of the β-lactam and anti-fungal activity, which has been proposed for some natural clavams.