Antifungal Properties of Novel N- and α,β-Substituted Succinimides against Dermatophytes

The synthesis and antifungal properties of a series of new N-aryl α,β-substituted succinimides against a panel of dermatophytes of clinical relevance are reported. Among those compounds possessing a N-phenyl substituent, 7-thia-2-azabicyclo[2,2,1]hept-2-en-3-amine[5,6-c]succinimide was the better inhibitor of Trichophyton rubrum , the major ethiological agent of all infections produced by dermatophytes. In contrast, succinimides containing a N-(p-sulfonylphenyl) substituent, only inhibited Epidermophyton floccosum , all active compounds possessing an oxabicyclo group in positions α,β of the imide. Substituents on the oxabicyclo group were important for the activity. Regarding the mechanism of action, N-(p-N’-4-methoxyphenylsulfamoylphenyl)-8-oxabicyclo[2,2,1]hept-4-en-3-methyl[5,6-c]succinimide produced a mottled inhibition halo in the Neurospora crassa assay, showing that it would act by inhibiting the synthesis or assembly of the fungal cell wall.