Gladiolic acid, a metabolic product of Penicillium gladioli. 2. Structure and fungistatic activity

Abstract

Gladiolic acid (4-methoxy-5-methyl-o-phthal-aldehyde-3-carboxylic acid in the open-chain form) is the only fungistatic compound among the known metabolic products of Penicillium gladioli Machacek. o-Phthalaldehyde shows fungistatic activity in the same concn. range as gladiolic acid, and tests on a large number of derivatives of gladiolic acid and on simple model substances indicate that activity is connected with the presence of 2 formyl substituents in the ortho position on the aromatic nucleus. The lactol form of gladiolic acid (4-formyl-3-hydroxy-7-methoxy-6-methylphthalide) is believed to be inactive. The percentage of dissociated molecules of gladiolic acid present at any given pH is in good agreement with the percentage of hydrated open-chain (dihydroxyphthalan) form calculated from the ultraviolet absorption. The undissociated lactol and hydrated open-chain anion make up 99% of the total gladiolic acid present at any given pH. An attempt to explain the variation of the equieffective concentration of gladiolic acid with the external pH, on the basis that whereas the hydrated open-chain anion is the active species, only the undissociated lactol form penetrates into the spore, is not unsuccessful The variation with pH of the activity of acetyl-gladiolic acid and certain closely related neutral derivatives is not quite so satisfactorily explained on the hypothesis that the molecules penetrate unchanged but undergo internal enzymic hydrolysis to gladiolic acid. The enhanced specificity of the fungistatic action of gladiolic acid compared with that of o-phthalaldehyde arises from the presence of the carboxyl substituent adiacent to the o-diformyl grouping.