Inhibitors of brassinin oxidase (BOLm), a unique phytoalexin detoxifying enzyme produced by the plant pathogenic fungus Leptosphaeria maculans (asexual stage Phoma lingam), were designed based on scaffolds of the phytoalexins brassilexin and wasalexin. Evaluation of these compounds using purified BOLm established that the inhibitory effect of brassilexin and derivatives decreased as follows: 6-chlorobrassilexin approximately 6-bromobrassilexin>5-bromobrassilexin approximately 5-chlorobrassilexin approximately 6-fluorobrassilexin>8-methylbrassilexin>brassilexin approximately 5-fluorobrassilexin. 6-Chlorobrassilexin was determined to be the best competitive inhibitor of BOLm discovered to date, with a K(i)=31microM. Importantly, brassilexin and derivatives did not appear to induce BOLm in fungal cultures. Overall, these results suggest that the brassilexin scaffold is a good lead for further development of paldoxins against L. maculans, as it inhibits competitively BOLm without apparent induction.
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