Cyclobutane carboxamide inhibitors of fungal melanin: Biosynthesis and their evaluation as fungicides

A new fungicide lead has been identified by enzyme screening of a focused c ombinatorial library. The lead compound 4, a potent inhibitor of scytalone dehydratase (SD), exhibits fungicidal activity upon foliar application but does not show systemic activity. The X-ray crystal structure of the enzyme- inhibitor complex and an appreciation for the relationship between physical properties and systemic activity enabled us to rapidly improve upon this i nitial lead. The geminal halogen-methyl group combination was found to be o ptimal for interaction with the bounding serine and asparagine side-chain r esidues. Replacement of CF3 with methyl was a key discovery, giving inhibit ors with slightly diminished enzyme inhibition potency while significantly increasing systemic activity. Amides prepared from amines with 2,4-dichloro substitution on the phenyl ring gave the most potent enzyme inhibitors. Tw o compounds from this series showed systemic activity comparable to the com mercial standard and were selected for outdoor testing in flooded plots whi ch simulate rice paddies. (C) 2000 Elsevier Science Ltd. All rights reserve d.