Undefeated—Changing the phenamacril scaffold is not enough to beat resistant Fusarium

Abstract

Filamentous fungi belonging to the genus Fusarium are notorious plant-pathogens that infect, damage and contaminate a wide variety of important crops. Phenamacril is the first member of a novel class of single-site acting cyanoacrylate fungicides which has proven highly effective against important members of the genus Fusarium. However, the recent emergence of field-resistant strains exhibiting qualitative resistance poses a major obstacle for the continued use of phenamacril. In this study, we synthesized novel cyanoacrylate compounds based on the phenamacril-scaffold to test their growth-inhibitory potential against wild-type Fusarium and phenamacril-resistant strains. Our findings show that most chemical modifications to the phenamacril-scaffold are associated with almost complete loss of fungicidal activity and in vitro inhibition of myosin motor domain ATPase activity.

Effects of Mutations in the Phenamacril-Binding Site of Fusarium Myosin-1 on Its Motor Function and Phenamacril Sensitivity

“…Because the cyano group of phenamacril does not form any discernible interaction with FgMyo1 except for the nonessential hydrogen bond with the S217 OH group, we propose the cyano group of phenamacril as a key modification site for the development of novel fungicides. Wollenberg et al recently showed that substitution of the cyano group of phenamacril with an ethyl ester completely abolishes the fungicidal activity and the inhibition of FgMyo1 ATPase activity . This is likely caused by the steric hindrance of the ethyl ester, which is much bulkier than the cyano group.…”

“…Wollenberg et al recently showed that substitution of the cyano group of phenamacril with an ethyl ester completely abolishes the fungicidal activity and the inhibition of FgMyo1 ATPase activity. 25 This is likely caused by the steric hindrance of the ethyl ester, which is much bulkier than the cyano group. We expect that phenamacril analogues with smaller substituents in place of the cyano group might retain the fungicidal activity.…”