Mode of action of novel acaricide pyflubumide: Effects on the mitochondrial respiratory chain

Abstract

This study aimed to determine the mode of action of pyflubumide, a novel acaricide under development by Nihon Nohyaku Co., Ltd. Because of its structural similarity to succinate-dehydrogenase inhibitor (SDHI) fungicides, its ability to inhibit mitochondrial complex II was investigated. Pyflubumide exhibited low inhibitory activity on spider mite mitochondria; conversely, its deacylated metabolite (NH-form) showed high mitochondrial inhibitory activity. Pyflubumide was quickly metabolized to its NH-form in the homogenate of spider mites. These results suggest that pyflubumide is a prodrug and that the NH-form is active. Indeed, the NH-form of pyflubumide and the OH-form of cyenopyrafen, a complex II inhibitory acaricide, act on the same enzyme; a double-inhibitor titration assay showed that the binding sites on mitochondrial complex II and/or the manners of binding of these compounds exhibit clear differences. This finding suggests that these two acaricides should be classified into different groups in terms of their mode of action.

Synthesis and biological activity of a novel acaricide, pyflubumide

“…Taking into consideration the possible decomposability of these functional groups, the excellent activity of less-hindered acyl-substituted In fact, when pyflubumide was incubated with spider mite (T. urticae) homogenate, its deacylated derivative 9 was observed. 20) This result strongly supports our hypothesis that the deacylated derivatives would be the active forms and excellent acaricidal activity is derived by improving penetration and metabolic activation.…”

“…21,22) However, it was also suggested that their binding sites on mitochondrial complex II and/ or the manners of binding are not identical. 20,23,24) These results demonstrate that pyflubumide could be a promising new acaricide. Pyflubumide has been tested in official trials with the code number NNI-0711 in Japan since 2007, and a registration petition for this acaricide has already been made in 2012.…”

“…1,3-Dimethylbutyl derivative 11 showed good acaricidal activity. Further investigation revealed that the 1,3-dimethylbutyl group was the most favorable substituent for the 2′-position (16)(17)(18)(19)(20). It was noteworthy that the most favorable substituent was the same as that of penthiopyrad and penflufen.…”

The economic importance of acaricides in the control of phytophagous mites and an update on recent acaricide mode of action research

“…Similar to cyenopyrafen and cyflumetofen, it was found that pyflubumide is a pro-acaricide, with its metabolite exhibiting high inhibitory activity on mitochondrial complex II. Interestingly, its binding manner was suggested to be different than that from cyenopyrafen, but detailed data to support this claim are currently lacking [82,95].…”

Chance and design in proinsecticide discovery

“…Metabolic activation occurs through an N‐dealkylation of a small alkyl ether to form the secondary amide active compound (Fig. ) …”