5.5.6
DIFFERENCES IN THE MODE OF ACTION OF LY214352 AND QUINOXYFEN

MJ HENRY1, AJ SMITH1, GD GUSTAFSON1, S AIGLE1, A HANNUM1, W ARNOLD1, M BARKHAM2, H HILL1, A ORTH1 and C LINGHURST2

1Dow AgroSciences LLC, Discovery Research, 9330 Zionsville Rd. Indianapolis IN 46268-1054, USA; 2 Dow AgroSciences LLC, Letcombe Research Laboratories, Letcombe Regis, Wantage, Oxfordshire, UK OX12 9JT

Quinoxyfen (XDE-795), a 5,7-dichloroquinoline compound, is a novel fungicide highly specific for the control of powdery. In contrast, a series of 8-chloro-quinoline analogs, typified by LY214352, are broad spectrum in their in vitro growth inhibition activity and have demonstrated disease control activity on several fungal pathogens in greenhouse and laboratory studies particularly for the control of Botrytis cinerea on grape.

In vitro growth studies with 47 fungi from different classes were unable to identify any species with appreciable sensitivity to quinoxyfen at concentrations of 50 ppm while LY214352 at concentrations less than 10 ppm was a potent inhibitor of mycelial growth of species such as Aspergillus nidulans, Septoria nodorum, Pyricularia oryzae and Botrytis cinerea. LY214352 has been shown by biochemical and genetic analysis to be a potent inhibitor of the enzyme dihydroortate dehydrogenase (DHO-DH) in A. nidulans and this appears to be the primary mode of toxicity for the 8-chloro-quinolines [1]. Similarly, LY214352 and related analogs demonstrated potent enzyme inhibition of DHO-DH from several fungal pathogens that was consistent with the inhibition of growth and disease control. DHO-DH enzyme isolated from fungal species insensitive to LY214352 was not inhibited by LY214352. Structure activity and cross resistance analysis of analogs showed that the substitution pattern on the quinoline as well as the phenoxy moieties had strong influence on the DHO-DH activity and cross resistance. Cell free preparations of DHO-DH activity isolated from Erysiphe graminis conidia harvested from barley leaves, failed to show any significant inhibition of enzyme activity by quinoxyfen or LY214352 or related analogs. Specific activity measurements of the DHO-DH enzyme activity from Erysiphe conidia were consistent with those measured from other sources. Failure of quinoxyfen to inhibit DHO-DH from the only organism that is highly sensitive to it indicates that quinoxyfen is not a DHO-DH inhibitor, but has a alternative mechanism of action that has yet to be elucidated.

References
1. Gustafson 1996. Current Genetics 30, 159.