This paper reviews the discovery of isoxa¯utole (IFT), focusing on the chemical and physicochemical properties which contribute to the herbicidal behaviour of this new herbicide. IFT (5-cyclopropyl-1,2-isoxazol-4-yl aaa-tri¯uoro-2-mesyl-p-tolyl ketone) is a novel herbicide for pre-emergence control of a wide range of important broadleaf and grass weeds in corn and sugarcane. The ®rst benzoyl isoxazole lead was synthesised in 1989 and IFT in 1990, and the herbicidal potential of the latter was identi®ed in 1991. The decision to develop the molecule was taken after two years of ®eld testing in North America.The biochemical target of IFT is 4-hydroxyphenylpyruvate dioxygenase (HPPD), inhibition of which leads to a characteristic bleaching of susceptible species. The inhibitor of HPPD is the diketonitrile derivative of IFT formed from opening of the isoxazole ring. The diketonitrile (DKN) is formed rapidly in plants following root and shoot uptake. The DKN is both xylem and phloem mobile leading to high systemicity. IFT also undergoes conversion to the DKN in the soil. The soil half-life of IFT ranges from 12 h to 3 days under laboratory conditions and is dependent on several factors such as soil type, pH and moisture. The log P of IFT is 2.19 and the water solubility is 6.2 mg litre À1 , whereas the corresponding values for the DKN are 0.4 and 326 mg litre À1 , respectively. These properties restrict the mobility of IFT, which is retained at the soil surface where it can be taken up by surface-germinating weed seeds. The DKN, which has a laboratory soil half-life of 20±30 days, is more mobile and is taken up by the roots. In addition to in¯uencing the soil behaviour of IFT and DKN, the greater lipophilicity of IFT leads to greater uptake by seed, shoot and root tissues. In both plants and soil, the DKN is converted to the herbicidally inactive benzoic acid. This degradation is more rapid in maize than in susceptible weed species and this contributes to the mechanism of selectivity, together with the greater sowing depth of the crop.

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This paper reviews the discovery of isoxaflutole (IFT), focusing on the chemical and physicochemical properties which contribute to the herbicidal behaviour of this new herbicide. IFT (5-cyclopropyl-1,2-isoxazol-4-yl alpha alpha alpha-trifluoro-2-mesyl-p-tolyl ketone) is a novel herbicide for pre-emergence control of a wide range of important broadleaf and grass weeds in corn and sugarcane. The first benzoyl isoxazole lead was synthesised in 1989 and IFT in 1990, and the herbicidal potential of the latter was identified in 1991. The decision to develop the molecule was taken after two years of field testing in North America. The biochemical target of IFT is 4-hydroxyphenylpyruvate dioxygenase (HPPD), inhibition of which leads to a characteristic bleaching of susceptible species. The inhibitor of HPPD is the diketonitrile derivative of IFT formed from opening of the isoxazole ring. The diketonitrile (DKN) is formed rapidly in plants following root and shoot uptake. The DKN is both xylem and phloem mobile leading to high systemicity. IFT also undergoes conversion to the DKN in the soil. The soil half-life of IFT ranges from 12 h to 3 days under laboratory conditions and is dependent on several factors such as soil type, pH and moisture. The log P of IFT is 2.19 and the water solubility is 6.2 mg litre-1, whereas the corresponding values for the DKN are 0.4 and 326 mg litre-1, respectively. These properties restrict the mobility of IFT, which is retained at the soil surface where it can be taken up by surface-germinating weed seeds. The DKN, which has a laboratory soil half-life of 20-30 days, is more mobile and is taken up by the roots. In addition to influencing the soil behaviour of IFT and DKN, the greater lipophilicity of IFT leads to greater uptake by seed, shoot and root tissues. In both plants and soil, the DKN is converted to the herbicidally inactive benzoic acid. This degradation is more rapid in maize than in susceptible weed species and this contributes to the mechanism of selectivity, together with the greater sowing depth of the crop.

The benzoyl isoxazole herbicide RPA 201772, common name isoxaÑutole ( Fig. 1), is a novel product being developed for pre-and early post-emergence weed control in maize and sugarcane.1 In plants and soil the isoxazole ring opens, forming a diketonitrile derivative (Fig. 1).2 This is likely to be the active herbicidal principle of isoxaÑutole, as it is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD) in plants. Furthermore, the subsequent metabolic degradation of the diketonitrile occurs more rapidly in tolerant species such as maize and this appears to be the basis for herbicidal selectivity.2IsoxaÑutole causes a bleaching symptomology in susceptible species similar to that seen with herbicidal inhibitors of carotenoid biosynthesis, e.g. deÑufenican and other phytoene desaturase (PDS) inhibitors. Coincident with decreases in carotenoid levels following isoxaÑutole treatment is an accumulation of the PDS substrate, phytoene. IsoxaÑutole and its diketonitrile derivative were tested for their ability to inhibit PDS isolated from cultured carrot cell microsomes. At concentrations up to 100 kM neither compound signiÐ-cantly inhibited PDS activity, whereas standards such as diÑufenican and Ñurtamone had values of 100 IC 50 and 400 nM respectively. Therefore, the accumulation of phytoene in treated leaves and bleaching symptoms appears to be due to an indirect e †ect on PDS.HPPD catalyses the oxidative decarboxylation of 4-hydroxyphenylpyruvate forming homogentisate. The reaction mechanism, which is still not fully understood, involves ring peroxidation, leading to ring hydroxylation and side chain migration.3,4 Homogentisate then undergoes prenylation and methylation forming isoprenoid quinones required in biological redox reactions, such as plastoquinone. In bleached leaves levels of plastoquinone are depleted in advance of carotenoids. For example, HPLC analysis of Brassica kaber Wheeler seedlings revealed 40 and 75% decrease in plastoquinone 24 and 48 h after treatment with 63 g ha~1 isoxaÑutole. Carotenoid levels were identical to untreated controls after 24 h and were decreased by 35% after 48 h when bleaching became visible. Furthermore, accumulation of phytoene became apparent after 48 h. It is suggested that inhibition of HPPD results in an indirect e †ect on carotenoid biosynthesis due to the depletion of plastoquinone, a proposed cofactor of PDS.HPPD is a low-abundance enzyme in plants but it has now been puriÐed and characterized from cultured carrot cells.5 An assay has been developed involving the 83 Pestic. Sci. 0031-613X/97/$17.50 1997 SCI. Printed in Great Britain (