In the mid-1980s, scientists at Stauffer Chemical Company published patents to benzoyl-substituted cyclohexanediones (triketones) which led to their product mesotrione.[3] This encouraged workers at Rhône-Poulenc to expand their own research into molecules with the same mode of action as these 4-hydroxyphenylpyruvate dioxygenase inhibitors. In doing so, they found that isoxaflutole had commercial potential as a propesticide of a biologically active diketonitrile that it was converted into within plants.[4] It was developed under the code number RPA201772.[5][6]
The isoxazole ring of the heterocycle product is formed when hydroxylamine reacts in ethanol with an intermediate which is made from an appropriately substituted diketone with triethyl orthoformate, using acetic anhydride as solvent.[7]
The crystal structure of isoxaflutole has been determined.[8] Within plants, it is converted to the diketonitrile shown, which is herbicidally active as an HPPD inhibitor.[2] The advantage of applying isoxafluole rather than the diketonitrile is that the former is more readily taken up into plants from a soil treatment.[5]
Isoxaflutole was first marketed by Rhône-Poulenc in 1996. It controls weeds which are important in crops including corn and sugarcane.[5][9][10] These include broad-leaved-weeds from Amaranthus, Datura stramonium and ragweed species and annual grass weeds of Alopecurus, Eriochloa and Panicum species.[11]
The herbicide is usually applied to the soil in which the crop is growing, before the emergence of the weeds.[1] In the US it is applied almost exclusively in corn with annual use in 2018 about 600,000 pounds (270,000 kg).[12] The compound is often formulated in combination with the herbicide safener, cyprosulfamide.[13] For example, in the EU the product that was evaluated by regulators was a suspension concentrate containing 240 g/L isoxaflutole and 240 g/L cyprosulfamide.[14]
The LD50 of isoxaflutole is over 5000 mg/kg (rats, oral),[1] The European Food Safety Authority set an acceptable daily intake for it at 0.02 mg/kg bodyweight.[14] The Codex Alimentarius database maintained by the FAO lists the maximum residue limits for isozaflutole in various food products, most of which are set at its 0.01 mg/kg or 0.02 mg/kg limit of detection for the combination of the compound and its diketonitrile.[15]
Isoxaflutole is the ISOcommon name[16] for the active ingredient which is formulated into the branded product sold to end-users. The brand names in use for herbicides containing isoxaflutole include Balance, Cadu Star, Merlin and Spade.[1]
^Beaudegnies, Renaud; Edmunds, Andrew J.F.; Fraser, Torquil E.M.; et al. (2009). "Herbicidal 4-hydroxyphenylpyruvate dioxygenase inhibitors—A review of the triketone chemistry story from a Syngenta perspective". Bioorganic & Medicinal Chemistry. 17 (12): 4134–4152. doi:10.1016/j.bmc.2009.03.015. PMID19349184.
^Garcia, Isabelle; Job, Dominique; Matringe, Michel (2000). "Inhibition of p -Hydroxyphenylpyruvate Dioxygenase by the Diketonitrile of Isoxaflutole: A Case of Half-Site Reactivity". Biochemistry. 39 (25): 7501–7507. doi:10.1021/bi000135h. PMID10858299.
^ abcPallett, Kenneth E.; Cramp, Susan M.; Little, Julian P.; Veerasekaran, Ponnan; Crudace, Amanda J.; Slater, Ashley E. (2001). "Isoxaflutole: The background to its discovery and the basis of its herbicidal properties". Pest Management Science. 57 (2): 133–142. doi:10.1002/1526-4998(200102)57:2<133::AID-PS276>3.0.CO;2-0. PMID11455644.
^EP patent 0527036, Cain, P.A.; Cramp, S.M. & Little, G.M. et al., "4-Benzoylisoxazole derivatives and their use as herbicides", issued 1996-11-06, assigned to Rhone Poulenc Agriculture Ltd.
^Van Almsick, Andreas (2009). "New HPPD-Inhibitors – A Proven Mode of Action as a New Hope to Solve Current Weed Problems". Outlooks on Pest Management. 20: 27–30. doi:10.1564/20feb09.
^Ndikuryayo, Ferdinand; Moosavi, Behrooz; Yang, Wen-Chao; Yang, Guang-Fu (2017). "4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals". Journal of Agricultural and Food Chemistry. 65 (39): 8523–8537. doi:10.1021/acs.jafc.7b03851. PMID28903556.
^Ahrens, Hartmut; Lange, Gudrun; Müller, Thomas; Rosinger, Chris; Willms, Lothar; Van Almsick, Andreas (2013). "4-Hydroxyphenylpyruvate Dioxygenase Inhibitors in Combination with Safeners: Solutions for Modern and Sustainable Agriculture". Angewandte Chemie International Edition. 52 (36): 9388–9398. doi:10.1002/anie.201302365. PMID23893910.
