4-Hydroxyphenylpyruvate dioxygenase inhibitor
They were originally used primarily in Japan in rice production, but since the late 1990s have been used in Europe and North America for corn, soybeans, and cereals, and since the 2000s have become more important as weeds have become resistant to glyphosate and other herbicides.
[1] There is a pharmaceutical drug on the market, nitisinone, that was originally under development as an herbicide as a member of this class and is used to treat an orphan disease, type I tyrosinemia.
[2] Plants turn white without deformation due to a complete loss of chlorophyll, which has led compounds of this class to be classified as "bleaching herbicides", as are protox inhibitors.
[2][5][6] More specifically, inhibition of HPPD prevents the formation of a breakdown product, homogentisic acid, which in turn is a key precursor for the biosynthesis of both tocopherols and plastoquinone.
Plastoquinone is, in turn, a critical co-factor in the formation of carotenoids, which protect chlorophyll in plants from being destroyed by sunlight.
[8][9] As of 2009, HPPD inhibitors had three fundamental chemical frameworks:[2][10] Pyrazolate, pyrazoxyfen and benzofenap were first commercialized in the Japanese rice market starting in 1980, but became less important when sulfonylurea herbicides were introduced.
[2] Topramezone was introduced in 2006 for corn and soy, and is the most potent HPPD inhibitor, but has serious carry-over issues especially for soybean in US, where the minimum time from application to planting is 18 months.
[14] In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is mutated and does not work, leading to very harmful products building up in the body.
[20] All of the herbicidal and pharmaceutical triketone HPPD inhibitors including mesotrione (Callisto)(I),[21] sulcotrione (Mikado)(II)[22] and nitisinone (Orfadin)(III)[23] had their common origin in the observation in 1977 by Reed Gray, a biologist at Stauffer Chemical's Western Research Center (WRC) in California, that few weeds emerged under bottlebrush plants (Callistemon citrinus) in the back yard of his house.
The resulting extracts were applied to soil flats containing watergrass (Echinochloa crus-galli) as an indicator species at the very high application rate of 100 pounds per acre (112 kg/ha).
He approached a chemist, Ron Rusay, at the Western Research Center who independently synthesized the compound and submitted it for further greenhouse testing.
These tests showed that it had modest herbicidal activity against grass weeds at a very high application rate of 100 pounds per acre (112 kg/ha).
A small task force consisting of David Lee, Bill Michaely and Don James prepared a number of substituted triketones with chloro-, bromo- and methyl-substituents in the ortho position.
It was not until David Lee was able to show that these compounds were in equilibrium with the 2-hydroxy triketones(VIII) by trapping the intermediate with methyl iodide that the reason for the biological activity was understood.
David Lee had a strong background in quantitative structure–activity relationships (QSAR) after a post-doctoral year with Professors Manfred Wolff and Peter Kollman where he used the Prophet system.
Linda Mutter in the WRC Toxicology Section used a spot test for tyrosine on the urine of treated rats and had positive results.
[37] Work on the mode of action and toxicology of the triketones took on a broader range of interactions when Stauffer Chemical was purchased by ICI in June 1987.
