Discovery of the Neonicotinoids

Comparing the structures of nicotine and epibatidine to the first neonicotinoid, imidacloprid, one may suspect the example of a consequent further development of a highly potent lead compound from the natural products pool (Fig. 8.42). This is indeed not the case. Nicotine has been used as an insecticide for more than a hundred years. However, Izuru Yamamoto s structure variations in the 1960s did not result in any promising active substances. [135] Epibatidine, the nAChR agonist from a poisonous frog skin, which could have served as a pharmacophore template, had still not been discovered at the time when neonicotinoids were being developed. 

In 1978, at a lUPAC conference in Zurich, Samuel Barney Soloway from the Shell organisation reported on the insecticidal activity of nitro-substituted ket-ene aminals. These compounds resulted from syntheses around 2-(dibromoni-tromethyl)-3-methylpyridine, a molecule, which Henry Feuer at Purdue University had submitted for screening at Shell in 1970. Nithiazine turned out to be the most active representative of this series, and was selected as a development candidate. However, due to its photolabUity, the compound never reached the market, except as the active ingredient in a flytrap. Additional structure variations at Shell led, among others, also to l-benzyl-3-methyl-2-(nitromethylene) imidazolidine, a compound almost devoid of activity. 

While the plant protection division of Shell was sold to Dupont in 1986, the neonicotinoid research came to a halt. Independently, chemists at Nihon Tok-ushu Noyaku Seizo K. K. (now part of Bayer CropScience) in Japan had begun to modify the nitromethylene lead structure already at the beginning of the 1980s. Among other changes, they replaced the phenyl substituent in 1-ben-zyl-2-(nitromethylene)-imidazolidine by a 2-pyridyl unit, and found that this derivative had comparatively low insecticidal activity. With a 3- or 4-pyridyl substituent, the potency increased however by a factor of around 25. Retrospectively, it became clear why the introduction of a 3-pyridyl residue was so beneficial (Fig. 8.43). [136,137] 

0 LC90 the lethal concentration, at which 90 % of the insects die within four days. 

An additional chloro-substituent at the carbon atom next to nitrogen provided a further gain in activity by a factor of around 625. The combination of the apparently xenobiotic 2-chloro-5-pyridyl residue with the novel nitroguanidine moiety led after some 2,000 structure variations eventually to the identification of imidacloprid, a verypotent, light-stable insecticide with systemic activity and low toxicity for vertebrates (Fig. 8.44). 

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Neonicotinoids are one of the more recent highlights in the area of insect control. This chapter reviews the discovery, chemistry and properties of six-membered neonicotinoids. The most prominent representatives of this subclass are nifhia-zine, AKD-1022 and thiamethoxam. Nithiazine has served as lead structure for the discovery of the neonicotinoid sales products and thiamethoxam is the only six-membered neonicotinoid entering the market-place. 

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