Neonicotinoid insecticides nithiazine

Nithiazine was the lead compound in syntheses of the first commercially successful neonicotinoids that surpassed the parent compound in both insecticidal properties and environmental stability. A 6-chloro-3-methylpyridine moiety and a pharmacophore of varying structures (Figure 2) are the two components of a neonicotinoid molecule. Insecticides of the first generation of neonicotinoids are best represented by imidacloprid (Nihon Bayer Agrochem, Japan) (Figure 2) and are also called chloronicotinyls or chloropyridyls. 

Nithiazine has historical importance as a compound on which neonicotinoids, a new class of insecticides, have been modeled. Its synthesis was accomplished by Shell (Modesto, CA) in the 1970s based on selection from a series of nitroalkyl heterocyclic compounds. 

The lead compound, which initiated interest in the neonicotinoids, is a nitro-methylene heterocycle, nithiazine (Figure 1) [1]. Nifhiazine, with its unique nitromethylene moiety, showed low mammalian toxicity, but its insecticidal potency and field stability were inferior to commercial organophosphates and pyrethroids. Thus, nithiazine was not of commercial use for pest control. However, the introduction of 6-choloronicotinyl and 2-nitroimino-imidazolidine moieties led to the development of the first commercial neonicotinoid imidacloprid (Figure 1)... 

Research on six-membered neonicotinoids described above yielded three development compounds nithiazine (6), AKD-1022 (12) and thiamethoxam (13), the latter being the only one to enter the market-place as an agricultural insecticide. 

In 1984, Mark E. Schroeder and Roger F. Flattum at Shell explored for nithiazine as the example, at which site these nitromethylene insecticides interact to effect their pharmacological activity. In cockroaches, the nicotinic acetylcholine receptor turned out to be the target. [140] In insects, the expression of these receptors is limited to the nervous system. There they reach a density, which is comparable only to the electric organ of the South American electric eel (Electro-phorus electricus). [ 141 ] From ligand displacement studies with nerve cell receptors of the American cockroach (Periplaneta americana), the honey-bee (Apis mellifera) and the common housefly (Musca domestica), the a-subrmit of the receptor became evident as the prime locus of interaction for neonicotinoids. 

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