Neonicotinoids commercialized

Neonicotinoids are a new class of synthetic insecticides that became commercially available in the 1990s. Currently there are only a few neonicotinoid insecticides on the market but those are being increasingly used with a good prognosis for their further development. These new-generation pesticides have potential as replacements for some of the more toxic organophosphorus and methylcarbamate insecticides. 

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. 

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)... 

Since the discovery of 7, diverse imidacloprid-related insecticides referred to as neonicotinoids have been synthesized. Like 7, all commercial neonicotinoids 8-13 bind with high affinity (I50 1 mM) to [ H]-7 binding sites on insect nAChRs. 

Table 29.1.3 Specificity of commercial neonicotinoids (7-13) for insect and vertebrate nAChRs. (According to M. Tomizawa and J. E.

Figure 29.1.3 shows the whole cell currents elicited by application of 1 xm nithiazine (6) and the commercial open-chain neonicotinoids nitenpyram (8), acetamiprid (9) and clothianidin (12). 

This correlation for commercial neonicotinoids 8-13 may indicate that houseflies (binding data) and tobacco budworms (electrophysiology) have similar binding sites for 7 and related compounds. 

In general, all commercialized neonicotinoids can be divided into open-chain compounds (Chapter 29.2.1) and neonicotinoids having ring systems such as five-membered (Chapter 29.2.2) and six-membered compounds (Chapter 29.2.3) that differ in their molecular characteristics. The structural requirements for both neonicotinoids having open-chain stmctures and ring-system containing neonicotinoids consist of different segments Usted below (Fig. 29.2.1, Tables 29.2.1 and 29.2.2) [1, 2]. 

Table 29.2.1 Structure types of neonicotinoid insecticides, including commercialized products 1, 3-10).

The subdivision of commercialized neonicotinoids into different generations implies their ranking regarding novelty - a view not based on chemical or biochemical classification. The I RAC classification places all neonicotinoids in group 4A. 

To date, four open-chain type neonicotinoids have been commercialized, mainly from Japanese companies. These open-chain type neonicotinoids can have, as separate substituents, (i) (R, R ), e.g., R = hydrogen or alkyl like ethyl (1, niten-pyram) and methyl (2, acetamiprid, E-R = Me) and in the case of E = NH for the substituent R an alkyl group such as methyl (3, clothianidin and 4, dinote-furan) (Chapter 29.2, Table 29.2.1 and Eig. 29.2.1). 

In contrast to other commercial neonicotinoids, 4 has an alicyclic and racemic (RS)-(+)-TFM moiety instead of the halogenated heteroaromatic CPM and CTM moieties (see Chapter 29.3). The non-aromatic oxygen atom of the TFM residue is situated in the position corresponding to that of the aromatic nitrogen atom of the other heterocyclic moieties of neonicotinoids - consequently the TFM stmc-ture can be taken as an isostere of the CPM and CTM moiety [61]. 

Two commercial neonicotinoids containing five-membered ring systems belong to this group, imidacloprid (1) and thiadoprid (9). 

The synthesis of this compound was first described by Agro Kanesho [16]. Further preparations have been discussed in Section 29.2.3.4. As with all neonicoti-noids, AKD-1022 (12) interacts with nicotinic acetylcholine receptors however, it is much less potent than imidacloprid (8) and other commercial neonicotinoids. In particular, this has been demonstrated with Myzus and Drosophila membranes [23], as well as on American cockroaches [33]. It has been speculated that AKD-1022 (12), as a basic molecule, is ionized in the fluids of insects and, therefore, reaches the synapse only slowly through the lipophilic cuticles and the ion barriers. During retarded movement, the compound is prone to decompose, e.g., due to partial hydrolysis mediated enzymatically and/or non-enzymatically [33]. Therefore, acyclic nitroguanidines such as 19 may also contribute to the insecticidal activity observed in glasshouse and field studies. 

These data showed that thiamethoxam (13), like imidadoprid (8) and the other neonicotinoids, binds with high affinity to nicotinic receptors [57]. However, there are clear differences to the other commercial neonicotinoids, as documented by a kinetic analysis of competition experiments [56]. While [ H]thiamethoxam (13) binds to receptors with nanomolar affinity, micromolar concentrations are required to displace [ H]imidadoprid (8). Further, the interaction between the two compounds is non-competitive , meaning that binding of thiamethoxam (13) reduces the binding capacity of the receptor preparation for imidadoprid (8) but not its affinity. Thiamethoxam (13) shares this unusual mode of inhibition with other neonicotinoids (not commercialized) containing a N-methyl group as pharmacophore substituent [56, 58]. 

Neonicotinoids are insecticides acting on insect nAChRs (1). For a long time they are very effective on commercially important Hemipteran pest species such as aphids, whiteflies and planthoppers, but also control Coleopteran and some Lepidopteran pests (/). The biochemical mode of action (MoA) of neonicotinoids has been studied and characterized extensively in the past 10 years. Ail neonicotinoids act selectively as agonists at the insect nAChRs and they are part of a single MoA group as defmed by the Insecticide Resistance Action Committee (IRAC an Expert Conunittee of Crop Life) for resistance management purposes (2). Today the neonicotinoids are ... 

Neonicotinoids do not act as a homogenous class of insecticides. Radioligand receptor binding assays revealed two classes of neonicotinoids described here as competitive and non-competitive , respectively, relative to [ H]imidacloprid. Differences in affinity, mode of displacement, number of binding sites and temperature sensitivity suggest that thiamethoxam binds in a way unique among the commercial neonicotinoids. Metabolic transformation is not relevant for its insecticidal effects. 

As thiamethoxam is the only iV-Methyl compound on the market, its noncompetitive behavior contrasted to all other commercial neonicotinoids, which all displayed a competitive mode. The A -Methyl rule was not plicable to acetamiprid, thiacloprid and nithiazine (no tyical neonicotinoid) a possible interpretation has been given in a recent publication (S). 

This review documents that thiamethoxam shows properties distinct from those of other neonicotinoids under a number of aspects. Chemically, it represents the first commercialized chlorothiazolyl-type neonicotinoid. The combination of an oxadiazine ring with a iV-Methyl group is unique and seems to shape the biological properties of thiamethoxam. 

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