Thiamethoxam neonicotinoids

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

Most soils have a pH ranging from 4 to 9. The degradation of pesticides such as organo-phosphates and carbamates is affected by the pH of the soil. Most organophosphates are hydrolyzed under alkaline conditions, but diazinon is unstable in acid soils. Carbamates such as carbofuran are also hydrolyzed under alkaline conditions. The persistence of neonicotinoids is primarily determined by the pH. Imidacloprid and thiamethoxam are hydrolyzed under alkaline conditions, whereas thiacloprid and acetamiprid are less stable... 

Karmakar, R., Singh, S.B., and Kulshrestha, G., Persistence and transformation of thiamethoxam, a neonicotinoid insecticide, in soil of different agroclimatic zones of India, Bull. Environ. Contam. Toxicol, 76,400, 2006. 

The toxicokinetics of the thianicotinyl thiamethoxam is similar to that of imidacloprid. When applied orally to rats, goats, or chickens, thiamethoxam is rapidly and almost quantitatively absorbed. Its excretion, predominantly in urine, is fast. Accumulation in tissues is negligible. Thiamethoxam itself does not bind strongly to the neonicotinoid binding site of the nicotinic acetylcholine receptor but it is reported to be converted to clothianidin, a neonicotinoid with high affinity for the insect receptors, in insects and plants (Figure 6). It is possible that this activation proceeds via formation of an N-desmethyl thiamethoxam intermediate, another... 

Recently, resistance to imidacloprid became a serious problem for crop protection. Comparative studies of other neonicotinoids revealed a high crossresistance to acetamiprid and thiamethoxam against imidacloprid-resistant strains [22]. However, bioassays exhibited that 4a has good activity against imidacloprid-resistant strains of brown planthopper (Table IV), showing very low cross-resistance to imidacloprid, as shown in Table V. 

Thiamethoxam. This new insecticide is classed as a member of the important neonicotinoid family, which act as agonists of the nicotinic acetylchoMne receptor. Thiamethoxam has systemic activity, meaning that a level of it or active metabolic products is maintained in the plant and ingested by the attacking insects. It is especially used in the protection of tomato crops. 

From the lead structure 2-nitromethylene-tetrahydro-l,3-thiazine (6, nithiazine) [7, 8], resulting neonicotinoids [9] such as the open-chain compounds, e.g., nitenpyram (8), acetamiprid (9), dothianidin (12), dinotefuran (13) (Chapter 29.2.1), the five-membered ring systems, e.g., imidacloprid (7), thiacloprid (11) (Chapter 29.2.2), and the six-membered ring systems, e.g., thiamethoxam (10), AKD 1022 (14)... 

One notable omission is the five-membered thiamethoxam (10) (Chapter 29.2.3), showing binding affinities up to 10000-fofd fess than other neonicotinoids, using housefly head membrane preparations. This fow affinity may be attributed to its proneonicotinoid structure, as it was shown to be activated to the open-chain dothianidin (12) (Chapter 29.2.1) in plants and insects [135]. The latter exhibits high activity as agonist on isolated neurons at concentrations as low as 30 mM. 

AKD 1022 (18) as well as thiamethoxam (17) (Chapter 29.2.3) can form the open-chain neonicotinoid 3 by ring cleavage, either by hydrolysis (see synthesis methods in this chapter) or metabolism (Scheme 29.2.1.4). 

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. 

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. 

Ciba-Geigy (since 1996 Novartis now Syngenta) started a research program on neonicotinoids in 1985 that resulted in the discovery of thiamethoxam (13) [13,... 

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]. 

In summary, varied and minor structural differences in neonicotinoid molecules may confer diversity in their binding modes, depending upon insect spedes and may explain the unique receptor binding behavior of thiamethoxam (13) [56-58] as well as of dinotefiiran [64]. 

Effects on Beneficial Arthropods Thiamethoxam (13) is classified as slightly too moderately harmful to most beneficial insects, but safe to predatory mites in the field. This rating is quite similar to other neonicotinoid compounds [13]. 

Biochemical experiments with several neonicotinoids on insect membranes showed that both, thiamethoxam and imidacloprid bind to the nicotinic acetylcholine receptor. Imidacloprid however inhibits the binding of thiamethoxam, while not competing for the same binding site. Thiamethoxam and other equally non-competitive neonicotinoids, which only served as research tools, share as a common structural element the N-methyl group at position 5 of the 1,3,5-oxadiazinane ring. 

Thiamethoxam A Neonicotinoid Precursor Converted to Clothianidin in Insects and Plants... 

Thiamethoxam High-Affinity Binding and Unusual Mode of Interference with Other Neonicotinoids at Aphid Membranes... 

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. 

Thiamethoxam was the first marketed chorothiazolyl-type neonicotinoid, a second-generation neonicotinoid 10, 14) that, as another specific and unique structural detail, is differentiated by an oxadiazine pharmacophore with an N-Methyl group. Thiamethoxam is used for seed treatment under the trademark CRUISER and for foliar and soil application as ACTARA and PLATIMUM . It is highly effective against sucking pests (e.g. aphids, jassids, whiteflies, rice hoppers), beetles (e.g. the Colorado potato beetle), as well as Thysanoptera and some Lepidoptera. 

In extending the determinations of IC50 values for displacement potencies of competitors we analyzed in detail also their mode of displacement of [ H]imidacloprid (5). As a most remarkable result, we identified two types of displacement of the labeled compound, which we described as competitive and non-competitive , respectively (Figure 1 Table III). Non-competitive displacement of [ HJimidacloprid was found with thiamethoxam and a number of other neonicotinoids that were all characterized by a common structural feature, namely an iV-Methyl group in the pharmacophore. 

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). 

In conclusion, temperature affects binding of thiamethoxam as well as imidacloprid in a reversible way, though the former compound is clearly stronger affected. This also suggests that the binding modes or sites of the two neonicotinoids at the target receptor are obviously not identical. 

As previously demonstrated (75), thiamethoxam, like the other examined neonicotinoids and known natural nicotinic ligands, competes with the binding... 

Like other insecticides, thiamethoxam is transformed in the insect, crop, soil and other compartments to variable degrees to yield products that may not or may be active in their own right. An example for the latter case m the neonicotinoid class is imidacloprid, which is metabolized via hydroxylated intermediates to an olefin product that is more active than the parent compound by one order of magnitude in aphids screens and in receptor binding 20. 21). 

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. 

As effects like those documented for thiamethoxam have not yet been described in the receptor binding field, the results, though based on thorough and self-critical experimentation, may be questioned. In our view, these novel results necessarily call for novel interpretations. A most evident conclusion from the present results is that binding of thiamethoxam has a different impact (as measurable in binding assays) on the receptor complex as binding of other, competitive neonicotinoids. Whether this different mode of interaction is due... 

Neonicotinoid Acetamipirid, imidacloprid, thiamethoxam, clothianidin, dinotefuran, nitenpyram... 

Chloronicotinyl and neonicotinoids. Active as neurotoxins, this group includes the compounds imidacloprid, thiocloprid and thiamethoxam (Xamox). These compounds demonstrate a broad spectrum of activity including beetles and termites. These are very new chemistries for the wood protection industry although some products have already been registered in a few countries for lower hazard end uses. Both imidacloprid and thiocloprid are very specific in their activity towards insect nervous tissue as mimics of the neurotransmitter acetylcholine. 

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