Imidacloprid structure

The top 20 agrochemicals in terms of sales dollars are compiled in Tables 11.6 and 11.7. The list shows both modern products requiring small dosages and old ones with high dosages. The former products require much smaller application rates, but also have much higher unit prices. The most expen-sive agrochemicals in terms of unit prices are the modern insecticides -cyhalothrin ( 768/kg) and Imidacloprid ( 461/kg) the cheapest ones are the old herbicides Atrazin ( 4.90/kg) and 2.4-D ( 5.80/kg). As shown in Table 11.8, the cheaper products are the simpler ones in terms of their chemical structure. 

The acute toxicity (i.e., lethal potency) of imidacloprid, other neonicotinoids, and related analogs in mammals is most closely related to potency at the 7 nicotinic receptor subtype, followed in order by potency at 1x4, fSx, 0(3, and aj nicotinic receptors, respectively. However, acute toxicity in mammals involves complex actions (agonist and antagonist) at multiple receptor subtypes and these actions vary greatly with minor changes in chemical structure. 

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 cholinergic system in insects is the main target of insecticides. One class of molecules, the neonicotinoids, induces direct activation of the neuronal nicotinic acetylcholine receptors (nAChRs). In the honey bee these receptors are mainly distributed in the olfactory pathways that link sensory neurons to antennal lobes and mushroom bodies. These structures seem to play an important role in olfactory conditioning. We have previously shown that cholinergic antagonists injected in different parts of the brain impaired the formation and retrieval of olfactory memory. We then advanced the hypothesis that, through the activation of the nAChR, the neonicotinoid imidacloprid (IMI) would lead to facilitation of the memory trace. 

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)... 

The term neonicotinoids [9] was originally proposed for imidacloprid (1) (Chapter 29.2.2) and related insecticidal compounds with structural similarity... 

Generally, the open-chain neonicotinoids are less lipophilic than the corresponding neonicotinoids with a ring structure (Chapters 29.2.2 and 29.2.3). Based on CoMFA results, a binding model for imidacloprid (11) has been described. 

In contrast to the structure-activity relationships in the imidacloprid series, the introduction of a methyl group at N(5) (R1 = CH3) led to a strong increase of the insecticidal activity. 

Although the structure of flonicamid (12) has some similarity to the neonicotinoids it does not bind to the nicotinic acetylcholine receptor as directly compared with nicotine and imidacloprid [37, 53]. However, flonicamid (12) is active on the A-type potassium channel currents. The current hypothesis is that flonicamid blockade of the A-type potassium channel in the presynaptic terminal underlies its lethal effect in insects. The loss of the A-type potassium rectifying current would lead to the disruption of controlled neurotransmitter release [53]. 

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. 

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). 

Selected structure-activity relationship along the development path from nithiazine to imidacloprid. 

Structural variations lead from imidacloprid via nitenpyram to acetamiprid. 

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. 

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. 

Karunker I, Morou E, Nikou D, Nauen R, Sert-chook R, Stevenson BJ, Paine MJ, Morin S, Von-tas J (2009) Structural model and functional characterization of the Bemisia tabaci CYP6CMlvQ, a cytochrome P450 associated with high levels of imidacloprid resistance. Insect Biochem Mol Biol 39 697-706... 

These consecutive structural transformations towards newer generation compounds could be called "lead evolution" (5). Examples of the simplified lead evolution "tree" for azole fungicides starting from clotrimazole (I) (5,9), nitromethylene heterocycles leading to imidacloprid (II) and analogs (5,70, Iwataki, 1., Nippon Soda Co., personal communication, 1992), and synthetic pyrethroids (4J1) are shown in Figs. 1-3, respectively. The prototype structure has been transformed enormously with improvements in the activity profile through the lead evolution processes in these examples. 

Since the discovery of imidacloprid, diverse imidaclqnid-related insecticides referred to as necmicotinoids have beoi thesized (Fig. 1). There are several lines of evidence fca their nicotinic adions (ICf) but much less is known about the mechanism of selectivity to insect nAChRs. Thoefore, structural features of necmicotinoids and insect nAChRs have been investigated. 

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