Pharmacophore neonicotinoids

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. 

Nicotine and neonicotinoids are agonists, both of which act at the nicotinic acetylcholine receptor -Na" /K+ ionophore. The structural differences between the insect and mammalian receptors define the selectivity of neonicotinoid toxicity to insects and nicotine toxicity to vertebrates. The proposed concept of the neonicotinoid electronegative pharmacophore... 

Figure 4 Moiecuiar modeis of binding subsites in the Drosophila or vertebrate nicotinic acetyichoiine-reguiated receptors. (Reprinted with permission from Tomizawa etal. (2003) The neonicotinoid eiectronegative pharmacophore piays the cruciai roie in the high affinity and seiectivity for the Drosophila nicotinic receptor An anomaiy for the nicotinoid cation-pi interaction modei. Biochemistry 42 7819-7827 American Chemicai Society.)...

The metabolism of neonicotinoids in vertebrates, insects, and plants has many common features. It may result in cleavage and the separation of the heterocyclic and pharmacophore moieties, or modifications of a pharmacophore in an intact parent molecule. Oxidations, reductions, and elimination reactions are the major mechanisms that result mostly in a reduced or diminished insecticidal potency of the metabolites. Dehydration of the 4-hydroxyimidazolidinyl resulting in a formation of the imidazolinyl (olefin) or reduction of the N-nitroimine ( = N—NO2) to N-nitrosoimine ( = N—NO) group (Figure 5) are examples of a... 

For example, in 1970 a useful nicotinic pharmacophore model was already described by Beers and Reich and subsequently improved by Sheridan et al. [103]. Starting from different models a distance from the onium group to a point on the van der Waals surface of the H-bond acceptor of 5.9 A was common to several ligands. Up to now three binding models of neonicotinoids have been proposed (cf Fig. 29.1.2) [104]. 

Because of no acidic or alkaline properties of 3 at the relevant pH [32], the pH of the aqueous system has no influence on its physicochemical properties. Clothianidin (3) is stable to hydrolysis in the pH range 4—9, but photolysis contributes significantly to its degradation in the environment, resulting in an elevated mineralization rate. Its degradation in water/sediment systems was observed to be significantly faster (factor 2-3) under anaerobic conditions than in aerobic conditions. The water solubility (0.327 g at 20 °C), vapor pressure (1.3 x 10 " Pa at 25 °C) and volatility of 3 are relatively low compared with other neonicotinoids that have a N-nitroguanidine pharmacophore (Tables 29.2.1.7 and 29.2.1.8). 

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]. 

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. 

Regarding the structural features of neonicotinoids, the pharmacophore part is characterized by a polar group represented by eidier a nitro group or a cyano group 13). Based on neighboring structural differences in the pharmacophore and on the heterocycle that typically is aromatic and mono-substituted by chlorine, neonicotinoids can be grouped as presented in Table II. 

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. 

---