Neonicotinoids insecticidal activity

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... 

Acetamiprid is a neonicotinoid insecticide with outstanding systemic activities and a broad insecticidal spectrum. Acetamiprid controls diverse soil and foliar insect pests infesting cotton, sugar beet, vegetables, fruits and other major food crops by both contact and stomach action... 

The tobacco compound nicotine has been used as an insecticide for over 200 years. It is especially effective against sucking insects, such as aphids, and has excellent contact activity. Related compounds are neonicotinoids (e.g., imidacloprid), which have similar insecticidal activity, but are less toxic to mammals. Nicotine and imidacloprid mimic the action of acetylcholine, which is the major excitatory neurotransmitter in an insect s central nervous system. The action of acetylcholine is stopped by the enzyme acetylcholinesterase, which rapidly breaks down acetylcholine. Nicotine and imidacloprid are also neuroexcitatory, but do so persistendy, since they are not affected by acetylcholinesterase. Overstimulation of the nervous system often leads to convulsions, paralysis, and death. 

Imidacloprid is a neonicotinoid insecticide that is registered for many uses, including grub and termite control, crop protection, and to control fleas and ticks on companion animals. Its insecticidal activity is attributed to nicotinic activity on post-synaptic receptors. 

Bolboaca, S. and Jantschi, L. (2005a) Molecular descriptors family on structure—activity relationships. 2. Insecticidal activity of neonicotinoid compounds. Leonardo Journal of Sciences, 6, 78-85. 

These examples indicate the complexity of insect nAChRs, which is difficult to understand. The considerable diversity of potential subunit combinations probably accounts for the multiplicity of distinctive pharmacological profiles in insect nAChRs. In that context, electrophysiology will play an essential role in determining the significance of certain subunit combinations in the MoA of neonicotinoid and further insecticidally active ligands. 

The discovery of the N-nitroguanidine dinotefiiran (4, 2002, Mitsui Chemicals) [58, 59], resulted from the idea of incorporating an N-nitro-imino group into the ACh structure as lead compound [60]. After synthesis of neonicotinoids containing a N-(3-methoxy-propyl) moiety (hydrogen acceptor site) the investigation of cyclic ether groups led to the discovery of the novel THF moiety, which shows a more than ten-fold increase of insecticidal activity. 

The extremely high insecticidal activity of neonicotinoids of the imidacloprid-type 7 (Chapter 29.2.1) triggered extensive research activities within several other companies Ciba-Geigy (later Novartis, now Syngenta), Takeda, Nippon Soda,... 

Table 29.2.3.4 Insecticidal activity of six-membered neonicotinoids 14-16 compared with imidacloprid (8) and its six-ring analogue 17.

The 2insecticidal activity than the 6-chloro-3-pyridyl, which is present in the first generation neonicotinoids, and all the other heterocychc groups investigated. 

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. 

While the plant protection division of Shell was sold to Dupont in 1986, the neonicotinoid research came to a halt. Independently, chemists at Nihon Tok-ushu Noyaku Seizo K. K. (now part of Bayer CropScience) in Japan had begun to modify the nitromethylene lead structure already at the beginning of the 1980s. Among other changes, they replaced the phenyl substituent in 1-ben-zyl-2-(nitromethylene)-imidazolidine by a 2-pyridyl unit, and found that this derivative had comparatively low insecticidal activity. With a 3- or 4-pyridyl substituent, the potency increased however by a factor of around 25. Retrospectively, it became clear why the introduction of a 3-pyridyl residue was so beneficial (Fig. 8.43). [136,137]... 

Therefore, handling of resistant management strategies in pest control using neonicotinoid insecticides is essential (4). A conversion of neonicotinoid sub types, so-called precursors, into an active neonicotinoid could have a significant impact on this matter. 

The most potent neonicotinoid insecticide in feeding bioassays with H. virescens and S. frugiperda was CLOTHI 8. THIAM 6 was considerably less active against larvae of both lepidopteran pests, and A-desmethyl-THIAM 9 was the least active compound, being 25-fold less active than CLOTHI 8 (17). 

In addition to haemolymph sample analyses, whole larvae of S. frugiperda were homogenized in order to determine the proportion of THIAM 6, CLOTHI 8 and iV-desmethyl THIAM 9 at two different time intervals. Just four hours after oral dosing of 1 pg THIAM 6 30% of neonicotinoid equivalents in larvae represent CLOTHI 8. From the biological point of view, this small amount of CLOTHI 8 should be sufficient for the strong insecticidal activity observed after oral application of THIAM 6 (Figure 6). 

Neonicotinoid insecticides have experienced a most remarkable and steady increase in use since their market introduction in 1991, now exceeding 10% of the total insecticide market 1-3). An overview of these products is given in Table I (cf. 4). The major advantages of the new products over the previously preferred organophosphates are a novel chemistry, a new mode of action, systemic action and human safety. The systemic activity makes them the insecticide class of choice for the control of plant sucking pests. 

In contrast, the neonicotinoids are not protonated and therefore bind differently, resulting in greater activity on insects than manunals. It is this selective toxicity that has led to extensive use of the neonicotinoids and they represent about 20% of the global insecticide market [34]. Worldwide sales of neonicotinoid insecticides are estimated at 1 billion [35]. Imidacloprid and thiacloprid are examples of neonicotinoid insecticides. 

In 2003, Kagabu et al. reported on the racemic synthesis of a chiral analog of imidacloprid, the reference compound of the neonicotinoid insecticide family. Although the recently synthesized Me-imidacloprid (rac-35) is less active than imidacloprid, the (5)-35 enantiomer has shown a higher potency than its (R)-counterpart. Backvall et al. developed an asymmetric synthesis leading to the active (5)-enantiomer, which includes a very efficient DKR of the alcohol intermediate rac-32 (Scheme 57.8). " ... 

The neonicotinoids have very low fish toxicity, are not adsorbed through mammalian skin, and are not irritating or allergenic in the tests carried out so far. The pyrethroids (and DDT group) have a negative temperature correlation these insecticides are more active in warm weather. 

Univ., China) presented his recent research results entitled Structure-activity relationship of novel sulfonylurea inhibitors on AHAS . H. Matsumoto (Univ. of Tsukuba, Japan) then introduced his study Mode of action of several classes of herbicides causing photooxi dative injury in plants . The second one dealt with insecticides, where X.-H. Qian (East China Univ. of Science and Technology, China) and K. Matsuda (Kinki Univ., Japan) presented their recent findings on chemistry and biochemistry of neonicotinoids. Interchange between Pesticide Science Societies of Korea and Japan was also maintained at a seminar entitled Current and future R D activities in agrochemical area in Korea and Japan . 

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. 

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. 

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