▪ Abstract The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-π interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate ...

NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action

In recent years, neonicotinoid insecticides have been the fastest growing class of insecticides in modern crop protection, with widespread use against a broad spectrum of sucking and certain chewing pests. As potent agonists, they act selectively on insect nicotinic acetylcholine receptors (nAChRs), their molecular target site. The discovery of neonicotinoids can be considered as a milestone in insecticide research and greatly facilitates the understanding of functional properties of the insect nAChRs. In this context, the crystal structure of the acetylcholine-binding proteins provides the theoretical foundation for designing homology models of the corresponding receptor ligand binding domains within the nAChRs, a useful basis for virtual screening of chemical libraries and rational design of novel insecticides acting on these practically relevant channels. Because of the relatively low risk for nontarget organisms and the environment, the high target specificity of neonicotinoid insecticides, and their ...

Overview of the Status and Global Strategy for Neonicotinoids

Since their discovery in the late 1980s, neonicotinoid pesticides have become the most widely used class of insecticides worldwide, with large-scale applications ranging from plant protection (crops, vegetables, fruits), veterinary products, and biocides to invertebrate pest control in fish farming. In this review, we address the phenyl-pyrazole fipronil together with neonicotinoids because of similarities in their toxicity, physicochemical profiles, and presence in the environment. Neonicotinoids and fipronil currently account for approximately one third of the world insecticide market; the annual world production of the archetype neonicotinoid, imidacloprid, was estimated to be ca. 20,000 tonnes active substance in 2010. There were several reasons for the initial success of neonicotinoids and fipronil: (1) there was no known pesticide resistance in target pests, mainly because of their recent development, (2) their physicochemical properties included many advantages over previous generations of insecticides (i.e., organophosphates, carbamates, pyrethroids, etc.), and (3) they shared an assumed reduced operator and consumer risk. Due to their systemic nature, they are taken up by the roots or leaves and translocated to all parts of the plant, which, in turn, makes them effectively toxic to herbivorous insects. The toxicity persists for a variable period of time—depending on the plant, its growth stage, and the amount of pesticide applied. A wide variety of applications are available, including the most common prophylactic non-Good Agricultural Practices (GAP) application by seed coating. As a result of their extensive use and physicochemical properties, these substances can be found in all environmental compartments including soil, water, and air. Neonicotinoids and fipronil operate by disrupting neural transmission in the central nervous system of invertebrates. Neonicotinoids mimic the action of neurotransmitters, while fipronil inhibits neuronal receptors. In doing so, they continuously stimulate neurons leading ultimately to death of target invertebrates. Like virtually all insecticides, they can also have lethal and sublethal impacts on non-target organisms, including insect predators and vertebrates. Furthermore, a range of synergistic effects with other stressors have been documented. Here, we review extensively their metabolic pathways, showing how they form both compound-specific and common metabolites which can themselves be toxic. These may result in prolonged toxicity. Considering their wide commercial expansion, mode of action, the systemic properties in plants, persistence and environmental fate, coupled with limited information about the toxicity profiles of these compounds and their metabolites, neonicotinoids and fipronil may entail significant risks to the environment. A global evaluation of the potential collateral effects of their use is therefore timely. The present paper and subsequent chapters in this review of the global literature explore these risks and show a growing body of evidence that persistent, low concentrations of these insecticides pose serious risks of undesirable environmental impacts.

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Systemic insecticides (neonicotinoids and fipronil): trends, uses, mode of action and metabolites

The task of inventing and developing active ingredients with useful biological activities requires a search for novel chemical substructures. This process may trigger the discovery of whole classes of chemicals of potential commercial interest. Similar biological effects can often be achieved by completely different compounds. However, compounds within a given structural family may exhibit quite different biological activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compound, its interaction with the active site of the target protein, as well as its physicochemical, pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated organic compounds represent an important and growing family of commercial agrochemicals. A number of recently developed agrochemical candidates represent novel classes of chemical compounds with new modes of action; several of these compounds contain new fluorinated substituents. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compound depending on its changed mode of action, physicochemical properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a molecule at which fluorine substitution will result in optimal desired effects.

The Unique Role of Fluorine in the Design of Active Ingredients for Modern Crop Protection

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras

Inhibitors of farnesyl protein transferase

Specific amine derivatives have been found to possess excellent activities as pest control agents.

Noxious organism control agent

Pest control agent

The binding study on nicotinoids, neonicotinoids and the related compounds using [ 3 H]α-bungarotoxin and [ 3 H]nicotine as probes revealed that binding to the recognition site of nicotinic acetylcholine receptor (nAChR) in insects requires the molecules to have 3-pyridylmethylamino moiety, while high ionization in vertebrates. When [ 3 H]phencyclidine was used as a probe for the ion channel opening of Torpedo nAChR, it was indicated that high ionization of the molecule is important to be agonistic, although the presence of 3-pyridylmethylamino moiety is preferred. 15 N NMR of the amino nitrogen atom of nicotinoids and the corresponding one of neonicotinoids indicated that the latter was far deshielded as compared with the former. The result implies that the unshared electron pair on the concerned nitrogen atom is delocalized by the presence of strong electron-withdrawing group and the nitrogen atom becomes partially positive. Such nitrogen is enough to interact with the insect nAChR, but not with the vertebrate one. The overall results explain why nicotine is highly toxic to mammals and rather limited in insecticidal activity, whereas imidacloprid is highly insecticidal and low in mammalian toxicity.

Molecular mechanism for selective toxicity of nicotinoids and neonicotinoids

(1992). 1-(6-Chloronicotinyl)-2-nitroimino-imidazolidines and Related Compounds as Potential New Insecticides. Bioscience, Biotechnology, and Biochemistry: Vol. 56, No. 2, pp. 364-365.

1-(6-chloronicotinyl)-2-nitroimino-imidazolidines and related compounds as potential new insecticides

The invention of imidacloprid, the most important neonicotinoid insecticide, was initiated by replacement of the framework of nithiazine with an imidazolidine ring. Through the finding of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, imidacloprid was invented. At the same time cyanoiminothiazolidinyl neonicotinoid thiacloprid was discovered. These products possess pronounced systemic properties and improved photostability in addition to supreme insecticidal ability. Crystal structure analysis led to the drug-receptor interaction model consisting of the guanidine (amidine) part conjugated to a powerful electron-withdrawing group bearing an H-bond accepting tip such as NO(2) or CN, and the chloronicotinyl group enhances the binding to the receptor. The QSAR study not only supports the key pharmacophore but also clarifies the crucial involvement of the phamacokinetic factors in the insecticidal activity. A concept for strategic and rational design led to the discovery of alkylene-tethered bis-imidacloprid derivatives with unexpected systemic insecticidal property and the unique binding mechanism revealing the second cavity in the neonicotinoid receptor.

Shinzo Kagabu

Papers

Noxious organism control agent

Pest control agent

Molecular mechanism for selective toxicity of nicotinoids and neonicotinoids

1-(6-chloronicotinyl)-2-nitroimino-imidazolidines and related compounds as potential new insecticides

Discovery of Imidacloprid and Further Developments from Strategic Molecular Designs