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

■ Abstract Neonicotinoids, the most important new class of synthetic insecticides of the past three decades, are used to control sucking insects both on plants and on companion animals. Imidacloprid (the principal example), nitenpyram, acetamiprid, thiacloprid, thiamethoxam, and others act as agonists at the insect nicotinic acetylcholine receptor (nAChR). The botanical insecticide nicotine acts at the same target without the neonicotinoid level of effectiveness or safety. Fundamental differences between the nAChRs of insects and mammals confer remarkable selectivity for the neonicotinoids. Whereas ionized nicotine binds at an anionic subsite in the mammalian nAChR, the negatively tipped (“magic” nitro or cyano) neonicotinoids interact with a proposed unique subsite consisting of cationic amino acid residue(s) in the insect nAChR. Knowledge reviewed here of the functional architecture and molecular aspects of the insect and mammalian nAChRs and their neonicotinoid-binding site lays the foundation for continued development and use of this new class of safe and effective insecticides. CONTENTS

Selective toxicity of neonicotinoids attributable to specificity of insect and mammalian nicotinic receptors

Neonicotinoids: insecticides acting on insect nicotinic acetylcholine receptors

In recent years, neonicotinoids 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, their molecular target site The discovery of neonicotinoids can be considered as a milestone in insecticide research and facilitates greatly the understanding of the functional properties of insect nicotinic acetylcholine receptors Because of the relatively low risk for non-target organisms and environment, the high target specificity of neonicotinoid insecticides and their versatility in application methods, this important class has to be maintained globally for integrated pest management strategies and insect resistance management programmes This review comprehensively describes particularly the origin, structure and bonding as well as associated properties of neonicotinoid insecticides

Neonicotinoids—from zero to hero in insecticide chemistry

The first neonicotinoid insecticide introduced to the market was imidacloprid in 1991 followed by several others belonging to the same chemical class and with the same mode of action. The development of neonicotinoid insecticides has provided growers with invaluable new tools for managing some of the world's most destructive crop pests, primarily those of the order Hemiptera (aphids, whiteflies, and planthoppers) and Coleoptera (beetles), including species with a long history of resistance to earlier-used products. To date, neonicotinoids have proved relatively resilient to the development of resistance, especially when considering aphids such as Myzus persicae and Phorodon humuli. Although the susceptibility of M. persicae may vary up to 20-fold between populations, this does not appear to compromise the field performance of neonicotinoids. Stronger resistance has been confirmed in some populations of the whitefly, Bemisia tabaci, and the Colorado potato beetle, Leptinotarsa decemlineata. Resistance in B- and Q-type B. tabaci appears to be linked to enhanced oxidative detoxification of neonicotinoids due to overexpression of monooxygenases. No evidence for target-site resistance has been found in whiteflies, whereas the possibility of target-site resistance in L. decemlineata is being investigated further. Strategies to combat neonicotinoid resistance must take account of the cross-resistance characteristics of these mechanisms, the ecology of target pests on different host plants, and the implications of increasing diversification of the neonicotinoid market due to a continuing introduction of new molecules.

Resistance of insect pests to neonicotinoid insecticides: current status and future prospects.

(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

Novel nitro compounds of the formula (I) (see formula I) and the use of the new compounds as insecticides.

Insecticidally active nitro compounds

Novel insecticides of the formula ##STR1## in which n is 0 or 1, X is S, O, ##STR2## Y is N or ##STR3## Z is a 5- or 6-membered nitrogen-containing heterocyclic ring, and R to R9 variously represent hydrogen or specified organic radicals.

Novel heterocyclic compounds

Es werden neue Nitromethylen-Derivate der Formel There are new nitromethylene derivatives of the formula bereitgestellt, in der provided in the R ein Wasserstoff-Atom oder eine niedere Alkyl-Gruppe bezeichnet, R denotes a hydrogen atom or a lower alkyl group, X ein Halogen-Atom, eine niedere Alkyl-Gruppe, eine niedere Alkoxy-Gruppe, eine niedere Alkylthio-Gruppe, eine niedere Alkylsulfinyl-Gruppe, eine niedere Alkylsulfonyl-Gruppe, eine niedere Alkenyl-Gruppe, eine niedere Alkinyl-Gruppe, eine Aryl-Gruppe, eine Aryloxy-Gruppe, die gegebenenfalls durch ein Halogen-Atom substituiert sein kann, eine Arylthio-Gruppe, die gegebenenfalls durch ein Halogen-Atom substituiert sein kann, oder eine Aralkyl-Gruppe bezeichnet, X is a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkenyl group, a lower alkynyl group, an aryl designated group, an aryloxy group which may optionally be substituted by a halogen atom, an arylthio group which may optionally be substituted by a halogen atom, or an aralkyl group, 1 fur 1, 2, 3 oder 4 steht, 1 for 1, 2, 3 or 4, m fur 2, 3 oder 4 steht und m is 2, 3 or 4 and n fur 0, 1, 2 oder 3 steht. n is 0, 1, 2 or 3. Die Verbindungen der Formel (I) konnen durch Umsetzung von Verbindungen der Formel The compounds of formula (I) may be prepared by reacting compounds of the formula mit Verbindungen der Formel with compounds of formula wobei R' die im Anmeldungstext angegebene Bedeutung besitzt, hergestellt werden und besitzen sehr stark ausgepragte insektizide Eigenschaften. wherein R 'has the meaning indicated in the application text, manufactured and very strong possess distinct insecticidal properties.

Nitromethylene derivatives, intermediates, and process for their preparation as insecticides

Insecticidal heterocyclic compounds of the formula ##STR1## wherein A represents a five-membered or six-membered heteroaryl group containing one to three hetero atoms selected from the group consisting of S, O and N, said heteroaryl group being unsubstituted or substituted by a halogen atom or C1-4 alkyl group, Z represents a three-membered straight chain, each member being selected from the group consisting of CH2 --, O, S and N--R2 with at least one of said three members being O, S or N--R2, E represents CH2, O, S or N--R2, wherein R2 represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkoxy group or the group ##STR2## wherein R3 represents a hydrogen atom or halogen atom, X represents CH or N, Y represents a nitro group or cyano group, and R1 represents a hydrogen atom or methyl group.

Shinichi Tsuboi

Papers

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

Insecticidally active nitro compounds

Novel heterocyclic compounds

Nitromethylene derivatives, intermediates, and process for their preparation as insecticides

Insecticidal heterocyclic compounds