Peter Jeschke

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

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.

Overview of the Status and Global Strategy for Neonicotinoids

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 versatility in application methods, this important class has to be maintained globally for integrated pest management strategies and insect resistance management programs. Innovative concepts for life-cycle management, jointly with the introduction of generic products, have made neonicotinoids the most important chemical class for the insecticide market.

Neonicotinoids—from zero to hero in insecticide chemistry

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.

Nicotinic Acetylcholine Receptor Agonists: A Milestone for Modern Crop Protection

The destruction of crops by invertebrate pests is a major threat against a background of a continuously rising demand in food supply for a growing world population. Therefore, efficient crop protection measures in a vast range of agricultural settings are of utmost importance to guarantee sustainable yields. The discovery of synthetic agonists selectively addressing the nicotinic acetylcholine receptors (nAChRs), located in the central nervous system of insects, for use as insecticides was a major milestone in applied crop protection research. These compounds, as a result of their high target specificity and versatility in application methods, opened a new innovative era in the control of some of the worlds most devastating insect pests. These insecticides also contributed massively to extending our knowledge of the biochemistry of insect nicotinic acetylcholine receptors. The global economic success of synthetic nAChR agonists as insecticides renders the nicotinic acetylcholine receptor still one of the most attractive target sites for exploration in insecticide discovery.

α-Fluorinated Ethers as “Exotic” Entity in Medicinal Chemistry

After nitrogen, fluorine occupies the position of second favorite heteroelement in life science-oriented research. In contrast, the trifluoromethoxy group is still perhaps the least well understood fluorine substituent, although its occurrence has significantly increased in the recent years. Today, significant application areas for trifluoromethoxy substituted pharmaceuticals are in the field of analgesics, anesthetics, cardiovascular drugs, respiratory drugs, psychopharmacologic drugs, neurological drugs, gastrointestinal drugs and anti-infective therapeutics. The present review will give an overlook of its use in medicinal chemistry.

PF1022A and Related Cyclodepsipeptides - A Novel Class of Anthelmintics

Parasitic nematodes are a major cause of morbidity and mortality in man and also cause widespread loss of food production by infection of livestock. A milestone in the chemotherapy of nematode infections, especially in animals, was the discovery of the avermectins and milbemycins during the 1970s. Since the discovery of these highly active macrolides, reports of potent new classes of anthelmintics have been scarce. One of the most outstanding recently reported anthelmintics is the cyclooctadepsipeptide PF1022A, the most active member of a novel class of anthelmintic agents. During the past years several total syntheses of PF1022A and manifold structure-activity relationships have been established. Additionally, the biosynthesis of PF1022A has been elucidated and intensive investigations into the mode of action of this novel anthelmintic are underway. Comprehensive studies including cyclodepsipeptides with smaller ring-sizes, such as the enniatins, proved the PF1022 family and related cyclodepsipeptides to be the most promising follow-up candidates for the avermectins and milbemycins, which suffer from increasing nematode resistance.

Flupyradifurone: a brief profile of a new butenolide insecticide

BACKGROUND The development and commercialisation of new chemical classes of insecticides for efficient crop protection measures against destructive invertebrate pests is of utmost importance to overcome resistance issues and to secure sustainable crop yields. Flupyradifurone introduced here is the first representative of the novel butenolide class of insecticides active against various sucking pests and showing an excellent safety profile. RESULTS The discovery of flupyradifurone was inspired by the butenolide scaffold in naturally occurring stemofoline. Flupyradifurone acts reversibly as an agonist on insect nicotinic acetylcholine receptors but is structurally different from known agonists, as shown by chemical similarity analysis. It shows a fast action on a broad range of sucking pests, as demonstrated in laboratory bioassays, and exhibits excellent field efficacy on a number of crops with different application methods, including foliar, soil, seed treatment and drip irrigation. It is readily taken up by plants and translocated in the xylem, as demonstrated by phosphor imaging analysis. Flupyradifurone is active on resistant pests, including cotton whiteflies, and is not metabolised by recombinantly expressed CYP6CM1, a cytochrome P450 conferring metabolic resistance to neonicotinoids and pymetrozine. CONCLUSION The novel butenolide insecticide flupyradifurone shows unique properties and will become a new tool for integrated pest management around the globe, as demonstrated by its insecticidal, ecotoxicological and safety profile.

Therapy and prevention of parasitic insects in veterinary medicine using imidacloprid

Ectoparasitic insects play a major role in veterinary medicine. The flea, especially the cat flea (Ctenocephalides felis felis Bouch 1835) is the most important ectoparasite worldwide. The cat flea parasitizes not only on dogs and cats but also on other warm-blooded animals including humans. The veterinary importance of flea infestation are dermatological conditions due to allergic reactions to antigens in the flea saliva and the transmission of infectious agents like bacteria, viruses and helminths. Insecticides used in veterinary medicine today have to fulfil criteria of elimination of a existing flea infestation (therapy) and prevention (prophylaxis) of new infestation for weeks. Imidacloprid is a compound of the chemical class of CNI (chloronicotinyl insecticides syn. neonicotinoids) that fits these criteria. The high selectivity towards the site of action within insects together with the high safety margin on mammals allowed to develop imidacloprid as an insecticide for agricultural use and finally for the application as a veterinary medicine. The major features of imidacloprid chemistry, toxicology and the development and use as a veterinary medicinal remedy are described.

Anthelmintic cyclooctadepsipeptides: complex in structure and mode of action

The broad-spectrum anthelmintic cyclooctadepsipeptide PF1022A is a fungal metabolite from Rosellinia sp. PF1022, which is a Mycelia sterilia found on the leaves of Camellia japonica. A broad range of structurally related cyclooctadepsipeptides has been characterized and tested for anthelmintic activities. These metabolites have been used as starting points to generate semisynthetic derivatives with varying nematocidal capacity. Predominant among these compounds is emodepside, which exhibits a broad nematocidal potential against gastrointestinal and extraintestinal parasites. Here we review the chemical biology and mode of action of cyclooctadepsides with particular attention to PF1022A and emodepside. We illustrate how they target nematode neuromuscular function, opening up new avenues for antiparasitic treatments with potential capability for important selective toxicity.

Alkaloids from Stems and Leaves of Stemona japonica and Their Insecticidal Activities

Five new alkaloids, 6beta-hydroxystemofoline (1), 16-hydroxystemofoline (2), neostemofoline (3), protostemodiol (4), and 13-demethoxy-11(S*),12(R*)-dihydroprotostemonine (5), along with 10 known alkaloids, were isolated from stems and leaves of Stemona japonica. Their structures were elucidated by 1D and 2D NMR and other spectroscopic studies. The insecticidal activity of the agonist 16-hydroxystemofoline (2) and antagonist 13-demethoxy-11(S*),12(R*)-dihydroprotostemonine (5) was demonstrated by electrophysiological in vitro tests on the insect nicotinic acetylcholine receptor and by in vivo screenings against relevant agricultural insect pests.