Matthias Haas

Applied aspects of neonicotinoid uses in crop protection.

Neonicotinoid insecticides comprise seven commercially marketed active ingredients: imidacloprid, acetamiprid, nitenpyram, thiamethoxam, thiacloprid, clothianidin and dinotefuran. The technical profiles and main differences between neonicotinoid insecticides, including their spectrum of efficacy, are described: use for vector control, systemic properties and versatile application forms, especially seed treatment. New formulations have been developed to optimize the bioavailability of neonicotinoids through improved rain fastness, better retention and spreading of the spray deposit on the leaf surface, combined with higher leaf penetration. Combined formulations with pyrethroids and other insecticides are also being developed with the aim of broadening the insecticidal spectrum of neonicotinoids and to replace WHO Class I products from older chemical classes. These innovative developments for life-cycle management, jointly with the introduction of generic products, will, within the next few years, turn neonicotinoids into the most important chemical class in crop protection.

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.

Flupyradifurone (Sivanto™) and its novel butenolide pharmacophore: Structural considerations☆

Flupyradifurone (4-[(2,2-difluoroethyl)amino]-2(5H)-furanone), a member of the new class of butenolide insecticides, contains a novel bioactive scaffold as pharmacophore. It is very versatile in terms of application methods to a variety of crops, exhibits excellent and fast action against a broad spectrum of sucking pest insects including selected neonicotinoid resistant pest populations such as whiteflies and aphids expressing metabolic resistance mechanisms. As a partial agonist flupyradifurone reversibly binds to insect nicotinic acetylcholine receptors (nAChRs) and lacks metabolization by CYP6CM1, a cytochrome P450 over-expressed in cotton whiteflies resistant to imidacloprid and pymetrozine. The butenolide insecticides exhibit structure-activity relationships (SAR) that are different from other nAChR agonists such as the classes of neonicotinoids and sulfoximines. The paper briefly reviews the discovery of the butenolide insecticide flupyradifurone, its SAR differentiating it from established nAChR agonists and a molecular docking approach using the binding site model of CYP6CM1vQ of Bemisia tabaci known to confer metabolic resistance to neonicotinoid insecticides.

Biotransformation of Metamitron by Human P450 Expressed in Transgenic Tobacco Cell Cultures

In the present investigation, the oxidative metabolism of 14C-labeled metamitron was examined in plant cell cultures of tobacco overexpressing human P450 enzymes CYP1A1 or CYP1A2; special interest was in the aromatic hydroxylation of the herbicide. The oxidative metabolites deaminometamitron (DAM) and 4-hydroxydeaminometamitron (4-HDAM) were found in the untransformed control culture as well as in the transgenic culture. The transgenic cultures, however, exhibited higher turnover rates after 48 h of incubation with 20 μg 14C-metamitron per assay (untransformed: 40%, CYP1A1: 80%, CYP1A2: 100%). Primary metabolite 4-HDAM was partially found in glucosylated form in the transgenic cultures. As minor oxidative metabolites, 6-hydroxyphenyl-3-methoxymethyl-1,2,4-triazine-5(4H)-one and 3-hydroxymethyl-6-phenyl-1,2,4-triazine-5(4H)-one were identified in the transgenic cultures by GC-MS, LC-MS. Additionally, it could be demonstrated that both foreign enzymes (CYP1A1, CYP1A2) also catalyzed the deamination of metamitron. In a large-scale study (up to 400 μ g per assay) with the transgenic culture expressing CYP1A2, the high efficiency of this P450 system toward metamitron was demonstrated: turnover of the xenobiotic was almost complete with 400 μ g. Since large portions of unglucosylated 4-H-DAM were found, the activity of foreign CYP1A2 apparently exceeded that of endogenous O-glucosyltransferases of the tobacco cell culture. We concluded that in comparison to the nontransformed cell culture, the extent of metabolism was considerably higher in the transgenic cultures. The transgenic cell cultures expressing human CYP1A1 or CYP1A2 are thus suitable tools for the production of large quantities of primary oxidized metabolites of metamitron.