Flupyradifurone: a brief profile of a new butenolide insecticide

Abstract

BACKGROUNDThe 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.RESULTSThe 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.CONCLUSIONThe 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. © 2014 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Modes of Action, Resistance and Toxicity of Insecticides Targeting Nicotinic Acetylcholine Receptors

“…The results point to activation of insect nAChRs and action as a partial agonist. The flupyradifurone dose-response curve revealed a Hill coefficient close to one suggesting a single binding site [39].…”

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors

“…Clothianidin (Bayer CropScience, 2002) 51) followed as an acyclic analogue and dinotefuran (Mitsui 2002) 52) retains the acyclic nitroguanidine pharmacophore but branches an unprecedented tetrahydrofuranyl saturated heterocycle. Sulfoxaflor is the first example of a sulfoximine nicotinic agonist (Dow Agrosciences 2012), 53) flupyradifurone introduces a butenolide pharmacophore (Bayer CropScience 2014) 54) and the latest molecule entering the marketplace, triflumezopyrim features a mesoionic heterocycle (DuPont 2015) 55) as novel sucking pest solutions.…”

“…TMX stimulated a cationic current in Xenopus oocytes expressing either Nlα1 with ratβ2 or Nlα3/Nlα8 with ratβ2, with similar potency to the other commercial neonicotinoids. 54,110) This could not be the result of metabolism, as TMX is stable in solution and receptor responsiveness was equivalent to that of the other commercial neonicotinoids. 106) The fact that Nlα1, Nlα2 and Nlα8 in combination with a ratβ2 subunit did not apparently discriminate the commercial neonicotinoids argues that in native insects the β-subunit has an important role in discerning target site selectivity.…”

“…The fact that SFX only interacts at the high affinity IMI binding site and has much reduced ability to interact at the second lower affinity IMI binding site, explains the relative weakness of SFX to displace [ 3 H]-IMI under standard assay conditions. 118,119) 54) This novel systemic insecticide for sucking pest control was identified by stepwise chemical evolution of the enaminocarbonyl pharmacophore inspired by existing nAChR ligands [120][121][122] and also recognized as a recurrent motif of natural products such as stemofoline, another botanical insecticide. 123,124) Flupyradifurone modulates insect nAChRs at the orthosteric binding site potently displacing [ 3 H]-IMI bound to M. domestica crude membranes with low nM affinity (IC 50 =2.38±1.93 nM).…”

“…Electrophysiology experiments on the Spodoptera frugiperda central nervous system suggest that it acts as a partial agonist with an efficacy of 56% compared to 1 mM ACh in the same preparation. 54) As with SFX, the main added value of this new nAChR competitive agonist lies in its lack of cross-resistance to whiteflies with acquired P450 metabolic resistance to IMI. Flupyradifurone is not affected by CYP6CM1 oxidative detoxi-fication when recombinantly expressed in insect cell lines and this was supported by molecular docking studies in the binding site model of this P450 enzyme in the whitefly Bemisia tabaci.…”