The nicotinic acetylcholine receptor pharmacological profile of sulfoxaflor in aphids is consistent with that of imidacloprid. Additionally, the insecticidal activity of sulfoxaflor and the current commercialised neonicotinoids is affected by the point mutation in FRC Myzus persicae. Therefore, it is suggested that sulfoxalfor be considered a neonicotinoid, and that this be taken into account when recommending insecticide rotation partnering for effective resistance management programmes.

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The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

M«0'^S^V'NH 'o chemists can play a leading role here. From their experiences in probing reaction mechanisms in vitro they can postulate likely intermediate metabolites and design experiments to follow the reaction sequences of drugs".2The majority of antitumor antibiotics inhibit cell division by interfering with the synthesis or use of nucleic acids.3 There is a constant need to discover new agents that interact with DNA in a mechanistically definable manner.4 In 1987 the Lederle5 and Bristol-Myers6 groups reported the unprecedented structures of calicheamicin 7i (1), esperamicin A, (2), Alb (3), and A2 (4), and the metabolite esperamicin X (5) (Chart I). They were isolated from fermentations of Micromonospora echinospora sp. calichensis and cultures of Actinomadura verrucosospora BBM 1675 and ATCC 39334, respectively. At present, these compounds are the most potent antitumor antibiotics known, being approximately 103 more active than adriamycin against murine tumors, and represent a new class of natural products based upon the Z-enediyne functionality.While they contain a number of unusual structural features such as the allylic trisulfide, a hydroxylamino sugar, and a Q-Q bridgehead double bond, it is the Z-enediyne that embues these molecules with a unique mechanism for cleaving DNA. It was proposed5'6 that the trisulfide is cleaved by nucleophilic attack at the central sulfur atom to give the thiol (or thiolate) 7, which can conjugatively add to Q to give the dihydrothiophene derivative(2) Ferguson, L. N. Chem. Soc. Rev. 1975, 4, 289.

The development of novel and safe insecticides remains an important need for a growing world population to protect crops and animal and human health. New chemotypes modulating the insect nicotinic acetylcholine receptors have been recently brought to the agricultural market, yet with limited understanding of their molecular interactions at their target receptor. Herein, we disclose the first crystal structures of these insecticides, namely, sulfoxaflor, flupyradifurone, triflumezopyrim, flupyrimin, and the experimental compound, dicloromezotiaz, in a double-mutated acetylcholine-binding protein which mimics the insect-ion-channel orthosteric site. Enabled by these findings, we discovered novel pharmacophores with a related mode of action, and we describe herein their design, synthesis, and biological evaluation.

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BACKGROUND Crop protection solutions for the control of key economic sucking pests derive essentially from neuronal and muscular acting chemistries, wherein neonicotinoid uses largely dominated for the last two decades. Anticipating likely resistance development of some of those arthropod species to this particular class, we intensified research activities on a non‐neuronal site of action targeting insect growth and development some 10 years ago. RESULTS Our innovation path featured reactivation of a scarcely used and simple building block from the 1960s, namely N‐methoxy‐4‐piperidone 3. Its judicious incorporation into the 2‐aryl‐1,3‐dione scaffold of IRAC group 23 inhibitors of fatty acid biosynthesis resulted in novel tetramic acid derivatives acting on acetyl‐coenzyme A carboxylase (ACCase). The optimization campaign focused on modulation of the aryl substitution pattern and understanding substituent options at the lactam nitrogen position of those spiroheterocyclic pyrrolidine‐dione derivatives towards an effective control of sucking insects and mites. This work gratifyingly culminated in the discovery of spiro N‐methoxy piperidine containing proinsecticide spiropidion 1. Following in planta release, its insecticidally active dione metabolite 2 is translaminar and two‐way systemic (both xylem and phloem mobile) for a full plant protection against arthropod pests. CONCLUSION Owing to such unique plant systemic properties, growing shoots and roots actually not directly exposed to spiropidion‐based chemistry after foliar application nevertheless benefit from its long‐lasting efficacy. Spiropidion is for use in field crops, speciality crops and vegetables controlling a broad range of sucking pests. In light of other performance and safety profiles of spiropidion, an IPM fit may be expected. © 2020 Society of Chemical Industry