Structural Biology-Guided Design, Synthesis, and Biological Evaluation of Novel Insect Nicotinic Acetylcholine Receptor Orthosteric Modulators.

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.

Spiro N-methoxy piperidine ring containing aryldiones for the control of sucking insects and mites: discovery of spiropidion.

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.

Synthesis and stability of boratriazaroles.

We describe the synthesis and stability analysis of novel boratriazaroles that can be viewed as bioisosteres of imidazoles or pyrazoles. These heterocycles could conveniently be obtained by condensing a boronic acid and amidrazone 1 in various solvents. A detailed stability analysis of selected compounds at different pH values as a function of time led to the identification of steric hindrance around the boron atom as a key element for stabilization.

Investigating the mode of action of sulfoxaflor: a fourth-generation neonicotinoid.

BACKGROUND: The precise mode of action of sulfoxaflor, a new nicotinic acetylcholine receptor-modulating insecticide, is unclear. A detailed understanding of the mode of action, especially in relation to the neonicotinoids, is essential for recommending effective pest management practices. RESULTS: Radiolabel binding experiments using a tritiated analogue of sulfoxaflor ([(3) H]-methyl-SFX) performed on membranes from Myzus persicae demonstrate that sulfoxaflor interacts specifically with the high-affinity imidacloprid binding site present in a subpopulation of the total nAChR pool. In competition studies, imidacloprid-like neonicotinoids displace [(3) H]-methyl-SFX at pM concentrations. The effects of sulfoxaflor on the exposed aphid nervous system in situ are analogous to those of imidacloprid and nitenpyram, and finally the high-affinity sulfoxaflor binding site is absent in a Myzus persicae strain (clone FRC) possessing a single amino acid point mutation (R81T) in the ß-nAChR, a region critical for neonicotinoid interaction. CONCLUSION: 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.

Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.

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.

New ventures in the chemistry of avermectins.

An overview is given on recent work towards new avermectin derivatives of extremely high insecticidal and acaricidal activity. These compounds were prepared from commercially available abamectin (avermectin B1) 1. For the synthesis, many novel entries have been opened up, making use of modern synthetic methods and applying them, for the first time, to the chemistry of avermectins. Several types of avermectin derivatives can be regarded as key innovations in the field. These are, in particular, 4''-deoxy-4''-(S)-amino avermectins 3, 4'-O-alkoxyalkyl avermectin monosaccharides 5, 4''-deoxy-4''-C-substituted 4''-amino avermectins 6 and 2''-substituted avermectins 7. 4''-Deoxy-4''-(S)-amino avermectins 3 were obtained by the consecutive application of the Staudinger and Aza-Wittig reaction. 4'-O-Alkoxyalkyl avermectin monosaccharides 5 were prepared by alkoxyalkylation of 5-O-protected avermectin monosaccharide. For the synthesis of 4''-deoxy-4''-C-substituted 4''-amino avermectins 6, several methods were used to construct the fully substituted 4''-carbon centre, such as a modified Strecker synthesis, the addition of organometallics to a 4''-sulfinimine and a modified Ugi approach. In order to prepare 2''-substituted avermectins 7, 5-O-protected avermectin monosaccharide was coupled with carbohydrate building blocks. An alternative synthesis involved the hitherto unknown enol ether chemistry of 4''-oxo-avermectin and the conjugate addition of a cuprate to an avermectin 2'',3''-en-4''-one. In addition, a number of other highly potent derivatives were synthesised. Examples are 4''-O-amino avermectins 8, as well as products arising from intramolecular rhodium catalysed amidations and carbene insertions. A radical cyclisation led to an intriguing rearrangement of the avermectin skeleton. Many of the new avermectins surpassed the activity of abamectin 1 against insects and mites.