Tri- and difluoromethoxylated N-based heterocycles − Synthesis and insecticidal activity of novel F3CO- and F2HCO-analogues of Imidacloprid and Thiacloprid

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The evolution of insecticide resistance in the peach-potato aphid, Myzus persicae

© 2014 The Authors. Published by Elsevier Ltd. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence e (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.The peach potato aphid, Myzus persicae is a globally distributed crop pest with a host range of over 400 species including many economically important crop plants. The intensive use of insecticides to control this species over many years has led to populations that are now resistant to several classes of insecticide. Work spanning over 40 years has shown that M. persicae has a remarkable ability to evolve mechanisms that avoid or overcome the toxic effect of insecticides with at least seven independent mechanisms of resistance described in this species to date. The array of novel resistance mechanisms, including several ‘first examples’, that have evolved in this species represents an important case study for the evolution of insecticide resistance and also rapid adaptive change in insects more generally. In this review we summarise the biochemical and molecular mechanisms underlying resistance in M. persicae and the insights study of this topic has provided on how resistance evolves, the selectivity of insecticides, and the link between resistance and host plant adaptation.Peer reviewedFinal Published versio

Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus Oocytes

The fetal rat muscle nicotinic acetylcholine receptor was expressed in Xenopus oocytes. Using the voltage-clamp technique, the response to a range of agonists was measured, listed in order of (decreasing) activity efficacy: anatoxin greater-than or equal to epibatidine > acetylcholine > DMPP (1,1-dimethyl-4-phenylpiperazinium) >> cytisine > pyrantel > nicotine > coniine > tubocurare > lobeline. The agonist responses were compared with the steric and electrostatic properties of the molecules, using molecular modelling. Single-channel currents were measured in outside-out patches for acetylcholine, nicotine, cytisine, anatoxin and epibatidine. The conductance of the single channels was independent of the type of agonist. The mean open times were characteristic of the agonist applied. Tubocurare, better known for its antagonist properties, was also a partial agonist. Single-channel currents were also observed for tubocurare, and for methyllycaconitine in patches with a very high density of the muscle nicotinic acetylcholine receptor, and these were blocked by small alpha, Greek-bungarotoxin. The agonist properties of physostigmine, galanthamine and their methyl derivatives were also investigated. The conductance of the channels observed in outside-out patches was similar to that obtained for the classical agonists. The single-channel currents observed for physostigmine, galanthamine and their methyl derivatives were blocked by small alpha, Greek-bungarotoxin, methyllycaconitine and mecamylamine, in contrast to previously reported studies on neuronal and adult muscle nicotinic acetylcholine receptors

A H258Y mutation in subunit B of the succinate dehydrogenase complex of the spider mite Tetranychus urticae confers resistance to cyenopyrafen and pyflubumide, but likely reinforces cyflumetofen binding and toxicity

Succinate dehydrogenase (SDH) inhibitors such as cyflumetofen, cyenopyrafen and pyflubumide, are selective acaricides that control plant-feeding spider mite pests. Resistance development to SDH inhibitors has been investigated in a limited number of populations of the spider mite Tetranychus urticae and is associated with cytochrome P450 based detoxification and target-site mutations such as I260 T/V in subunit B and S56L in subunit C of SDH. Here, we report the discovery of a H258Y substitution in subunit B of SDH in a highly pyflubumide resistant population of T. urticae. As this highly conserved residue corresponds to one of the ubiquinone binding residues in fungi and bacteria, we hypothesized that H258Y could have a strong impact on SDH inhibitors toxicity. Marker assisted introgression and toxicity bioassays revealed that H258Y caused high cross resistance between cyenopyrafen and pyflubumide, but increased cyflumetofen toxicity. Resistance associated with H258Y was determined as dominant for cyenopyrafen, but recessive for pyflubumide. In vitro SDH assays with extracted H258 mitochondria showed that cyenopyrafen and the active metabolites of pyflubumide and cyflumetofen, interacted strongly with complex II. However, a clear shift in IC50s was observed for cyenopyrafen and the metabolite of pyflubumide when Y258 mitochondria were investigated. In contrast, the mutation slightly increased affinity of the cyflumetofen metabolite, likely explaining its increased toxicity for the mite lines carrying the substitution. Homology modeling and ligand docking further revealed that, although the three acaricides share a common binding motif in the Q-site of SDH, H258Y eliminated an important hydrogen bond required for cyenopyrafen and pyflubumide binding. In addition, the hydrogen bond between cyenopyrafen and Y117 in subunit D was also lost upon mutation. In contrast, cyflumetofen affinity was enhanced due to an additional hydrogen bond to W215 and hydrophobic interactions with the introduced Y258 in subunit B. Altogether, our findings not only highlight the importance of the highly conserved histidine residue in the binding of SDH inhibitors, but also reveal that a resistance mutation can provide both positive and negative cross-resistance within the same acaricide mode of action group

Identification of Ustilago maydis Aurora Kinase As a Novel Antifungal Target

Infestation of crops by pathogenic fungi has continued to have a major impact by reducing yield and quality, emphasizing the need to identify new targets and. develop new agents to improve methods of crop protection. Here we present Aurora kinase from the phytopathogenic fungus Ustilago maydis as a novel target for N-substituted diaminopyrimidines, a class of small-molecule kinase inhibitors. We,, show that Aurora kinase is essential in U. maydis and that diaminopyrimidines inhibit its activity in vitro. Furthermore, we observed an overall good correlation between in vitro inhibition of Aurora kinase and growth inhibition of diverse fungi in vivo. In vitro inhibition assays with Ustilago and human Aurora kinases indicate that some compounds of the N-substituted diaminopyrimidine class show specificity for the Ustilago enzyme, thus revealing their potential as selective fungicides

Where Brain, Body and World Collide

The production cross section of electrons from semileptonic decays of beauty hadrons was measured at mid-rapidity (|y| < 0.8) in the transverse momentum range 1 < pt < 8 Gev/c with the ALICE experiment at the CERN LHC in pp collisions at a center of mass energy sqrt{s} = 7 TeV using an integrated luminosity of 2.2 nb^{-1}. Electrons from beauty hadron decays were selected based on the displacement of the decay vertex from the collision vertex. A perturbative QCD calculation agrees with the measurement within uncertainties. The data were extrapolated to the full phase space to determine the total cross section for the production of beauty quark-antiquark pairs