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ABSTRACT: This structure-activity relationship study for neonicotinoids with an N-haloacetylimino pharmacophore identifies several candidate compounds showing outstanding insecticidal potency and consequently leads to establishing their molecular recognition at an insect nicotinic receptor structural model, wherein the neonicotinoid halogen atoms (fluorine, chlorine, bromine, and iodine) variously interact with the receptor loops C-D interfacial niche via H-bonding and/or hydrophobic interactions.
Bioorganic & medicinal chemistry letters 06/2011; 21(12):3583-6. · 2.65 Impact Factor
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ABSTRACT: Neonicotinoid agonists with a nitroimino pharmacophore are used worldwide for crop protection and animal health care. Chemical and structural biology investigations on the nicotinic acetylcholine receptor structure in the neonicotinoid-bound state revealed a unique niche beyond the nitro oxygen tip toward the loop D subsite. The nitroimino pharmacophore can be replaced to suitably fit the newly recognized cavity by acylimino [═NC(O)R] and phenoxycarbonylmino [═NC(O)OPh] variants. The ═NC(O)R analogues, where R is a hydrogen acceptor pyridine, pyrazine, or trifluoromethyl, showed high receptor potency, suggesting that the extended pharmacophore undergoes hydrogen bonding with the loop D Arg basic residue. The ═NC(O)OPh analogues had appreciably higher affinity with an electron-donating substituent on the phenyl ring than with an electron-withdrawing group, predicting that the benzene plane and loop D Trp indole form a face-to-edge aromatic interaction. These studies illustrate strategic ligand design combining the chemorational approach with the three-dimensional receptor structure.
Journal of Agricultural and Food Chemistry 04/2011; 59(7):2918-22. · 2.82 Impact Factor
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Shinzo Kagabu
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ABSTRACT: The invention of imidacloprid, the most important neonicotinoid insecticide, was initiated by replacement of the framework of nithiazine with an imidazolidine ring. Through the finding of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, imidacloprid was invented. At the same time cyanoiminothiazolidinyl neonicotinoid thiacloprid was discovered. These products possess pronounced systemic properties and improved photostability in addition to supreme insecticidal ability. Crystal structure analysis led to the drug-receptor interaction model consisting of the guanidine (amidine) part conjugated to a powerful electron-withdrawing group bearing an H-bond accepting tip such as NO(2) or CN, and the chloronicotinyl group enhances the binding to the receptor. The QSAR study not only supports the key pharmacophore but also clarifies the crucial involvement of the phamacokinetic factors in the insecticidal activity. A concept for strategic and rational design led to the discovery of alkylene-tethered bis-imidacloprid derivatives with unexpected systemic insecticidal property and the unique binding mechanism revealing the second cavity in the neonicotinoid receptor.
Journal of Agricultural and Food Chemistry 04/2011; 59(7):2887-96. · 2.82 Impact Factor
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ABSTRACT: Substituted-phenoxycarbonylimino neonicotinoid ligands with an electron-donating group showed significantly higher affinity to the insect nicotinic receptor relative to that of the analogue with an electron-withdrawing substituent, thereby establishing in silico binding site interaction model featuring that the phenoxy ring of neonicotinoids and the receptor loop D tryptophan indole plane form a face-to-edge aromatic interaction.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5933-5. · 2.65 Impact Factor
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ABSTRACT: Bis-imidacloprid (bis-IMI) analogues with suitable alkylene spacers have plant-systemic insecticidal properties. The alkylene-tethered bis-IMI binds in a unique mode to the insect nicotinic acetylcholine receptor (nAChR) wherein the chloropyridine moieties are embraced by two distinct and distant domains. The heptamethylene spacer optimally bridges these two subsites, yet the linker itself binds in a relatively nonspecific manner. This investigation examines the hypothesis that a bis-IMI analogue with a heteroaromatic tether, which undergoes specific interaction(s) with the newly recognized receptor cavity, may enhance the potency relative to those of the alkylene-tethered derivatives. Remarkably, a novel bis-IMI with a furan-2,5-dimethylene fulcrum showed highest receptor potency and insecticidal activity among the analogues with various chemotype spacers. The nAChR structural model, simulating the binding site interactions of the furan-2,5-dimethylene-tethered bis-IMI, reveals that the furan ring is nestled in a hydrophobic pocket, consisting of three aromatic amino acids, and is stabilized via hydrogen bonding.
Journal of Agricultural and Food Chemistry 10/2010; 58(22):11832-6. · 2.82 Impact Factor
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ABSTRACT: The mesomorphic phase transitions have been studied for a series of 2-(4-alkoxybiphenyl-4-yl)5-(4-methylphenyl)pyridines (4R-Pn; the carbon number, n, of the alkoxy group is 1-10) by use of DSC and polarizing optical microscopy. The 4R-Pn compounds showed only a nematic phase for n=1 and 2, but underwent characteristic polymesomorphic sequences when n>3; Cr CrH SmF SmC SmA N I with n=3 and 4, and Cr CrH SmF SmA N I with n=5-10. This mesomorphic phase transition behaviour was similar to that of the 2-(4-alkoxyphenyl)-5-(4-methylphenyl)pyridine (3R-Pn) series reported previously and it is proposed that the 4R-Pn and 3R-Pn compounds have a minimum terminal alkoxy length (critical alkoxy length) for the generation of LC polymorphism.
Liquid Crystals 08/2010; August 1(1998):263-266. · 1.86 Impact Factor
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ABSTRACT: Neonicotinoids with nitro- or cyanoimino substituents are extensively utilized as plant-mobile (systemic) insecticides controlling the piercing-sucking insect pests. This investigation considers structural features of neonicotinoids with trifluoroacetyl pharmacophores, which may confer enhanced hydrophobicity and effectiveness. Fifteen trifluoroacetyl neonicotinoid analogues [=NC(O)CF(3) and =CHC(O)CF(3)] are therefore prepared to evaluate the hydrophobicity index, toxicity to houseflies (Musca domestica), and binding affinity to the Musca nicotinic receptor. The =NC(O)CF(3) and =CHC(O)CF(3) compounds showed a higher hydrophobicity than that of nitro- or cyanoimino analogues. The intrinsic insecticidal activities (defined by intrathoracic injection with a synergist pretreatment) of test compounds were well-correlated to their target site potencies. Although nitro or cyano neonicotinoids were not toxic via the topical application route in the absence of a synergist, trifluoroacetyl analogues exhibited excellent insecticidal activity under the same condition. Accordingly, the increased hydrophobicity of trifluoroacetyl neonicotinoids presumably improves the penetrability of compound into insect integument and insecticidal effectiveness.
Journal of Agricultural and Food Chemistry 04/2010; 58(8):4999-5003. · 2.82 Impact Factor
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ABSTRACT: The bis-pharmacophore approach applied to neonicotinoid insecticides reveals high binding affinity for heptamethylene bis-N(3),N(3')-imidacloprid fitting a nicotinic acetylcholine receptor model wherein the chloropyridine moieties contact loops E and F and the alkylene linker bridges these two distant domains.
Bioorganic & medicinal chemistry letters 08/2009; 19(13):3449-52. · 2.65 Impact Factor
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ABSTRACT: Imidacloprid (IMI) derivatives conjugated with benzo-15-crown-5 and benzo-18-crown-6 structures, applied for the first time to explore novel insecticidal molecule, elicited strong excitatory toxic signs to the house flies and stunningly exhibited three to five times higher insecticidal activity than that of the parent IMI, yet the two benzo-crown structures themselves had no effect.
Bioorganic & medicinal chemistry letters 07/2009; 19(11):2947-8. · 2.65 Impact Factor
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ABSTRACT: Neonicotinoid insecticides are extensively used for crop protection. The chloropyridinyl or chlorothiazolyl nitrogen and tetrahydrofuryl oxygen atoms of neonicotinoids serve as hydrogen acceptors at the target site. This investigation designs and prepares neonicotinoid probes to understand the structure-activity relationships (SARs) at the target site focusing on the water-mediated ligand-protein interactions. 2-Nitroiminoimidazolidine analogues with hydrogen-acceptor N-CH(2)CH(2)CH(2)F and N-CH(2)CH(2)C(O)CH(3) substituents showed higher binding affinities to the Drosophila melanogaster nicotinic receptor than probes with different hydrogen-bonding points in location and capability, suggesting that the appropriately positioned fluorine or carbonyl oxygen plays an important role on hydrogen-bond formation. Their binding site interactions were predicted using a crystal structure of the acetylcholine binding protein. The fluorine or carbonyl oxygen forms a water bridge to Ile-118 (and/or Ile-106) at the binding domain, consistent with that of neonicotinoids with a chloropyridinylmethyl, chlorothiazolylmethyl, or tetrahydrofurylmethyl moiety. Therefore, the present SAR study on binding site interactions helps design potent neonicotinoids with novel substituents.
Journal of Agricultural and Food Chemistry 04/2009; 57(6):2436-40. · 2.82 Impact Factor
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ABSTRACT: Molecular interactions of neonicotinoid insecticides with the nicotinic acetylcholine receptor have been mapped by chemical and structural neurobiology approaches, thereby encouraging the biorational design of novel nicotinic ligands. This investigation designs, prepares, and evaluates the target site potency of neonicotinoid analogues with various types of electronegative pharmacophores and subsequently predicts their molecular recognition in the ligand-binding pocket. The N-nitroimino (NNO2) neonicotinoid pharmacophore is systematically replaced by N-nitrosoimino (NNO), N-formylimino [NC(O)H], N-alkyl- and N-arylcarbonylimino [NC(O)R], and N-alkoxy- and N-aryloxycarbonylimino [NC(O)OR] variants. The NNO analogues essentially retain the binding affinity of the NNO2 compounds, while the isosteric NC(O)H congeners have diminished potency. The NC(O)R and NC(O)OR analogues, where R is methyl, trifluoromethyl, phenyl, or pyridin-3-yl, have moderate to high affinities. Orientation of the tip oxygen plays a critical role for binding of the NNO and NC(O)H pharmacophores, and the extended NC(O)R and NC(O)OR moieties are embraced by unique binding domains.
Chemical Research in Toxicology 02/2009; 22(3):476-82. · 3.78 Impact Factor
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ABSTRACT: Neonicotinoid agonists with a nitroimino or cyanoimino pharmacophore are the newest of the four most important classes of insecticides. Our studies on the nicotinic receptor structure in the neonicotinoid-bound state revealed a unique niche of about 6 A depth beyond the nitro oxygen or cyano nitrogen tip. The N-substituted imino pharmacophore was therefore extended to fill the gap. Excellent target site selectivity with high insecticidal activity and low toxicity to mammals were achieved rivaling those of the current neonicotinoid insecticides as illustrated here by 3-(6-chloropyridin-3-ylmethyl)-2-trifluoroacetyliminothiazoline and its pyrazinoylimino analogue.
Journal of Medicinal Chemistry 08/2008; 51(14):4213-8. · 4.80 Impact Factor
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ABSTRACT: Neonicotinoid insecticides target nicotinic acetylcholine receptors (nAChRs), which, in both vertebrates and invertebrates, mediate fast-acting synaptic neurotransmission in the nervous system. Recently, Kagabu et al. synthesized bis-neonicotinoids. The neural activities of bis-neonicotinoids have been evaluated on the central nerve cord of American cockroaches. However, the action of bis-neonicotinoids on nAChRs expressed by dissociated insect neurons has not yet been studied. Thus, the actions of several alkylene-tethered bis-neonicotinoids on the terminal abdominal ganglion neurons of the American cockroach, Periplaneta americana, were investigated using whole-cell patch-clamp electrophysiology. All of the ligands tested did not induce membrane currents, but reduced the responses to ACh when bath applied prior to co-application with ACh. Of the compounds tested, HK-13, which possesses two imidacloprid units linked with a hexamethylene bridge, had the highest antagonist potency. The antagonist action was reduced, not only by elongating, but also by shortening the linker.
Neuroscience Letters 11/2007; 425(3):137-40. · 2.11 Impact Factor
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ABSTRACT: Prodrugs of imidacloprid and the thiazolylmethyl analog masked with oxodioxolylmethyl group on the N3 site were prepared. The prodrugs decomposed in a buffer solution of pH 8.3 and in a physiological salt solution with half-lives of 10-15 h, releasing the parent insecticides. Being consistent with this, an inward current was evoked in dissociated cockroach neurons treated with the masked compound solutions, which were maintained for 24 h after preparation, as measured using patch-clamp electrophysiology, whereas no response was observed in neurons when the solutions were challenged immediately after preparation. The insecticidal test on the American cockroach showed that the minimum lethal dose for each compound at 24 h after injection was 6.4x10(-8) mol, which was similar to that for imidacloprid and the thiazolyl derivative. This result strongly suggested a regeneration of the active ingredients in vivo.
Bioorganic & Medicinal Chemistry Letters 09/2007; 17(16):4500-3. · 2.55 Impact Factor
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ABSTRACT: The pharmacophore of the neonicotinoid insecticide imidacloprid, nitroiminoimidazolidine, was modified to heterocycles such as thiazolidine, pyrrolidine, dihydroimidazole, dihydrothiazole, and pyridone conjugated to nitroimine (=NNO2) or nitromethylene (=CHNO2). Their 6-chloro-3-pyridylmethyl or 5-chloro-3-thiazolylmethyl derivatives were examined for insecticidal activity against the American cockroach by injection and for neuroblocking activity using the cockroach ganglion. Most of the compounds having the neonicotinoidal pharmacophore exhibited insecticidal activity at the nanomolar level, which was enhanced in the presence of synergists, and high neuroblocking activity at the micromolar level. Quantitative analysis for the compounds showed that the neuroblocking potency is proportional both to the Mulliken charge on the nitro oxygen atom and to the partition coefficient log P value. The equation for the insecticidal versus neuroblocking potencies indicated that both potencies are related proportionally with each other when the other factors are the same.
Journal of Agricultural and Food Chemistry 03/2007; 55(3):812-8. · 2.82 Impact Factor
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ABSTRACT: The insecticidal activities of imidacloprid derivatives with a wide range of substituents at the 5-position on the pyridine ring against American cockroaches, Periplaneta americana (L.), were measured by injection with and without synergists propyl 2-propynyl phenylphosphonate and piperonyl butoxide. The log(1/MLD) value (MLD = minimal lethal dose in mol) without synergists was 7.96 for the methyl derivative, and the values were lower for other derivatives. Synergists enhanced the potencies of all the compounds tested. Considering these compounds and those with other substituents at this position, the region for maximum activity was predicted to be in the conjunction of the pyridyl 6-chlorine atom with a lipophilic small group in the 5-position.
Pest Management Science 02/2007; 63(1):75-83. · 2.25 Impact Factor
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ABSTRACT: Prodrug-oriented molecular design was attempted for the potent acyclic neonicotinoid insecticide, clothianidin (1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine). Molecules bearing a CH2COCH2 bridge linking the 1,3-NH ends of clothianidin or their acetals would possibly be hydrolyzed, regenerating the mother compounds. This strategy was used to prepare seven acetals of clothianidin-based molecules that combined 2-chloro-5-thiazolylmethyl, 6-chloro-3-pyridylmethyl or 3-tetrahydrofurfuryl with a nitroimine, cyanoimine or nitromethylene group. The key intermediate, 1,3-diamino-2,2-dimethoxypropane, was prepared from the dihydroxyacetone dimer in four steps. A selected acetal showed a characteristic nerve-impulse pattern for neonicotinoids on an excised American cockroach ganglion, although the neuroblocking activity was fairly low. Some acetals were highly insecticidal against the pea aphid at 0.8-20 ppm 7 days after a spray treatment, this being in a contrast to their far weaker activity by injection into American cockroaches. The biological results suggest that the intrinsic insecticidal activities of the acetals are weak, but would exhibit enhanced activity if hydrolyzed in an external environment.
Bioscience Biotechnology and Biochemistry 05/2005; 69(4):705-13. · 1.28 Impact Factor
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ABSTRACT: The asymmetric chloronicotinyl insecticide, 1-[1-(6-chloro-3-pyridyl)ethyl]-2-nitroiminoimidazolidine, was prepared, and the absolute configurations of the enantiomers were determined by an X-ray analysis. The insecticidal activity against the housefly measured with metabolic inhibitors showed the (S) enantiomer to be slightly more active than the (R) isomer. Electrophysiological measurements on the American cockroach central nerve cord showed the compounds to elicite the impulses and subsequently blocked them. The neuroblocking potency of the (S) isomer was 5.9 microM, while that of the (R) isomer was as high as 73 microM. The molar concentrations required for 50% inhibition of the specific binding of [3H]imidacloprid to the housefly head membrane preparation were respectively 0.19 microM and 0.95 microM for the (S) and (R) isomers. This enatioselectivity ratio was smaller than 35 for nicotine isomers but greater than 2 for epibatidine isomers.
Bioscience Biotechnology and Biochemistry 06/2003; 67(5):980-8. · 1.28 Impact Factor
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ABSTRACT: Fifteen 5-substituted 1-(6-chloro-3-pyridylmethyl)-2-nitromethylene-1,3- diazacyclohexanes and three other related compounds having a five- or seven-membered ring were synthesized and their biological activities were measured in vivo and in vitro. The insecticidal (in vivo) activity was evaluated against houseflies Musca domestica L under synergistic conditions with propargyl propyl phenyl phosphonate and piperonyl butoxide. The binding activity of each compound to nicotinic acetylcholine receptor in vitro was measured using [125I] alpha-bungarotoxin. The insecticidal activities of the unsubstituted diazacyclohexane analogues were slightly higher than those of the imidazolidine analogues, but the enlargement of ring size to diazacycloheptane lowered the activity. Substitution of 1,3-diazacyclohexane or imidazolidine rings was not generally favourable for the activity, but the unsubstituted 1,3-diazacyclohexane analogue showed the highest binding activity. Ring substitutions and ring enlargement decreased the activity 100-30,000-fold.
Pest Management Science 06/2002; 58(5):483-90. · 2.25 Impact Factor
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ABSTRACT: The insecticidal and nerve-excitatory activities of imidacloprid and its alkylated congeners on the imidazolidine NH site were measured. In the insecticidal activity against the green rice leafhopper measured in a spraying test using rice seedlings, a few compounds with C3-alkyl groups were as active as imidacloprid. In the insecticidal test against the American cockroach by the injection method, the activity values were generally increased by the use of metabolic inhibitors of oxidative degradation mechanisms. Under these conditions, all of the alkyl derivatives were less active than imidacloprid, as shown by the nerve activity measured in the excised central nerve cords of American cockroaches. The higher the nerve activity, the higher the insecticidal activity when the hydrophobic factors of the compounds were considered separately.
Pesticide Biochemistry and Physiology.
