Abstract:SUMMARYNaB'H, and LiB'H, at 78% and 97% isotopic enrichments, respectively, were used in the synthesis of 'H-labeled 1-(6-chloro-3-pyridyl)-methyl-2-nitromethyleneimidazolidine (CH-IMI) and N'-[(6-chloro-3-pyridyl) methyl1 -N"-cyano-N' -methylacetamidine (acetarniprid) (two very potent insecticides) and of 1-(6-chloro-3-pyridyl)methyl-2-iminoimidazolidine (desnitro-IMI) (a metabolite of the commercial insecticide imidacloprid) . 6-Chloronicotinoyl chloride was treated with either NaB'H, in methanol or LiE3H, i… Show more
“…The yield of 1-[(6-chloro-3-pyridinyl)methyl]-1,4-diaminobutane was greatly improved when using 2 equiv of 1,4-diaminobutane. The products from monoalkylation of 1,2-diaminoethane, 1,3-diaminopropane, and 1,4-diaminobutane were then reacted in anhydrous conditions with cyanogen bromide using toluene, acetonitrile, and dimethylformamide (DMF), respectively, as the solvent. 1 Synthesis of 6-Chloro-3-pyridinylmethyl Ligands with Modifications in the Heterocyclic Imine Moiety ( 1 − 10 ) or Related Compounds ( 11 − 14 ) …”
1-[(6-Chloro-3-pyridinyl)methyl]-2-imidazolidine (1), the N-desnitro metabolite of the major insecticide imidacloprid, is known to have similar potency to that of (-)-nicotine as an inhibitor of [3H](-)-nicotine binding at the rat recombinant alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR); IC50 values in the present study are 3.8 nM for (-)-nicotine, 6.0 nM for 1, and 155 nM for imidacloprid. Synthesis of new analogues of 1, modified only in the heterocyclic moiety (five-, six-, or seven-membered rings with NH, S, O, and CH2 substituents), gave compounds varying from 4-fold higher potency (2-iminothiazole analogue 10) to >6000-fold less active than (-)-nicotine. Other potent N-[(6-chloro-3-pyridinyl)methyl] compounds are those in which the heterocyclic imine is replaced with pyrrolidine (19) (IC50 9 nM) or trimethylammonium (22) (IC50 18 nM). A novel conversion of (-)-nicotine to its 6-chloro analogue increased the potency 2-fold. These 6-chloro-3-pyridinyl compounds are of interest as novel nAChR probes and potential metabolites of candidate insecticides.
“…The yield of 1-[(6-chloro-3-pyridinyl)methyl]-1,4-diaminobutane was greatly improved when using 2 equiv of 1,4-diaminobutane. The products from monoalkylation of 1,2-diaminoethane, 1,3-diaminopropane, and 1,4-diaminobutane were then reacted in anhydrous conditions with cyanogen bromide using toluene, acetonitrile, and dimethylformamide (DMF), respectively, as the solvent. 1 Synthesis of 6-Chloro-3-pyridinylmethyl Ligands with Modifications in the Heterocyclic Imine Moiety ( 1 − 10 ) or Related Compounds ( 11 − 14 ) …”
1-[(6-Chloro-3-pyridinyl)methyl]-2-imidazolidine (1), the N-desnitro metabolite of the major insecticide imidacloprid, is known to have similar potency to that of (-)-nicotine as an inhibitor of [3H](-)-nicotine binding at the rat recombinant alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR); IC50 values in the present study are 3.8 nM for (-)-nicotine, 6.0 nM for 1, and 155 nM for imidacloprid. Synthesis of new analogues of 1, modified only in the heterocyclic moiety (five-, six-, or seven-membered rings with NH, S, O, and CH2 substituents), gave compounds varying from 4-fold higher potency (2-iminothiazole analogue 10) to >6000-fold less active than (-)-nicotine. Other potent N-[(6-chloro-3-pyridinyl)methyl] compounds are those in which the heterocyclic imine is replaced with pyrrolidine (19) (IC50 9 nM) or trimethylammonium (22) (IC50 18 nM). A novel conversion of (-)-nicotine to its 6-chloro analogue increased the potency 2-fold. These 6-chloro-3-pyridinyl compounds are of interest as novel nAChR probes and potential metabolites of candidate insecticides.
“…The simple synthesis of LiB 2 H 4 and LiB 3 H 4 , neither of which is commercially available, should open the door to a new phase of regioselective tritium and deuterium labeling chemistry. In addition to the simple aldehyde reduction presented here, our experience with LiB 3 H 4 has included the complete reduction of an acid chloride to R-C the presence of an aryl halide 34 and the stereoselective reduction of a ketone in the presence of a secondary amide. 35…”
Section: Discussionmentioning
confidence: 99%
“…After the solution was stirred at 0 °C for 15 min, it was refluxed at 70 °C with constant stirring for 30 min. One aliquot (300 µL) was withdrawn from the flask to be used in another reduction reaction, 34 and a second aliquot (80 µL) was taken for NMR study. The solvents were evaporated from the small aliquot, the residue was dissolved in NaOH/CD3OD (400 µL, saturated solution), and the solution was transferred into a Teflon tube for NMR study.…”
LiBH(4) is a powerful and selective reagent for regiospecific reduction reactions. A simple synthesis of LiB(3)H(4) at near theoretical specific radioactivity is reported. We have treated Li(3)H synthesized from tritium gas ((3)H(2), approximately 98%) with BBr(3) to produce LiB(3)H(4) (specific activity = 4120 GBq/mmol = 110 Ci/mmol. The maximum theoretical specific activity of LiB(3)H(4) is 4252 GBq/mmol = 115.04 Ci/mmol; 1 matom of (3)H = 1063 GBq = 28.76 Ci.) The tritium labeling performance of the reagent was tested by an exemplary reduction of 2-naphthaldehyde to 2-naphthalenemethanol. LiB(3)H(4) and the reduction products were characterized by a combination of (1)H, (3)H, and (11)B NMR techniques, as appropriate.
“…Imidacloprid, thiacloprid, and nitromethylene imidacloprid analog (CH-IMI) were donated by Bayer CropScience (Tokyo, Japan), whereas clothianidin was a gift from Sumitomo Chemical (Tokyo, Japan). DN-IMI was synthesized de novo as described (Latli et al, 1996). ACh and (-)-nicotine were purchased from Sigma-Aldrich (St. Louis, MO), and were used without further purification.…”
Neonicotinoid insecticides target insect nicotinic acetylcholine receptors (nAChRs). Their widespread use and possible risks to pollinators make it extremely urgent to understand the mechanisms underlying their actions on insect nAChRs. We therefore elucidated X-ray crystal structures of the Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) and its Gln55Arg mutant, more closely resembling insect nAChRs, in complex with a nitromethylene imidacloprid analog (CH-IMI) and desnitro-imidacloprid metabolite (DN-IMI) as well as commercial neonicotinoids, imidacloprid, clothianidin, and thiacloprid. Unlike imidacloprid, clothianidin, and CH-IMI, thiacloprid did not stack with Tyr185 in the wild-type Ls-AChBP, but did in the Gln55Arg mutant, interacting electrostatically with Arg55. In contrast, DN-IMI lacking the NO 2 group was directed away from Lys34 and Arg55 to form hydrogen bonds with Tyr89 in loop A and the main chain carbonyl of Trp143 in loop B. Unexpectedly, we found that several neonicotinoids interacted with Lys34 in loop G on the b1 strand in the crystal structure of the Gln55Arg mutant. Basic residues introduced into the a7 nAChR at positions equivalent to AChBP Lys34 and Arg55 enhanced agonist actions of neonicotinoids, while reducing the actions of acetylcholine, (-)-nicotine, and DN-IMI. Thus, not only the basic residues in loop D, but also those in loop G determine the actions of neonicotinoids. These novel findings provide new insights into the modes of action of neonicotinoids and emerging derivatives.
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