Azido-Neonicotinoids as Candidate Photoaffinity Probes for Insect Nicotinic Acetylcholine Receptors [1]

Abstract

The neonicotinoids are the most successful chemical class of insecticides reaching sales of more than 630 Mio $ in 2001, mainly due to the excellent market performance of imidacloprid and thiamethoxam. The insect nicotinic acetylcholine receptors (nAChRs) are the targets for these compounds, which are highly effective against a variety of sucking and chewing insects. Compared with the other neonicotinoid sales products, thiamethoxam binds in a different way, possibly to a different site of nAChRs in aphids. To gain further insight into the different modes of binding, a research program applying the photoaffinity labeling technique was started. A series of novel candidate photoaffinity probes containing a 5-azido-6-chloropyridin-3-ylmethyl group were prepared from 5-azido-6-chloropyridin-3-ylmethyl chloride, which was obtained in three steps from 6-chloropyridin-3-ylmethyl chloride. These probes showed good to excellent contact/feeding and systemic activity against Myzus persicae, however, they were at least 4- to 16-fold less effective against Aphis craccivora, Nilaparvata lugens, Spodoptera littoralis, and Diabrotica balteata than the neonicotinoid sales products. In general, the introduction of an azide group at C(5) of the 6-chloropyridin-3-ylmethyl substituent resulted in reduced potency as well as in a narrower pest spectrum. In competition binding assays with [3H]imidacloprid, analogues of imidacloprid, clothianidin, thiacloprid and thiamethoxam containing a 5-azido-6-chloropyridin-3-ylmethyl group showed high displacing potency with nAChRs from Aphis and Myzus (Ki values: 2 to 27 nM) suggesting that these compounds are valuable candidate photoaffinity probes. Taking into account the biological screening activity as well as the receptor binding potency, 1-(5-azido-6-chloropyridin-3-ylmethyl)-2-nitroimino-imidazolidine, N-(5-azido-6-chloropyridin-3-ylmethyl)-N?-methyl-N?-nitroguanidine and 3-(5-azido-6-chloropyridin-3-ylmethyl)-2-cyanoimino-thiazolidine were identified as the preferred candidate neonicotinoid photoaffinity probes to study the imidacloprid binding site.

(Z)-N-{3-[(6-Chloropyridin-3-yl)methyl]-1,3-thiazolidin-2-ylidene}cyanamide

“…For background to the title compound, a member of the neonicotinoide class of insecticides, see Maienfisch et al (2003). For the synthesis, see Ishimitsu et al, (1991) Experimental Crystal data…”

Mannich-Type Reaction for Synthesis of 3-Methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine

“…The results were different from the literature reports. [7][8][9][10][11][12][13][14][15][16] Otherwise, when alkaline catalyst instead of acidic catalyst was added, the reaction …”

“…[7] 3-Methyl-4-nitroimino-tetrahydro-1,3,5-oxadiazine (compound 2), N-(1,5-dimethyl-1,3,5-triazinan-2-ylidene)nitramide (compound 3a), and N-(5-ethyl-1-methyl-1,3,5-triazinan-2-ylidene)nitramide (compound 3b) are the major products of the Mannich reaction of 1, in which compound 2 is one of the most important intermediates in synthetic pesticides. In many reports, the major catalysts used for the transformation were acids, for example hydrochloric acid, trifluoroacetic acid, glacial acetic acid, and formic acid, which have been studied by Maienfisch et al, [7][8][9] Gobel et al, [10] Fan et al, [11] Kang et al, [12] Zhou et al, [13] Tao et al, [14] Scheme 1. Mannich reaction general formula.…”

Can mouth part deformities of Chironomus riparius serve as indicators for water and sediment pollution? A laboratory approach

“…Imidacloprid is slightly less toxic, affecting the survival rate (LOEC 1 µg/L), behavioural activity (LOEC 5 µg/L) and the total emergence rate (L0EC 1 µg/L; Langer-Jaesrich, unpublished data). Both substances are members of a very successful new insecticide group called neonicotinoids (Maienfisch et al 2003), which have been the fastest growing class of insecticides in modern crop protection in recent years (Jeschke and Nauen 2008). Information about measured imidacloprid and thiacloprid concentrations in the environment are rare.…”