321845-11-8Relevant articles and documents
Azido-neonicotinoids as candidate photoaffinity probes for insect nicotinic acetylcholine receptors [1]
Maienfisch, Peter,Haettenschwiler, Joerg,Rindlisbacher, Alfred,Decock, Arnaud,Wellmann, Henning,Kayser, Hartmut
, p. 710 - 714 (2007/10/03)
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.
Structural features of azidopyridinyl neonicotinoid probes conferring high affinity and selectivity for mammalian α4β2 and Drosophila nicotinic receptors
Zhang, Nanjing,Tomizawa, Motohiro,Casida, John E.
, p. 2832 - 2840 (2007/10/03)
The higher toxicity of neonicotinoid insecticides such as N-(6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine (imidacloprid) to insects than mammals is due in large part to target site specificity at the corresponding nicotinic acetylcholine receptors (nAChRs). We propose that neonicotinoids with a protonated N-unsubstituted imine or equivalent substituent recognize the anionic subsite of the mammalian α4β2 nAChR whereas the negatively charged (δ-) tip of the neonicotinoid, insecticides interacts with a putative cationic subsite of the insect nAChR. This hypothesis can be tested by using two photoaffinity probes that differ only in the N-unsubstituted imine vs negatively charged (δ-) tip. Synthesis methodology was developed for compounds combining three moieties: pyridin-3-ylmethyl or 6-chloropyridin-3-ylmethyl and their 4- and 5-azido analogues; imidazolidine, 4-imidazoline or 4-thiazoline; and N-unsubstituted imine, nitroimine, cyanoimine, or nitromethylene. Structure-activity studies compared displacement of [3H] nicotine binding in mammalian α4β2 nAChR and [3H]imidacloprid binding in Drosophila nAChR. Preferred compounds are N-(5-azido-6-chloropyridin-3-ylmethyl) with 2-iminothiazoline for α4β2 (Ki = 0.47 nM) and with 2-nitroiminothiazoline or 2-nitromethyleneimidazolidine for Drosophila (Ki = 0.72-3.9 nM).
5-Azidoimidacloprid and an acyclic analogue as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors
Kagabu,Maienfisch,Zhang,Granda-Minones,Haettenschwiler,Kayser,Maetzke,Casida
, p. 5003 - 5009 (2007/10/03)
The 5-azido analogue of the major insecticide imidacloprid, 1-(5-azido-6-chloropyridin-3-ylmethyl)-2-nitroiminoimidazolidine (1), and an acyclic analogue, N-(5-azido-6-chloropyridin-3-ylmethyl)-N′-methyl-N″′-nitrog uanidine (2), were prepared in good yields as candidate photoaffinity probes for mammalian and insect nicotinic acetylcholine receptors (nAChRs). The essential intermediate was 5-azido-6-chloropyridin-3-ylmethyl chloride (3) prepared in two ways: from 6-chloro-5-nitronicotinic acid by selective reduction and then diazotization, and from N-(6-chloropyridin-3-ylmethyl)morpholine by an electrophilic azide introduction with lithium diisopropylamide followed by chlorine substitution of morpholine with ethyl chloroformate. Coupling of 3 with 2-nitroiminoimidazolidine gave 1. Conversion of 3 to 2 was achieved in good yields via the hexahydrotriazine intermediate 14. Fortuitously, the azido substituent in 1 and 2 increases the affinity 7-79-fold for rat brain and recombinant α4β2 nAChRs (Kis 4.4-60 nM competing with [3H](-)-nicotine) while maintaining high potency on both insect nAChRs (Drosophila and Myzus) (Kis 1-15 nM competing with [3H]imidacloprid). Azidopyridinyl compounds 1 and 2 are therefore candidate photoaffinity probes for characterization of both mammalian and insect receptors.
