Thiamethoxam is the first commercial neonicotinoid insecticide from the thianicotinyl subclass. It was discovered in the course of our optimisation program on neonicotinoids started in 1985. Novel variations of the nitroimino-heterocycle of imidacloprid led to 4-nitroimino-1,3,5-oxadiazinanes exhibiting high insecticidal activity. Among these, thiamethoxam (CGA 293433) was identified as the best compound and selected for worldwide development. The compound can be synthesised in only a few steps and high yield from easily accessible starting materials. Thiamethoxam acts by binding to nicotinic acetylcholine receptors. It exhibits exceptional systemic characteristics and provides excellent control of a broad range of commercially important pests, such as aphids, jassids, whiteflies, thrips, rice hoppers, Colorado potato beetle, flea beetles and wireworms, as well as some lepidopteran species. In addition, a strong preventative effect on some virus transmissions has been demonstrated. Thiamethoxam is developed both for foliar/soil applications and as a seed treatment for use in most agricultural crops all over the world. Low use rates, flexible application methods, excellent efficacy, long-lasting residual activity and favourable safety profile make this new insecticide well-suited for modern integrated pest management programmes in many cropping systems.
Neonicotinoids represent a novel and distinct chemical class of insecticides with remarkable chemical and biological properties. In 1985, a research programme was started in this field, in which novel nitroimino heterocycles were designed, prepared and assayed for insecticidal activity. The methodology for the synthesis of 2-nitroimino-hexahydro-1,3,5-triazines, 4-nitroimino-1,3,5-oxadiazinanes and 4-nitroimino-1,3,5-thiadiazinanes is outlined. Bioassays demonstrated that 3-(6-chloropyridin-3-ylmethyl)-4-nitroimino-1,3,5-oxadiazinane exhibited better insecticidal activity than the corresponding 2-nitroimino-hexahydro-1,3,5-triazine and 4-nitroimino-1,3,5-thiadiazinane. In most tests, this compound was equally or only slightly less active than imidacloprid. A series of structural modifications on this lead structure revealed that replacement of the 6-chloro-3-pyridyl group by a 2-chloro-5-thiazolyl moiety resulted in a strong increase of activity against chewing insects, whereas the introduction of a methyl group as pharmacophore substituent increased activity against sucking pests. The combination of these two favourable modifications led to thiamethoxam (CGA 293 343). Thiamethoxam is the first commercially available second-generation neonicotinoid and belongs to the thianicotinyl sub-class. It is marketed under the trademarks Actara for foliar and soil treatment and Cruiser for seed treatment. The compound has broad-spectrum insecticidal activity and offers excellent control of a wide variety of commercially important pests in many crops. Low use rates, flexible application methods, excellent efficacy and the favourable safety profile make this new insecticide well-suited for modern integrated pest management programmes in many cropping systems.
Abstract:The insect nicotinic acetylcholine receptor (nAChR) is a major target for insecticide action. The rapidly expanding use of neonicotinoid insecticides of varied structures makes it increasingly important to define similarities and differences in their action, particularly for the first-generation chloropyridinyl compounds versus the second-generation chlorothiazolyl derivatives. We have shown with Musca domestica that a convenient and relevant determination of the neonicotinoid insecticide target is a binding site assay with. This study uses membranes from the aphids Myzus persicae and Aphis craccivora and from heads of the flies Drosophila melanogaster and Musca domestica to characterize the [ 3 H]IMI binding sites relative to their number and possible species variation in structure-activity relationships. With emphasis on commercial neonicotinoids, six potent chloropyridinyl compounds are compared with the corresponding six chlorothiazolyl analogues (syntheses are given for chemicals prepared differently than previously described). The preference for chloropyridinyl versus chlorothiazolyl is not dependent on the insect species examined but instead on other structural features of the molecule. The chlorothiazolyl substituent generally confers higher potency in the clothianidin and desmethylthiamethoxam series and the chloropyridinyl moiety in the imidacloprid, thiacloprid, acetamiprid, and nitenpyram series. Two chlorothiazolyl compounds compete directly with the chloropyridinyl [ 3 H]IMI for the same binding sites in Myzus and Drosophila membranes. This study shows conserved neonicotinoid specificity of the [ 3 H]IMI binding site in each of the four insect species examined.
Fluorine-containing compounds are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the number of fluorinated organic molecules reaching commercial status as crop protection products and pharmaceutical drugs has been observed: in 1978, ca. 600 pesticides were known, but only approximately 25 (4%) contained fluorine. Today, fluorine-containing compounds account for more than 17% of all commercially available crop protection agents and many others are currently under development. The structures of the fluorine-containing development compounds proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ca. 8% of all synthetic drugs. Six years later already more than 1500 fluorine-containing drugs were under development. Fluorine-containing compounds have also been successful in the marketplace, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac®), Paroxetine (Paxil®), Ciprofloxacin (Cipro®) and Cisaprid (Propulsid®). This success is mainly due to the fact that selectively fluorinated compounds can exhibit dramatically improved potency when compared to the non-fluorinated analogues. The incorporation of fluorine into a biologically active compound alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chemical and metabolic stability, and the bioavailability. The positive effects of fluorine on the biological efficiency is outlined by three examples: in the chemical class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biological activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem -difluorovinyl group results in a strong decrease of biological activity.
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