The spinosyns, spinosad, spinetoram, and synthetic spinosyn mimics - discovery, exploration, and evolution of a natural product chemistry and the impact of computational tools.

Natural products (NPs) have long been a source of insecticidal crop protection products. Like many macrolide NPs, the spinosyns originated from a soil inhibiting microorganism (Saccharopolyspora spinosa). More than 20 years after initial registration, the spinosyns remain a unique class of NP-based insect control products that presently encompass two insecticidal active ingredients, spinosad, a naturally occurring mixture of spinosyns, and spinetoram, a semi-synthetic spinosyn product. The exploration and exploitation of the spinosyns has, unusually, been tied to an array of computational tools including artificial intelligence (AI)-based quantitative structure activity relationship (QSAR) and most recently computer-aided modeling and design (CAMD). The AI-based QSAR directly lead to the discovery of spinetoram, while the CAMD studies have recently resulted in the discovery and building of a series of synthetic spinosyn mimics. The most recent of these synthetic spinosyn mimics show promise as insecticides targeting lepidopteran insect pests as demonstrated by field studies wherein the efficacy has been shown to be comparable to spinosad and spinetoram. These and a range of other aspects related to the exploration of the spinosyns over the past 30 years are reviewed herein. © 2020 Society of Chemical Industry.

Synthesis and biological potency of anilino-triazine insecticides.

BACKGROUND: An insecticide screening effort identified N-(4-bromophenyl)-4,6-bis(2,2,2-trifluoroethoxy)-1,3,5-triazine-2-amine as having weak potency against two lepidopteran species, Helicoverpa zea and Spodoptera exigua. A structure-activity relationship study about the trifluoroethoxy substituents and the aniline of this compound was carried out in an effort to improve insecticidal potency. RESULTS: Initially, a series of analogs bearing various substituents on the aniline were prepared, and the insecticidal potency was evaluated against H. zea and S. exigua in greenhouse diet feeding assays. The results showed that electron-withdrawing substituents, such as Cl, Br and CF3 , were preferred over electron-donating substituents, such as methoxy, and that potency was significantly better when the substituent was in the para-position. Additional investigations showed that bis(anilino)trifluoroethoxytriazines were more potent. Replacement of the remaining trifluoroethyl group in the bis(anilino)triazine series with an alkyl amine lead to compounds of equal or superior efficacy. CONCLUSION: The work presented showed that electron-withdrawing substituents in the para-position of the aniline ring of the initial hit delivered the best levels of insecticidal potency against the two insect species tested. Further investigations showed that potency could be improved by replacing one of the two trifluoroethoxy groups with additional 4-substituted aniline. This level of potency was maintained or further improved when the remaining trifluoroethoxy was replaced with a substituted amine. © 2017 Society of Chemical Industry.