Michael R. Loso

Discovery and Characterization of Sulfoxaflor, a Novel Insecticide Targeting Sap-Feeding Pests

The discovery of sulfoxaflor [N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] resulted from an investigation of the sulfoximine functional group as a novel bioactive scaffold for insecticidal activity and a subsequent extensive structure-activity relationship study. Sulfoxaflor, the first product from this new class (the sulfoximines) of insect control agents, exhibits broad-spectrum efficacy against many sap-feeding insect pests, including aphids, whiteflies, hoppers, and Lygus, with levels of activity that are comparable to those of other classes of insecticides targeting sap-feeding insects, including the neonicotinoids. However, no cross-resistance has been observed between sulfoxaflor and neonicotinoids such as imidacloprid, apparently the result of differences in susceptibility to oxidative metabolism. Available data are consistent with sulfoxaflor acting via the insect nicotinic receptor in a complex manner. These observations reflect the unique structure of the sulfoximines compared with neonicotinoids.

Biological characterization of sulfoxaflor, a novel insecticide

BACKGROUND The commercialization of new insecticides is important for ensuring that multiple effective product choices are available. In particular, new insecticides that exhibit high potency and lack insecticidal cross-resistance are particularly useful in insecticide resistance management (IRM) programs. Sulfoxaflor possesses these characteristics and is the first compound under development from the novel sulfoxamine class of insecticides. RESULTS In the laboratory, sulfoxaflor demonstrated high levels of insecticidal potency against a broad range of sap-feeding insect species. The potency of sulfoxaflor was comparable with that of commercial products, including neonicotinoids, for the control of a wide range of aphids, whiteflies (Homoptera) and true bugs (Heteroptera). Sulfoxaflor performed equally well in the laboratory against both insecticide-susceptible and insecticide-resistant populations of sweetpotato whitefly, Bemisia tabaci Gennadius, and brown planthopper, Nilaparvata lugens (Stål), including populations resistant to the neonicotinoid insecticide imidacloprid. These laboratory efficacy trends were confirmed in field trials from multiple geographies and crops, and in populations of insects with histories of repeated exposure to insecticides. In particular, a sulfoxaflor use rate of 25 g ha(-1) against cotton aphid (Aphis gossypii Glover) outperformed acetamiprid (25 g ha(-1) ) and dicrotophos (560 g ha(-1) ). Sulfoxaflor (50 g ha(-1) ) provided a control of sweetpotato whitefly equivalent to that of acetamiprid (75 g ha(-1) ) and imidacloprid (50 g ha(-1) ) and better than that of thiamethoxam (50 g ha(-1) ). CONCLUSION The novel chemistry of sulfoxaflor, its unique biological spectrum of activity and its lack of cross-resistance highlight the potential of sulfoxaflor as an important new tool for the control of sap-feeding insect pests.

Sulfoxaflor and the sulfoximine insecticides: chemistry, mode of action and basis for efficacy on resistant insects.

The sulfoximines, as exemplified by sulfoxaflor ([N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] represent a new class of insecticides. Sulfoxaflor exhibits a high degree of efficacy against a wide range of sap-feeding insects, including those resistant to neonicotinoids and other insecticides. Sulfoxaflor is an agonist at insect nicotinic acetylcholine receptors (nAChRs) and functions in a manner distinct from other insecticides acting at nAChRs. The sulfoximines also exhibit structure activity relationships (SAR) that are different from other nAChR agonists such as the neonicotinoids. This review summarizes the sulfoximine SAR, mode of action and the biochemistry underlying the observed efficacy on resistant insect pests, with a particular focus on sulfoxaflor.

Novel nicotinic action of the sulfoximine insecticide sulfoxaflor

The novel sulfoximine insecticide sulfoxaflor is as potent or more effective than the neonicotinoids for toxicity to green peach aphids (GPA, Myzus persicae). The action of sulfoxaflor was characterized at insect nicotinic acetylcholine receptors (nAChRs) using electrophysiological and radioligand binding techniques. When tested for agonist properties on Drosophila melanogaster Dα2 nAChR subunit co-expressed in Xenopus laevis oocytes with the chicken β2 subunit, sulfoxaflor elicited very high amplitude (efficacy) currents. Sulfoximine analogs of sulfoxaflor were also agonists on Dα2/β2 nAChRs, but none produced maximal currents equivalent to sulfoxaflor nor were any as toxic to GPAs. Additionally, except for clothianidin, none of the neonicotinoids produced maximal currents as large as those produced by sulfoxaflor. These data suggest that the potent insecticidal activity of sulfoxaflor may be due to its very high efficacy at nAChRs. In contrast, sulfoxaflor displaced [(3)H]imidacloprid (IMI) from GPA nAChR membrane preparations with weak affinity compared to most of the neonicotinoids examined. The nature of the interaction of sulfoxaflor with nAChRs apparently differs from that of IMI and other neonicotinoids, and when coupled with other known characteristics (novel chemical structure, lack of cross-resistance, and metabolic stability), indicate that sulfoxaflor represents a significant new insecticide option for the control of sap-feeding insects.

Molecular Modeling of Sulfoxaflor and Neonicotinoid Binding in Insect Nicotinic Acetylcholine Receptors: Impact of the Myzus β1 R81T Mutation

BACKGROUND Sulfoxaflor (Isoclast™ active), a new sulfoximine-class insecticide, targets sap-feeding insect pests, including those resistant to neonicotinoids. Sulfoxaflor acts on the insect nicotinic acetylcholine receptor (nAChR) in a distinct manner relative to neonicotinoids. Unlike any of the neonicotinoids, sulfoxaflor has four stereoisomers. A homology model of Myzus persicae (green peach aphid) based on the ACh binding protein from Aplysia californica, overlaid with M. persicae nAChR sequence (α2 and β1 subunits) was used to investigate the interactions of the sulfoxaflor stereoisomers with WT and R81T versions of the nAChR. RESULTS Whole-molecule van der Waals interactions are highly correlated with the binding affinity for the neonicotinoids and correctly predict the rank order of binding affinity for neonicotinoids and sulfoxaflor. The R81T mutation in M. persicae nAChR is predicted to have much less effect on binding of sulfoxaflors stereoisomers than that of the neonicotinoids. CONCLUSION All four stereoisomers predictably contribute to the activity of sulfoxaflor. The WT and R81T nAChR homology models suggest that changes in a whole-molecule electrostatic energy component can potentially explain the effects of this target-site mutation on the pattern of reduced efficacy for the modeled neonicotinoids, and provide a basis for the reduced effect of this mutation on sulfoxaflor.

Synthesis and antifungal activity of 3‐aryl‐1,2,4‐triazin‐6‐one derivatives

BACKGROUND As a result of resistance development in many plant-pathogenic fungi to agricultural fungicides, there is an ongoing need to discover novel antifungal chemistries to help sustain efficient crop production. A fungicide screening program identified 3-phenyl-1-(2,2,2-trifluoroethyl)-1,2,4-triazin-6(1H)-one (5) as a promising new starting point for further activity optimization. A series of analogs were designed, prepared and evaluated in growth inhibition assays using four plant-pathogenic fungi. RESULTS Thirty nine analogs (compounds 5 to 43) were prepared to explore structure-activity relationships at R1 and R2, and all targeted structures were characterized by (1)H NMR and MS. All compounds were in vitro tested against three ascomycetes [Leptosphaeria nodorum, Magnaporthe grisea and Zymoseptoria tritici (syn. Mycosphaerella graminicola)] and one basidiomycete (Ustilago maydis) pathogen. When R2 was trifluoroethyl, fungicidal activity was enhanced by a single electron-withdrawing substitution, such as Br, Cl and CF3 in the 3-position at R1 (compounds 9, 10 and 12), of which the 3-bromo compound (10) was the most active (EC50 = 0.08, averaged across four pathogens). More subtle activity improvement was found by addition of a second halogen substituent in the 4-position, with the 3-Br-4-F analog (20) being the most active against the commercially important cereal pathogen Z. tritici. Replacement of the R2 haloalkyl group with benzyl, alkyl (e.g. n-butyl, i-butyl, n-pentyl) and, particularly, CH2 -cycloalkyls (e.g. CH2-cyclopropyl, CH2-cyclobutyl) resulted in further activity enhancements against the ascomycete fungi, but was either neutral or detrimental to activity against U. maydis. One of the most active compounds in this series (41) gave control of Z. tritici, with an EC50 of 0.005 ppm, comparable with that of the commercial strobilurin fungicide azoxystrobin (EC50 0.002 ppm). CONCLUSIONS The present work demonstrated that the 3-phenyl-1,2,4-triazin-6-ones are a novel series of compounds with highly compelling levels of antifungal activity against agriculturally relevant plant-pathogenic fungi.

SAR studies directed toward the pyridine moiety of the sap-feeding insecticide sulfoxaflor (Isoclast™ active).

Sap-feeding insect pests constitute a major insect pest complex that includes a range of aphids, whiteflies, planthoppers and other insect species. Sulfoxaflor (Isoclast™ active), a new sulfoximine class insecticide, targets sap-feeding insect pests including those resistant to many other classes of insecticides. A structure activity relationship (SAR) investigation of the sulfoximine insecticides revealed the importance of a 3-pyridyl ring and a methyl substituent on the methylene bridge linking the pyridine and the sulfoximine moiety to achieving strong Myzus persicae activity. A more in depth QSAR investigation of pyridine ring substituents revealed a strong correlation with the calculated logoctanol/water partition coefficient (SlogP). Model development resulted in a highly predictive model for a set of 18 sulfoximines including sulfoxaflor. The model is consistent with and helps explain the highly optimized pyridine substitution pattern for sulfoxaflor.

Expanding the structure–activity relationship of sulfoxaflor: the synthesis and biological activity of N‐heterocyclic sulfoximines

BACKGROUND Sulfoxaflor, a new insect control agent developed by Dow AgroSciences, exhibits broad-spectrum control of many sap-feeding insect pests, including aphids, whiteflies, leafhoppers, planthoppers and lygus bugs. During the development of sulfoxaflor, structure-activity relationship (SAR) exploration of the sulfoximine functional group revealed that the nature of the sulfoximine nitrogen substituent significantly affects insecticidal acitivity. As part of the investigation to probe the various electronic, steric and lipophilic parameters at this position, a series of N-heterocyclic sulfoximines were synthesized and tested for bioactivity against green peach aphid. RESULTS Using a variety of chemistries, the nitrile substituent was replaced with different substituted five- and six-membered heterocycles. The compounds in the series were then tested for insecticidal acitivty against green peach aphid in foliar spray assays. In spite of the larger steric demand of these substituents, the resulting N-heterocyclic sulfoximine analogs displayed good levels of efficacy. In particular, the N-thiazolyl sulfoximines exhibited the greatest activity, with LC50 values as low as 1 ppm. CONCLUSIONS The novel series of N-heterocyclic sulfoximines helped to advance the current knowledge of the sulfoxaflor SAR, and demonstrated that the structural requirement for the sulfoximine nitrogen position was not limited to small, electron-deficient moeities, but rather was tolerant of larger functionality.

Characterization of a nicotinic acetylcholine receptor binding site for sulfoxaflor, a new sulfoximine insecticide for the control of sap-feeding insect pests☆

Sulfoxaflor (SFX, Isoclast™ Active) is a recently developed sulfoximine insecticide that is highly effective against sap-feeding insect pests. SFX has been shown to act through an interaction with insect nicotinic acetylcholine receptors (nAChRs). SFX was previously found to interact weakly with the binding site for the neonicotinoid imidacloprid. However, radioligand displacement studies characterizing the binding site of the insecticide SFX itself have not been conducted. In this study, we report the characterization of a high affinity [3H]SFX Myzus persicae (green peach aphid, GPA) binding site with relatively low abundance. Through the evaluation of a set of SFX analogs, we have demonstrated that displacement of [3H]SFX shows an excellent correlation with GPA toxicity, and thus is toxicologically relevant. Comparison with the previously described methyl-SFX binding site information reveals differences with the SFX binding site that are discussed herein. [3H]SFX therefore represents a new tool for the characterization of insect nAChRs.