Sulfoxaflor (Isoclast™ active) is a sulfoximine insecticide that is active on a broad range of sap-feeding insects, including species that exhibit reduced susceptibility to currently available insecticides. Colonies of Myzus persicae (green peach aphid) were established from aphids collected in the field from peach (Prunus persica) and nectarine (Prunus persica var. nucipersica) orchards in France, Italy and Spain. The presence of the nicotinic acetylcholine receptor (nAChR) point mutation R81T was determined for all the colonies. Eight of the 35 colonies collected were susceptible relative to R81T (i.e., R81T absent), three of the colonies were found to be homozygous for R81T while 24 colonies had R81T present in some proportion (heterozygous). Sulfoxaflor and imidacloprid were tested in the laboratory against these M. persicae field colonies, which exhibited a wide range of susceptibilities (sulfoxaflor RR = 0.6 to 61, imidacloprid RR = 0.7 to 986) (resistance ratios, RR) to both insecticides. Although sulfoxaflor was consistently more active than imidacloprid against these field collected M. persicae, there was a statistically significant correlation across all colonies between the RRs for imidacloprid and sulfoxaflor (Pearson's r = 0.939, p < 0.0001). However, when a larger group of the colonies from Spain possessing R81T were analyzed, there was no correlation observed for the RRs between imidacloprid and sulfoxaflor (r = 0.2901, p = 0.3604). Thus, consistent with prior studies, the presence of R81T by itself is not well correlated with altered susceptibility to sulfoxaflor. In field trials, sulfoxaflor (24 and 36 gai/ha) was highly effective (~avg. 88-96% control) against M. persicae, demonstrating similar levels of efficacy as flonicamid (60-70 gai/ha) and spirotetramat (100-180 gai/ha) at 13-15 days after application, in contrast to imidacloprid (110-190 gai/ha) and acetamiprid (50-75 gai/ha) with lower levels of efficacy (~avg. 62-67% control). Consequently, sulfoxaflor is an effective tool for use in insect pest management programs for M. persicae. However, it is recommended that sulfoxaflor be used in the context of an insecticide resistance management program as advocated by the Insecticide Resistance Action Committee involving rotation with insecticides possessing other modes of action (i.e., avoiding rotation with other Group 4 insecticides) to minimize the chances for resistance development and to extend its future utility.

The sulfoximines, as exemplified by sulfoxaflor (IsoclastTMactive), are a relatively new class of nicotinic acetylcholine receptor (nAChR) competitive modulator (Insecticide Resistance Action Committee [IRAC] Group 4C) insecticides that provide control of a wide range of sap-feeding insect pests. The sulfoximine chemistry and sulfoxaflor exhibits distinct interactions with metabolic enzymes and nAChRs compared to other IRAC Group 4 insecticides such as the neonicotinoids (Group 4A). These distinctions translate to notable differences in the frequency and degree of cross-resistance between sulfoxaflor and other insecticides. Most insect strains exhibiting resistance to a variety of insecticides, including neonicotinoids, exhibited little to no cross-resistance to sulfoxaflor. To date, only two laboratory-based studies involving four strains (Koo et al. 2014, Chen et al. 2017) have observed substantial cross-resistance (>100 fold) to sulfoxaflor in neonicotinoid resistant insects. Where higher levels of cross-resistance to sulfoxaflor are observed the magnitude of that resistance is far less than that of the selecting neonicotinoid. Importantly, there is no correlation between presence of resistance to neonicotinoids (i.e., imidacloprid, acetamiprid) and cross-resistance to sulfoxaflor. This phenomenon is consistent with and can be attributed to the unique and differentiated chemical class represented by sulfoxalfor. Recent studies have demonstrated that high levels of resistance (resistance ratio = 124-366) to sulfoxaflor can be selected for in the laboratory which thus far appear to be associated with enhanced metabolism by specific cytochrome P450s, although other resistance mechanisms have not yet been excluded. One hypothesis is that sulfoxaflor selects for and is susceptible to a subset of P450s with different substrate specificity. A range of chemoinformatic, molecular modeling, metabolism and target-site studies have been published. These studies point to distinctions in the chemistry of sulfoxaflor, and its metabolism by enzymes associated with resistance to other insecticides, as well as its interaction with insect nicotinic acetylcholine receptors, further supporting the subgrouping of sulfoxaflor (Group 4C) separate from that of other Group 4 insecticides. Herein is an expansion of an earlier review (Sparks et al. 2013), providing an update that considers prior and current studies focused on the mode of action of sulfoxaflor, along with an analysis of the presently available resistance / cross-resistance studies, and implications and recommendations regarding resistance management.

Insecticide resistance has been and continues to be a significant problem for invertebrate pest control. As such, effective insecticide resistance management (IRM) is critical to maintain the efficacy of current and future insecticides. A technical group within CropLife International, the Insecticide Resistance Action Committee (IRAC) was established 35 years ago (1984) as an international association of crop protection companies that today spans the globe. IRAC's focus is on preserving the long-term utility of insect, mite, and most recently nematode control products through effective resistance management to promote sustainable agriculture and improved public health. A central task of IRAC has been the continual development and documentation of the Mode of Action (MoA) Classification scheme, which serves as an important tool for implementing IRM strategies focused on compound rotation / alternations. Updates to the IRAC MoA Classification scheme provide the latest information on the MoA of current and new insecticides and acaricides, and now includes information on biologics and nematicides. Details for these new changes and additions are reviewed herein.

Improvements in food production and disease vector control, to feed and protect an expanding global population, require new options and approaches for insect control. A changing and an increasingly stringent regulatory landscape, shifts in pest spectrum due to changes in agronomic practices, and insect resistance to existing insecticides, all contribute to the challenges of, and need for, developing new insect control agents. The nature of insecticides emanating from discovery R&D-based companies in the European Union, Japan, and the United States have evolved from a concentration on a few classes of insecticides and modes of action (MoA), to a far more diversified collection of insecticidal molecules that embody many new, or under-utilized MoAs. Since 1990 there has arguably been a new age of insecticide discovery, with more new classes of insecticides introduced, with greater economic impact, than the prior 50 years combined. Although there has been an on-going evolution and consolidation in the size and shape of the crop protection industry, for the past two decades the output of new insecticides has remained relatively constant. The diversity of approaches employed in the insecticide discovery process (competitor inspired, bioactive hypothesis and natural products) has contributed to the discovery of these new classes of insecticides. Insecticide discovery is today a global enterprise, that armed with new tools and capabilities, will continue to build and provide the future insect control products to meet global grower and consumer demands.

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.

BACKGROUNDγ-Amino butyric acid (GABA) antagonists are proven targets for control of lepidopteran and other pests. New heterocyclic compounds with high insecticidal activity were discovered using a competitive-intelligence-inspired scaffold-hopping approach to generate analogs of fipronil, a known GABA antagonist. These novel aryl heterocyclic amines (AHAs) displayed broad-spectrum activity on a number of chewing insect pests.RESULTSThrough >370 modifications of the core AHA structure, a 7-pyrazolopyridine lead molecule was found to exhibit much improved activity on a number of insect pests. In field trial studies, its performance was 2-4 times lower than commercial standards and also appeared to be species dependent, with good activity seen for larvae of Spodoptera exigua, but inactivity on larvae of Trichoplusia ni.CONCLUSIONAn extensive investigational biology effort demonstrated that these AHA analogs appear to have multiple modes of action, including GABA receptor antagonism and mitopotential or uncoupler activity. The limited capability in larvae of T. ni to convert the lead molecule to its associated open form correlates with the low toxicity of the lead molecule in this species. This work has provided information that could aid investigations of novel GABA antagonists. © 2016 Society of Chemical Industry.

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 sulfoxaflor's 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. © 2016 Society of Chemical Industry.

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 log octanol/water partition coefficient (S log P). 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.

Pharmacophore based design was used effectively to increase the probability of synthesizing biologically active neonicotinic insecticides. The pharmacophore was derived from a set of compounds known to interact with insect nicotinic acetylcholine receptors (nAChRs) by using a computer modeling technique known as the active analog method and data from a [3H]imidacloprid binding assay. Statistical models were then constructed based on this pharmacophore, binding data and several insect assays. Three of these models were validated and used to evaluate proposed novel structures, some of which incorporated moieties that would be considered atypical for neonicotinic compounds. The design, synthesis and structure activity relationships (SARs) of several such molecules are discussed.

The spinosyns are insecticidal natural products originated from Saccharopolyspora spinosa. Spinosad, the first commercial product, is a mixture of two naturally occurring spinosyns (A & D). A second product, spinetoram, is a mixture composed of two synthetically modified spinosyns that, compared to spinosad, provides improved insecticidal potency and a broader pest insect spectrum. The spinosyns act on a subgroup of insect nicotinic acetylcholine receptors (nAChR), which are distinct from those targeted by the neonicotinoid insecticides. Selection of Drosophila for resistance to spinosad helped pinpoint the D alpha 6 as the nAChR subunit involved in the insecticidal action of the spinosyns. Cases of both target-site- and metabolism-based spinosyn resistance in insect pests in the field have been reported, and programmes have been developed to manage spinosyn resistance. This review highlights the discovery of the spinosyns, elucidation of the spinosyn target site, spinosyn-receptor interaction, and progress in spinosyn resistance management.