Insecticide discovery-"Chance favors the prepared mind".

New options for pest insect control, including new insecticides, are needed to ensure a plentiful food supply for an expanding global population. Any new insecticides must meet the increasingly stringent regulatory requirements for mammalian and environmental safety, and also address the need for new chemistries and modes of action to deal with resistance to available insecticides. As underscored by a paraphrase of a quote from Louis Pasteur "Chance favors the prepared mind", the agrochemical industry uses a variety of approaches that attempt to improve on "chance" for the discovery of new insecticides. Although there are a number of approaches to the discovery of new insecticidal active ingredients (AIs), historically most insecticides are based on a pre-existing molecule or product either from a competitor or from an internal company source. As such the first examples of a new insecticide representing a new type or class of AI (First-in-Class: FIC) are important as prototypes for other AIs stimulating further spectrum, efficacy, physicochemical, and environmental safety refinements. FIC insecticides also represent a measure of innovation. Understanding the origins of these FIC compounds and the approaches used in their discovery can provide insights into successful strategies for future new classes of insecticides. This perspective will focus on an analysis of the approaches that have been used for discovery of FIC insecticides highlighting those approaches that have been the most successful and providing a reference point for current and future directions.

Molecular targets of insecticides and herbicides - Are there useful overlaps?

New insecticide modes of action are needed for insecticide resistance management strategies. The number of molecular targets of commercial herbicides and insecticides are fewer than 35 for both. Few commercial insecticide targets are found in plants, but ten targets of commercial herbicides are found in insects. For several of these commonly held targets, some compounds kill both plants and insects. For example, herbicidal inhibitors of p-hydroxyphenylpyruvate dioxygenase are effective insecticides on blood-fed insects. The glutamine synthetase-inhibiting herbicide glufosinate is insecticidal by the same mechanism of action, inhibition of glutamine synthetase. These and other examples of shared activities of commercial herbicides with insecticides through the same target site are discussed. Compounds with novel herbicide targets shared by insects that are not commercialized as pesticides (such as statins) are also discussed. Compounds that are both herbicidal and insecticidal can be used for insect pests not associated with crops or with crops made resistant to the compounds.

Impact of the nicotinic acetylcholine receptor mutation R81T on the response of European Myzus persicae populations to imidacloprid and sulfoxaflor in laboratory and in the field.

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.

Sulfoxaflor - A sulfoximine insecticide: Review and analysis of mode of action, resistance and cross-resistance.

The sulfoximines, as exemplified by sulfoxaflor (Isoclast™active), 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.

Sulfoxaflor efficacy in the laboratory against imidacloprid-resistant and susceptible populations of the green peach aphid, Myzus persicae: Impact of the R81T mutation in the nicotinic acetylcholine receptor.

A key to effective insect pest management and insecticide resistance management is to provide growers with a range of new tools as potential alternatives to existing compounds or approaches. Sulfoxaflor (Isoclast™ active) is a new sulfoximine insecticide which is active on a broad range of sap-feeding insects, including species that have reduced susceptibility to currently used insecticides, such as imidacloprid from the neonicotinoid class. Sulfoxaflor (SFX) and imidacloprid (IMI) were tested in laboratory bioassays to compare the susceptibility of field populations of green peach aphid, Myzus persicae (Sulzer), exhibiting varying degrees of resistance involving an alteration (R81T) to the insect nicotinic acetylcholine receptor. The LC50 values for M. persicae exposed to SFX ranged from 0.09 to 1.31 (mg litre-1), whereas when the same populations were exposed to IMI the LC50 values ranged from 0.6 to 76.2 (mg litre-1). M. persicae were significantly more sensitive to SFX as compared to IMI for nine of the 13 populations tested. For M. persicae populations confirmed to be homozygous susceptible (ss) or heterozygous rs) for the R81T point mutation, there was no significant differences in the observed LC50 values for either SFX or IMI relative to the susceptible reference population (15LP1). However, in all M persicae populations that were homozygous (rr) for the R81T point mutation, susceptibility was significantly less to IMI as compared to the reference population with resistance ratios ranging from 22.1 to 63.5-fold. In contrast, only one homozygous resistant population (15MP9) exhibited a statistically significant change in susceptibility (RR = 10-fold) to SFX as compared to the reference population, which was far less than the 56-fold observed for imidacloprid in that same population. Thus, this study indicates there is no specific correlation between the laboratory efficacy of SFX and IMI in field collected populations in Spain displaying varying degrees of resistance to IMI. Furthermore, the presence of target site resistance in M. persicae to IMI, in the form of the R81T mutation, does not a priori translate to a reduction in sensitivity to sulfoxaflor. Consequently, SFX can be an effective tool for use in insect pest management programs for green peach aphid. These data also serve as a baseline reference for green peach aphid sensitivity to SFX prior to commercial uses in Spain.

Insecticides, biologics and nematicides: Updates to IRAC's mode of action classification - a tool for 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.

The new age of insecticide discovery-the crop protection industry and the impact of natural products.

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.

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.

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.

Natural product derived insecticides: discovery and development of spinetoram.

This review highlights the importance of natural product research and industrial microbiology for product development in the agricultural industry, based on examples from Dow AgroSciences. It provides an overview of the discovery and development of spinetoram, a semisynthetic insecticide derived by a combination of a genetic block in a specific O-methylation of the rhamnose moiety of spinosad coupled with neural network-based QSAR and synthetic chemistry. It also emphasizes the key role that new technologies and multidisciplinary approaches play in the development of current spinetoram production strains.

IRAC: Mode of action classification and insecticide resistance management.

Insecticide resistance is a long standing and expanding problem for pest arthropod control. Effective insecticide resistance management (IRM) is essential if the utility of current and future insecticides is to be preserved. Established in 1984, the Insecticide Resistance Action Committee (IRAC) is an international association of crop protection companies. IRAC serves as the Specialist Technical Group within CropLife International focused on ensuring the long term efficacy of insect, mite and tick control products through effective resistance management for sustainable agriculture and improved public health. A key function of IRAC is the continued development of the Mode of Action (MoA) classification scheme, which provides up-to-date information on the modes of action of new and established insecticides and acaricides and which serves as the basis for developing appropriate IRM strategies for crop protection and vector control. The IRAC MoA classification scheme covers more than 25 different modes of action and at least 55 different chemical classes. Diversity is the spice of resistance management by chemical means and thus it provides an approach to IRM providing a straightforward means to identify potential rotation/alternation options.

Insecticide mixtures-uses, benefits and considerations.

Insecticides remain an important tool for the control of many insect pests. There has long been an interest in insecticide mixtures (in-can and tank-mix) as a means to provide the needed efficacy and/or spectrum to control many insect public health, crop pests or crop pest complexes. This aspect has become more important since insecticides developed in the last 30 years tend to be narrower in spectrum with many primarily focused on either sap-feeding or chewing insect pests. Insecticide mixtures are also seen as an important approach to insect resistance management (IRM) with certain requirements for optimal implementation. Additionally, insecticide mixtures can also address certain agronomic, commercial and intellectual property needs and opportunities. This perspective will review some of the drivers and considerations for insecticide mixtures and their potential uses. © 2024 Society of Chemical Industry.

Insecticide discovery: an evaluation and analysis.

There is an on-going need for the discovery and development of new insecticides due to the loss of existing products through the development of resistance, the desire for products with more favorable environmental and toxicological profiles, shifting pest spectrums, and changing agricultural practices. Since 1960, the number of research-based companies in the US and Europe involved in the discovery of new insecticidal chemistries has been declining. In part this is a reflection of the increasing costs of the discovery and development of new pesticides. Likewise, the number of compounds that need to be screened for every product developed has, until recently, been climbing. In the past two decades the agrochemical industry has been able to develop a range of new products that have more favorable mammalian vs. insect selectivity. This review provides an analysis of the time required for the discovery, or more correctly the building process, for a wide range of insecticides developed during the last 60 years. An examination of the data around the time requirements for the discovery of products based on external patents, prior internal products, or entirely new chemistry provides some unexpected observations. In light of the increasing costs of discovery and development, coupled with fewer companies willing or able to make the investment, insecticide resistance management takes on greater importance as a means to preserve existing and new insecticides.

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.

Natural Product-Based Crop Protection Compounds─Origins and Future Prospects.

The continuing need to protect food and fiber production to address the demands of an expanding global population requires new pest management tools for crop protection. Natural products (NPs) have been and continue to be a key source of inspiration for new active ingredients (AIs) for crop protection, accounting for 17% of all crop protection AIs. However, potentially 50% of all crop protection compounds have or could have a NP origin if NP synthetic equivalents (NPSEs, synthetic compounds discovered by other approaches but for which a NP model also happens to exist) are also considered. The real and hypothetical NPs have their greatest impact as insight for new classes of crop protection compounds. Among the different product areas, NPs have their largest influence on the discovery of new insecticides, while herbicides have been the least affected by mining NPs for new AIs. While plants have historically been the largest (60% of the total) source of NPs of AIs for crop protection, in the last 30 years, bacterial NPs have become the largest source (42% of the total) of new classes (first in class) of NP-inspired crop protection AIs. Interest in NPs for crop protection continues, an aspect that is highlighted by the notable rise in the numbers of publications and patents on this topic, especially in the last 20 years. The present analysis further illustrates the continuing interest and value in NPs as sources of and inspiration for new classes of crop protection compounds.

Molecular Targets of Herbicides and Fungicides─Are There Useful Overlaps for Fungicide Discovery?

New fungicide modes of action are needed for fungicide resistance management strategies. Several commercial herbicide targets found in fungi that are not utilized by commercial fungicides are discussed as possible fungicide molecular targets. These are acetyl CoA carboxylase, acetolactate synthase, 5-enolpyruvylshikimate-3-phosphate synthase, glutamine synthase, phytoene desaturase, protoporphyrinogen oxidase, long-chain fatty acid synthase, dihydropteroate synthase, hydroxyphenyl pyruvate dioxygenase, and Ser/Thr protein phosphatase. Some of the inhibitors of these herbicide targets appear to be either good fungicides or good leads for new fungicides. For example, some acetolactate synthase and dihydropteroate inhibitors are excellent fungicides. There is evidence that some herbicides have indirect benefits to certain crops due to their effects on fungal crop pathogens. Using a pesticide with both herbicide and fungicide activities based on the same molecular target could reduce the total amount of pesticide used. The limitations of such a product are discussed.

Innovation in insecticide discovery: Approaches to the discovery of new classes of insecticides.

The continuing demand for agrochemical insecticides that can meet increasing grower, environmental, consumer and regulatory requirements creates the need for the development of new solutions for managing crop pest insects. The development of resistance to the currently available insecticidal products adds another critical driver for new insecticidal active ingredients (AIs). One avenue to meeting these challenges is the creation of new classes of insecticidal molecules to act as starting points and prototypes stimulating further spectrum, efficacy and environmental impact refinements. A new class of insecticides is foreshadowed by the first molecule exemplifying that class (first-in-class, FIC) and offers one measure of innovation within the agrochemical industry. Most insecticides owe their discovery to competitor-inspired (i.e. competitor patents/products) or next-generation (follow-on to a company's pre-existing product) strategies. In contrast, FIC insecticides primarily emerge from a bioactive hypothesis approach, with the largest segment resulting from the exploration of new areas of chemistry/heterocycles and underexploited motifs. Natural products also play an important role in the discovery of FIC insecticides. Understanding the origins of these FIC compounds and the approaches used in their discovery can provide insights into successful strategies for future FIC insecticides. This review analyses information on historic and recently introduced FIC insecticides. Its main objective has been to identify the most successful discovery strategies for identifying new agrochemical solutions to meet the challenge of minimizing crop losses resulting from insects. © 2022 Society of Chemical Industry.

Impact of natural products on discovery of, and innovation in, crop protection compounds.

Natural products (NPs) have long been an important source of, and inspiration for, developing novel compounds to control weeds, pathogens and insect pests. In this review, we use a dataset of 800 historic, current and emerging crop protection compounds to explore the influence of NPs on the introduction of new crop protection compounds (fungicides, herbicides, insecticides) as a function of time. NPs, their semisynthetic derivatives (NPDs) and compounds inspired by NPs (NP mimics, NPMs) account for 17% of all crop protection compounds. NPs, NPDs, and NPMs have been a fairly constant source of new agrochemicals over the past 70 years. NP synthetic equivalents (NPSEs) is a fourth group of NP-related crop protection compounds composed of synthetic compounds which by chance also happen to have an NP model (but are not involved in the discovery). If NPSE compounds are also included, then 50% of all crop protection compounds hypothetically could have had a NP origin. Similar trends also hold true for the impact of NPs on the discovery of new modes of action (MoA) or innovation in crop protection compounds as measured by the number of first-in-class compounds. NPs have had the largest impact on the numbers and global sales (2018 USD) of insecticides compared to fungicides and herbicides. The present analysis highlights NPs as a long-standing and continuing source of new chemistry, new MoAs and innovation in crop protection compound discovery. © 2021 Society of Chemical Industry.

East meets west: regional impact on agrochemical discovery and innovation.

The efficient production of the food needed to nourish an expanding global population continues to fuel the demand for new crop protection compounds. This task is made all the more difficult by the need to meet increasingly demanding grower, consumer and regulatory constraints. The discovery and development of new synthetic organic crop protection compounds has been largely the responsibility of the agrochemical industry in Europe, Japan and the USA, with government-funded academic research often playing a crucial role in the early stages of the invention and testing of novel activity. The way in which this process takes place has undergone a dramatic evolution over the past 75 years. Drastic consolidation and globalization among the research and development (R&D)-based companies in these regions have characterized these changes. This evolution in the agrochemical industry has, in turn, shaped the rate of introduction and geographic origin of new crop protection compounds. In spite of these changes, the rate of invention of new classes of crop protection compounds has remained relatively constant. During the past 30 years, the forefront of new compound introductions has moved towards Asia, and Japan in particular. Although there are now more agrochemical companies in Japan involved in the discovery and development of new crop protection compounds than in Europe and the USA combined, on a compound-per-company basis, US companies currently generate the highest output. However, it is expected that there will continue to be changes in the numbers and origins of new crop protection compounds, with contributions continuing from Europe, Japan and the USA, and increasingly from China. © 2021 Society of Chemical Industry.

Structure Simplification of Natural Products as a Lead Generation Approach in Agrochemical Discovery.

Natural products (NPs) have a long history as sources of compounds for crop protection. Perhaps a more important role for NPs has been as models and inspiration for the discovery and development of synthetic crop protection compounds. NPs and their synthetic mimics account for 18% of all crop protection compounds, whereas another 38% of all crop protection compounds have a NP that could have served as a model. Because NPs are often complex molecules, have limited availability, or possess structural features that constrain their suitability for use in agricultural settings, a key element in NP-inspired compounds is the simplification of the NP structure to provide a synthetically accessible molecule that possesses the physicochemical properties needed for use in crop protection. Herein we review a series of examples of NP mimics that demonstrate the structural or synthetic simplification of NPs as a guide for the discovery of future NP-inspired agrochemicals focused on fungicides, herbicides, and insecticides.