Agrochemical Discovery - Building the Next ... - ACS Publications

Chapter 1

Agrochemical Discovery - Building the Next Generation of Insect Control Agents Downloaded by 80.82.77.83 on October 26, 2017 | http://pubs.acs.org Publication Date (Web): October 24, 2017 | doi: 10.1021/bk-2017-1264.ch001

Thomas C. Sparks* and Beth A. Lorsbach Dow AgroSciences, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States *E-mail: [email protected]. E-mail: [email protected].

An expanding and often upwardly mobile global population requires large improvements in the quantity and quality of food production as well as freedom from the ravages of disease carrying insect vectors. This necessitates that new options and approaches for insect control be developed. Increasing pest resistance to existing insecticides, a changing regulatory landscape, and shifts in pest spectrum due to changes in climate and agronomic practices, including transgenic plants, all present challenges to developing new insect control agents. The agrochemical industry has been developing synthetic organic insecticide solutions to insect pest problems for more than 70 years. Early efforts produced just a few insecticide classes/modes of action (MoA), each with a large number of different active ingredients. More recent industry efforts have been focused on an increasingly diverse array of insecticide classes, most often coupled to new or underexploited MoAs, but with each class having only a few members. A wide range of approaches have been and continue to be employed in the discovery of these more recent commercial offerings as well as the insecticides currently under development. In spite of the decline in the number of agrochemical companies in the US, EU and Asia that are now involved in insecticide discovery, innovative solutions continue to be found. Powered by the availability of new research tools and an increase in the size of many of the remaining agrochemical companies, robust discovery platforms are being built which will provide additional novel insect control products in the future.

© 2017 American Chemical Society Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Downloaded by 80.82.77.83 on October 26, 2017 | http://pubs.acs.org Publication Date (Web): October 24, 2017 | doi: 10.1021/bk-2017-1264.ch001

Introduction The need to feed an expanding global population remains a fundamental factor in seeking improvements in crop production. Like the long standing global threat from malaria, the Zika virus outbreak in the Western Hemisphere is just the latest example of how the population can be placed in peril by insect disease vectors. Part of the equation to feeding the world and minimizing disease transmission lies in effective insect control. Although the fundamental tools and approaches to manage insect pests have been in place for some time, new options (e.g. transgenic plants, sprayable RNAi) continue to be implemented providing the growers and vector control operators with an expanding range of options (Figure 1). Although insecticides are just one option in the insect pest control toolbox (Figure 1), they remain a critical component in most integrated pest management (IPM) programs today. In a number of crops such as corn, cotton and soybeans, conventional insecticides have been replaced by transgenic plants expressing a range of toxins to control above and below ground insect pests (1). However, resistance to these insect toxins is appearing (1–3). This highlights the continuing importance and need for conventional insecticides as adjuncts to transgenic crops in many crop systems. Moreover, integrated solutions, that is traits coupled with a crop protection foliar products, can potentially provide new pest control options for growers. Alternatively, biopesticides (4, 5) present additional options for pest insect control. Although their use is on the rise, at present biopesticides represent a small component (ca 5%) of the total pesticide market (5) with conventional synthetic organic pesticides still the predominant tools in many crop production systems due to their cost, efficacy and reliability.

Figure 1. Options for insect control and delivery systems – current and potential. Options in red are innovations implemented in the past two decades or possible in the future. (see color insert) Key drivers for the development of new synthetic organic insecticides include expanding insect resistance to insecticides (2, 3) and increasingly stringent environmental, toxicological as well as regulatory requirements which limit the 2 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


use and/or availability of many older chemistries (6). The regulatory challenges restricting the use of older chemical insecticides also influence discovery strategies to identify new chemical pest control solutions. Those companies that can successfully navigate the evolving regulatory landscape will be rewarded by the market as new products are launched without significant delays. Likewise, changes in spectrum of insect pests in a crop as a result of changing agronomic practices, including the introduction of transgenic crops, also drive the need for new insect control options. As a prelude to understanding where agrochemical research and insecticide discovery is going it is useful to understand where the industry has come from. Thus, this review aims to provide a background on the evolution of insecticide discovery and some thoughts on directions moving forward. As will be noted later in this review, the insect nervous system has been the primary target for the majority of the insecticide classes developed in the past 70 years. In particular a range of ion channels and G-protein coupled receptors have been the targets of the neuroactive insecticides. In part, the emphasis on these types of molecular targets is due to their sensitivity to disruption by xenobiotics such as insecticides and the resulting rapid physiological cascade leading to the effective control of a wide range of pest insects.

Early Insecticide Research: Exploiting Few Modes of Action Since the introduction of the first synthetic organic insecticides more than 70 years ago, there has been a continuing evolution in the numbers, classes and modes of action of insecticidal chemistries explored and developed (Figures 2,3,4). For example, in the 1950s and into the early 1960s the primary focus was on four classes of chemistry that exploited only three different modes of action.

Figure 2. Changes in the numbers of new active ingredients introduced for the major classes of insecticides as a function of time. Chart based on data derived, in part, from the Allan Wood database (7) & Cropnosis (8). (see color insert) 3 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 3. Timing of the introduction and size (number of ais) of the different classes of insecticides during the past 70 years. Data derived, in part, from the Allan Wood database (7) & Agranova (9).

Commercial insecticide offerings included the organochlorine sodium channel modulators (DDT analogs), inhibitors of acetylcholinesterase (AChE) (organophosphates (OPs) & carbamates) and blockers of the gamma-aminobutyric acid (GABA) gated chloride channel (cyclodienes, BHC) (2, 7, 8). Within each class a large number of active ingredients were developed. For example, more than 150 different OP and 40 different N-methyl carbamate insecticides (Figure 3) were introduced; see also reference (2). While the first synthetic pyrethroid (allethrin) was developed in the late 1940s, the inherent photo-instability limited its use and impact. It was not until late 1970’s that the first photostable synthetic pyrethroids (e.g. permethrin, fenvalerate) were introduced for crop use. Continued commercial interest in this area of chemistry ultimately has given rise to more than 75 different active ingredients (ais) (Figure 3). Interestingly, nearly four decades after their initial introduction, new pyrethroids are still being launched today, albeit primarily for public health and vector control uses (7, 9). The late 1970s also saw the introduction of the acylureas (Figure 2) eventually totaling 14 different ais to date (Figures 2,3) (2). Shortly thereafter, the avermectins were introduced (Figure 3), which served to reaffirm the value of natural products (NPs) in the agrochemical and especially the public health arenas. Since the high water mark of the 1980s there has been an overall decline in the introduction of new insecticidal ais (10, 11). This decline is due in part to advances in intellectual property protection coupled with consolidation in the agrochemical industry and increasingly more stringent regulatory requirements (6) which have all contributed to more classes of chemistries, but with fewer members. 4 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 4. Timing of the introduction and size (number of ais) of the different insecticidal modes of action for synthetic organic insecticides during the past 70 years. Data derived, in part, from the Allan Wood database (7), Cropnosis (8) & Agranova (9).

Although not directly derived from the NP nicotine, the development of the neonicotinoids in the early 1990’s gave rise to what may be the most impactful class of insecticides in the past 25 years. Although comparatively few in number (presently seven different ais) compared to prior classes of insecticides, such as the OPs, carbamates, pyrethroids, and acylureas (Figure 3), the neonicotinoids captured one-quarter of the total global insecticide market in 2015 (Figures 5,6; end user sales = 24%) (9), down slightly from a high of nearly 30% in 2012 (Figure 5). The 1990s through the 2000s also gave rise to an expanding array of new classes of insecticides including the fiproles, spinosyns, METI (inhibitors of mitochondrial electron transport at complex I) acaricides, ecdysone agonists, oxadiazines, cyclic ketoenols, diamides, etc. (Figure 3), representing a range of new modes of action (MoA) (Figure 4) (2).

Current Insecticide Research: Identification of New Modes of Action In contrast to prior decades where few modes of action were utilized by the majority of insecticides in use, today more than 25 different MoAs (Figure 4) are exploited by mainstream insecticides and acaricides (2, 3), although clearly not all MoAs are available for every combination of crop-pest-location. Likewise, there are more than 30 different chemical classes of insecticides (Figures 3,4), with other new options in development (7, 11). One benefit of these new classes of chemistry is to provide new options for insecticide rotation, an important 5 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


approach in the management of insecticide resistance (2, 3). In addition, since the late 1990’s growers have had additional options for some pest-crop combinations in the form of transgenic plants. What has been rather interesting, but not surprising, is the virtual disappearance of the some early classes of insecticidal chemistries such as the cyclodienes, and other organochlorines, and the rather precipitous decline in global sales of the OPs and carbamates over the past two decades. These declines, in many instances, reflect regulatory agencies removing classes of chemistry with undesired toxicological and environmental profiles coupled with expanding pest resistance. Declines in sales for the above mentioned insecticide classes have been countered with rapid market penetration of new products such as the neonicotinoids, and most recently the diamide class of insecticides (Figure 5). The latter is especially interesting in that the diamides now garner a larger percentage of the global sales (10%) than either of the former mainstream insecticides, the OPs (9%) or carbamates (4%) (Figure 5). Of equal importance is the rise in sales of “other” classes of insecticides outside the OPs, carbamates, pyrethroids, and most recently the neonicotinoids, that have all been major forces in the insect control, and which clearly highlight that the market values innovation. In 1988 the OPs and carbamates together accounted for more than 60% of the total global insecticide sales and pyrethroids another 20%. Thus 80% of the market was dominated by just three classes of chemistry and two modes of action. The combined “other” classes accounted for just 11% of the sales (Figure 4). In sharp contrast, “other” classes of insecticidal compounds (including the diamides) now account for 47% of insecticide sales (Figure 4), a trend that is likely to continue.

Figure 5. A. Changes in the percentages of the insecticide market (global sales) as a function of time for selected classes of insecticides. Data from Agranova (9). B. Makeup of the Others group of insecticides based on Insecticide Resistance Action Committee (IRAC) classification (2, 3) and Agranova 2015 end user sales data (9) - millions USD. (see color insert) 6 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 6. Global sales [2015 end user, Agranova (9)] for the major classes of insecticides based on IRAC classification (2, 3). 50% of the global end user sales is from classes of insecticides introduced since 1990 (red & yellow). Total value in 2015 = $18.3 billion USD. Sales since 1990 are about equally divided between sap-feeding (red) and chewing (yellow) insecticides. (see color insert) As noted in Figure 3, the number of members within the more recent insecticidal chemical classes are relatively small compared to that of the carbamates (41), pyrethroids (81), acylureas (14), and especially OPs (165). Even the DDT analogs and the cyclodienes which only had 9-15 members each have not yet been matched by the most prolific insecticidal classes of the last two decades. There are currently 8 neonicotinoids, 6 METI acaricides / insecticides (Figure 3), and perhaps in the near future as many as 6 diamides. Currently flubendiamide, chlorantraniliprole and cyantraniliprole are in the market and cyclanilprole, tetraniliprole, cyhalodiamide are in the later stages of development. As noted above, in part, the smaller size of the recent new classes of insecticides is due to a number of factors including the nature of the chemistries, current chemistries being arguably more complex and more expensive, and fewer companies (US and Europe) involved in insecticide discovery than two decades ago (6, 12). Likewise, the desire for new MoAs tends to focus discovery efforts on different types of chemistries more likely to have a novel MoA. However, some of these latter factors have been mitigated in part by the expanding discovery programs of Japanese agrochemical companies (13, 14). Today, companies also tend to submit more and larger patents around an area of chemistry (6), increasing the resources required by competitors to successfully create novel compounds outside of these patents. There are also the increasing costs of discovery, registration and development of new insecticides limiting the number of chemical classes and products that a company can afford to invest in (6, 12, 15, 16). Regardless of these considerations, new chemistries, often with new MoAs, continue to be discovered and developed. Importantly, market considerations, as well as IPM and insecticide resistance management programs place a premium on new MoAs, helping to drive the search for and development of new classes of chemistries possessing these 7 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


new MoAs. Interestingly, in some cases very different chemistires have been discovered that are later found to address the same target site, as has been the case with the METI inhibitors fenproximate, pyridaben, fenzaquin, and tebufenpyrad (17) and, more recently, the vanilloid-type transient receptor potential (TRPV) chordotonal channel modulators pymetrozine, pyrafluquinazone and afidopyropen (18, 19). Thus, when discovered or built (see below), new classes of insecticides do not always result in new MoAs as reflected in the numbers of new molecules / classes (Figure 3) compared to the fewer numbers of new MoAs in the same time period (Figure 4). While instances of unexpected MoA repetition do limit options for rotation of MoAs for resistance management (2, 3), there can still be significant differences in spectrum, efficacy and susceptibility to metabolic resistance mechanisms, potentially minimizing the impact of the same MoA and bringing a favorable value to a new molecule.

Approaches to Insecticide Discovery – Present and Future Agrochemical discovery and the approaches that have been or could be employed have been frequently discussed (12, 15, 20–28). An examination of insecticide lead chemistries that ultimately became products since 1990 illustrates that there are a wide array of starting points/approaches for agrochemical discovery (Figure 7). In this analysis, the focus was on the new classes of chemistry (Figure 3); hence older chemical starting points (OPs, carbamates, pyrethroids, etc.) were omitted. Many of the six approaches highlighted in Figure 7 are not new and have been used in agrochemical discovery since the beginning of the insecticide revolution of the 1940s-1950s.

Figure 7. Approaches to insecticide discovery. Origins of insecticides belonging to new classes of chemistry introduced since 1990 (see Figure 3). n = 57. (see color insert) 8 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


1 – Competitor inspired (CI) starting points remain one of the most important sources of inspiration for new agrochemicals (Figure 7). Recent examples include the neonicotinoids (e.g. imidacloprid, thiamethoxam, clothianidin, etc.), some diamides (chlorantrianiliprole, cyclantraniliprole), oxadiazines (indoxacarb), and semicarbazones (metaflumizone). In some cases the second or third product in a class of chemistry ultimately does better, in terms of sales as critical improvements are made to the later generation ais to enhance their efficacy, spectrum, cost, regulatory or environmental profiles relative to the original product. However, CI-based discovery typically concedes points in terms of innovation, especially where a new MoA is desired, since the MoA typically mirrors the earlier molecules used as starting point(s). On occasion, however, a new MoA can arise. For example, in exploring the diamide chemistry motif, moving from an ortho-configuration to a meta-configuration for the amides resulted in a remarkable shift in MoA. The original chemistry acting at an allosteric site on the ryanodine receptor (29) evolved to a new class of insecticides (e.g. broflanilide, Figure 8) which interacts with an allosteric site on the GABA-gated chloride channel (30). Certainly, this MoA shift is the exception and not the rule. However, the above example does demonstrate that new MoAs can arise from any discovery approach. 2 – A next or second generation product derived from an existing internal product remains a validated approach to new agrochemical products and really represents a variation of the CI approach. Instead of looking externally, the research maintains an inward focus with the potential advantage of having fewer intellectual property issues than with the CI approach. The concept has been aptly demonstrated both in the past (e.g. parathion–methyl parathion; permethrin–cypermethrin–deltamethrin) and more recently (e.g. spirodiflofen–spiromesifen–spirotetramat; chloranthraniliprole–cyanthraniliprole; spinosad–spinetoram, tebufenpyrad–tolfenpyrad, abamectin–emamectin benzoate, etc.). The key, much like the CI approach, is to identify areas for possible differentiation, with efficacy and especially spectrum, being the more prominent areas for separation. 3 – A third validated approach to identify new agrochemcials is to exploit NPs (Figure 7), either directly as products (e.g. abamectin, spinosad), as semi-synthetics (e.g. emamectin benzoate, spinetoram, lepimectin, afidopyropen), or as inspiration for synthetic mimics (31, 32). NP-inspired insecticides include the aryl N-methylcarbamates (33), synthetic pyrethroids, nereistoxin analogs, chlorfenapyr, juvenoids, and more recently the butenolides (34). The use of NPs as a source of new chemistry has the advantage of being a good source of new MoAs with more than 60% of all agrochemcials MoAs having a potential NP model (31). For insecticides the value of NPs as a source of new MoAs is close to 75% (31, 32). Certainly pharmaceutical companies have leveraged NPs for inspiration as many drug products have roots in NPs (35). Moreover, there is a continuing interest in exploiting natural products for agrochemical starting points. NPs have been, or potentially could have been models for most classes of insecticides (32), with the 2015 global sales value approaching 80% of the total. However, a distinct disadvantage with NPs is that the goal of searching for a new NP 9 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


starting point can be more resource intensive than other approaches depending on the implementation (i.e. screening for new NPs). Also, attempting to morph a NP into an agriculturally viable molecule can require more time than other approaches (12). 4 – Compounds possessing ag-like properties or bioactive scaffolds (BAS) have also served as starting points for the discovery of more recent insecticides (Figure 7) including sulfoxaflor, pyflubumide, pyridalyl, flonicamid, and etoxazole. Also included in this broad suite of approaches are fragment, ligand, shape, and pharmacophore-based tactics (28). The focus on physical properties, Lipinski rule of 5 (36) as well as Tice ag-like properties (37) have also directed many discovery efforts to begin with a BAS or ag-like building blocks that possess the desired attributes. While there are always exceptions to these rules, in particular natural products, many of the commercial insecticides past and present fall within the ranges of ag-like properties. Moreover, as environmental factors become increasingly difficult to manage, physical properties of modern insecticides will be increasingly important. Solubility and log P in particular could be factors for ground water and soil persistence. In addition to ag-like properties, the use of novel building blocks (38) or privileged structures (39, 40) have been widely utilized in pharmaceutical drug discovery. Privileged structures are molecular frameworks that have the potential for diverse binding properties, allowing them to be developed into potent compounds for a broad range of biological targets. Moreover, privileged structures can have ag-like properties at the start which accelerates optimization. Recent efforts to focus on developing chemical reactions and transformations that deliver polar motifs have been showcased by AstraZeneca (41). The need for smaller, polar starting scaffolds, perhaps with chirality will open new chemical space that has yet to be exploited in agrochemical discovery in general and certainly for insecticide research. 5 – Broad screening of internal chemistries coupled with data-mining (Figure 7) has also been an effective means to identify new leads that in turn have been developed as products. Bifenazate, spirodiclofen, tebufenozide, fipronil, and tebufenpyrad are all examples of recent insecticides with origins in other therapeutic areas (e.g. herbicides) that were identified by screening all chemistries broadly. Likewise, the initial lead chemistry for the isoxazolines (e.g. fluxametamide, Figure 8) appears to have also come from the broad screening of synthetic intermediates. 6 – Among the approaches employed for insecticide discovery (Figure 7), screening 3rd party compounds for insecticidal activity would appear to be the least favored in the last two decades. However, these 3rd party inputs have had a very large impact on the agrochemical industry, especially for insecticides. It was a 3rd party input that led to the discovery of nithiazine (42) which in turn led to the discovery of imidacloprid (43) and the beginnings of the neonicotinoid class of insecticides (44), currently the largest class of insecticides in terms of global sales (24%, Figures 5,6). Likewise, a 3rd party herbicidal diamide lead chemistry gave rise to flubendiamide and the diamide class of insecticides (45) which now accounts for 10% of the global market (Figures 5,6). The value of 3rd party compound inputs can be further enhanced through careful hypothesis testing 10 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


and the use of chemoinformatic tools to narrow and focus the inputs towards more ag-like or lead-like chemistries (27, 28). The above approaches to insecticide discovery can also be enhanced or augmented through the use of in vitro screening and/or the application of quantitative structure activity relationships (QSAR). In vitro screening has been examined as a tool for insecticide discovery for quite some time, and remains of interest (46). Genomics also presents opportunities to identify new targets of interest. However, the translation of in vitro target-site inhibition to the whole organism bioactivity, to commercial levels of field efficacy, has proved rather elusive. Some success was observed in very early insecticide discovery efforts where in vitro screening was part of discovery programs for aryl-N-methyl (propoxur (33),) and later N-methyl oxime (aldicarb (47),) carbamates. Likewise, QSAR has been widely used as a tool to understand insecticide action and efficacy after the fact, but somewhat surprisingly, only rarely has QSAR been the driving force in the insecticide discovery process. Two such examples where QSAR has played a pivotal role in insecticide discovery include the discovery of the pyrethroid bifenthrin (48) and the next generation spinosyn insecticide, spinetoram (49).

Summary and Conclusion As noted above, in the early days of synthetic organic insecticides, there were only a few modes of action that were widely exploited. Current trends and data suggest that a new MoA is and will continue to be an important attribute for a new insecticide. Since 1990 a number of new classes of insecticides have been developed (Figure 3) that possess new modes of action (Figure 4), and these new classes presently account for 50% of the global agrochemical sales (Figure 6). Pesticide discovery is now a global enterprise spread increasingly across companies in the US, EU and Asia (esp. Japan and China). As outlined above, there also continues to be an array of new insecticides and MoAs being brought to the market (Figures 3,4). However, notwithstanding these advances in insecticides and acaricides, there remains a pressing need for new insect and mite control options, since (as also noted above) some crop-pest-location complexes may have very few options. There are several new sap-feeding insecticides in development, some exploiting known MoAs (e.g. afidopyropen (19);), while the MoA of others (fluhexafon, benzpyrimoxan, Figure 8) is currently unknown. Their commercialization could be especially important to fill a market void should any reduction in the use of neonicotinoids, which presently hold a large share of the insecticide market, occur due to resistance, regulatory aspects or public perception. During the past two decades, the agrochemical industry has incorporated an array of tools including combinatorial chemistry (50, 51), high throughput screening (52), and structure-based design (15), all focused on enhancing agrochemical discovery. Random screening of compounds has generally given way to more targeted efforts to bring in compounds that fit some a priori hypothesis (15, 28) or have been pre-filtered for agrochemical lead-like properties 11 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


or computational likeness for molecules targeted for pest group (52). The ‘omics revolution presents opportunities to better understand insecticide MoA or envision new potential target sites for new insecticides. However, as with any new technology, hope and hype runs high, but thus far, none of these past or present techniques have proven a panacea for insecticide discovery. Nevertheless, these new technologies have made the discovery process more efficient and have proven useful in the exploration and exploitation of new insecticidal leads. Likewise, MoA determination now has more tools available to potentially speed the process (53). These tools can be further enhanced by collaboration with academic research groups that can bring greater focus or expertise to MoA determination to allow the more problematic MoAs to be successfully resolved. This concept has been aptly demonstrated by the recent elucidation of the MoA of pymetrozine through a collaboration between an agrochemical company and a university (18).

Figure 8. Structures of recent insecticides. Regardless of the approach taken, it is self-evident that the best place to look for biological activity is in other biologically active molecules. Hence the continued interest in NPs, and the long term overriding interest in CI as a means to discover new insecticides. Likewise, broad screening of chemistries from other therapeutic areas has frequently identified insecticidal analogs that have served as leads for future products. The fiproles, cyclic ketoenols, formamidines, and diamides all had their origins in herbicidal chemistries. Thus, it is reasonable to assume that other sources such as pharmaceuticals can also give rise to new insecticides. In many respects the physical properties of pharmaceuticals and agrochemicals are not dissimilar (54, 55), and it has also been suggested that agrochemcials may, in turn, provide starting points for new drugs (54). 12 Gross et al.; Advances in Agrochemicals: Ion Channels and G Protein-Coupled Receptors (GPCRs) as Targets for Pest ... ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


The fundamental approaches (as outlined above) to find that initial discovery have remained constant for at least the last three decades, but the terminology and tools available have evolved with time, and have contributed to delivery of new insecticidal products. Computer aided molecular design (CAMD), QSAR and chemoinformatics can aid in that task providing the tools to more easily uncover the next new insecticide lead. However, the essential catalyst in insecticide discovery process has been and will remain the scientist(s) asking new questions that can drive innovation. Importantly, new insecticides / agrochemicals are not so much “discovered” as they are “built”. What does this mean? Typically starting with a screen hit, idea, NP, inspiration from a competitor molecule, model, etc., hypothses are formed to address a liability or limitation of the starting point, most often in the early phases, efficacy. This involves several to many iterations where a succession of analogs are evaluated until the ai with the best combination of efficacy, toxicology, cost, physical properties and environmental parameters emerges. Thus, most new agrochemicals are built substituent by substituent, sometimes atom by atom. At times this optimal analog is immediately obvious, other times it is only recognized hundreds of analogs after the fact when the summation of attribute data becomes available. It is in these instances where CAMD, QSAR and chemoinformatic tools can expedite the process by providing an effective means to summarize / visualize the data enabling the optimal analog and potential future insecticide to be identified.

Acknowledgments We thank Mr. Greg Hanger (DAS), Drs. Ronda Hamm (DAS), Jim Hunter (DAS), Frank Wessels (DAS), Debra Camper (DAS), John Casida (University of California, Berkeley), and Rob Bryant (Agranova) for their very helpful discussions and comments.

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