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.

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.

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.

Discovery of novel insecticidal 3-aminopyridyl ureas.

BACKGROUND: Commercial compound databases represent rich sources of potential starting points for pharmaceutical and agrochemical product development. Routine insecticidal screening of compounds ordered from these sources led to the identification of a 3-aminopyridyl urea with activity against Myzus persicae (Sulzer) (green peach aphid). Based on this activity and its structural novelty, further exploration of the chemical space around this hit was initiated. RESULTS: A series of ureas based on the structure of the initial hit were synthesized and screened for insecticidal activity. A broad range of tail groups derived from cyclic secondary amines were explored, and many of these compounds were found to be insecticidally active. However, only compounds featuring a 3-aminopyridine or 4-aminopyridazine head group exhibited significant insecticidal potency. Although activity against M. persicae was consistently observed, these ureas were largely inactive against another key sap-feeding insect pest, Bemisia tabaci (Glennadius) (sweetpotato whitefly). CONCLUSIONS: Follow-up of an insecticide hit identified from commercial compound acquisition led to the discovery of a novel class of ureas with activity against M. persicae. Despite considerable effort to identify related compounds with additional insecticidal spectrum, however, activity on other important pests remains limited. © 2019 Society of Chemical Industry.

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.

Crop Protection Discovery: Is Being the First Best?

Current crop protection chemicals span an array of chemistry classes and modes of action. Typically, within each chemistry class, there are multiple chemically distinct active ingredients competing with each other for market position. In this competition, the first product to market in a new class or mode of action may or may not have an advantage depending upon a number of parameters, including relative efficacy against the target pests, pest resistance, regulatory pressures, synthetic complexity, and marketing effectiveness. The number of companies involved in the discovery of new crop protection compounds has been declining, and patenting strategies have become more sophisticated, making it more challenging to break into an existing area of chemistry. One result is new classes of chemistry tend to be smaller, making first to market more beneficial than in the past. Additionally, the first into a market with a new class of chemistry has the opportunity to set positioning and expectations.

Fifty years of herbicide research: comparing the discovery of trifluralin and halauxifen-methyl.

Fifty years separate the commercialization of the herbicides trifluralin and halauxifen-methyl. Despite the vast degree of technological change that occurred over that time frame, some aspects of their discovery stories are remarkably similar. For example, both herbicides were prepared very early in the iterative discovery process and both were developed from known lead compound structures by hypothesis-driven research efforts without the use of in vitro assays or computer-aided molecular design. However, there are aspects of the halauxifen-methyl and trifluralin discovery stories that are substantially different. For example, the chemical technology required for the cost-effective production of halauxifen-methyl simply did not exist just two decades prior to its commercial launch. By contrast, the chemical technology required for the cost-effective production of trifluralin was reported in the chemical literature more than two decades prior to its commercial launch. In addition, changes in regulatory environment since the early 1960s ensured that their respective discovery to commercial launch stories would also differ in substantial ways. Ultimately, the time and cost required to develop and register halauxifen-methyl demanded a global initial business case while the lower registration hurdles that trifluralin cleared enabled a narrow initial business case mainly focused on the USA. © 2017 Society of Chemical Industry.

Natural products, their derivatives, mimics and synthetic equivalents: role in agrochemical discovery.

Natural products (NPs) have a long history as a source of, and inspiration for, novel agrochemicals. Many of the existing herbicides, fungicides, and insecticides have their origins in a wide range of NPs from a variety of sources. Owing to the changing needs of agriculture, shifts in pest spectrum, development of resistance, and evolving regulatory requirements, the need for new agrochemical tools remains as critical as ever. As such, NPs continue to be an important source of models and templates for the development of new agrochemicals, demonstrated by the fact that NP models exist for many of the pest control agents that were discovered by other means. Interestingly, there appear to be distinct differences in the success of different NP sources for different pesticide uses. Although a few microbial NPs have been important starting points in recent discoveries of some insecticidal agrochemicals, historically plant sources have contributed the most to the discovery of new insecticides. In contrast, fungi have been the most important NP sources for new fungicides. Like insecticides, plant-sourced NPs have made the largest contribution to herbicide discovery. Available data on 2014 global sales and numbers of compounds in each class of pesticides indicate that the overall impact of NPs to the discovery of herbicides has been relatively modest compared to the impact observed for fungicides and insecticides. However, as new sourcing and approaches to NP discovery evolve, the impact of NPs in all agrochemical arenas will continue to expand. © 2016 Society of Chemical Industry.

Insecticidal activity of novel thioureas and isothioureas.

BACKGROUND: We hypothesized that the exploration of chemical space around compounds with reported insecticidal activity could be a viable strategy for discovering novel, insecticidally active areas of chemistry. RESULTS: A series of thioureas and isothioureas were prepared as part of a scaffold-hopping effort around known insecticidal compounds. Many of these compounds showed excellent activity against key sap-feeding insect pests in insecticidal bioassays. While analogs bearing monocyclic thiophene head groups showed activity against Myzus persicae (green peach aphid), analogs with diarylethane head groups were active against both M. persicae and Bemisia tabaci (sweetpotato whitefly). Despite compelling activity in these laboratory tests, these compounds showed diminished activity when applied to host plants via tracksprayer. CONCLUSIONS: The initial hypothesis that structural modification of molecules reported to have insecticidal activity would yield novel compounds that also exhibit insecticidal activity was validated. Despite excellent activity in laboratory bioassays, these new compounds failed to show compelling activity in more demanding tracksprayer tests. © 2016 Society of Chemical Industry.

Perspectives on the agrochemical industry and agrochemical discovery.

Agrochemicals have been critical to the production of food and fiber, as well as the control of vectors of disease. The need for the discovery and development of new agrochemicals continues unabated 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 spectra, and changing agricultural needs and practices. As presented in the associated analysis of the agrochemical industry, the rising costs and complexities of agrochemical discovery have, in part, led to increasing consolidation, especially in the USA and Europe. However, as demonstrated by the present analysis, the discovery of new agrochemicals continues in spite of the challenges. © 2016 Society of Chemical Industry.

Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method.

Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate "what is the IDM" and "why to use" and "how to use" it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years.