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    Professor Liu Changling discusses the “intermediate derivatization method” and recent advances in the development of new agrochemicals.

    Release Date:

    2019-03-21

    As is well known, conducting optimization studies based on environmentally compatible natural products represents an important pathway toward greening agrochemicals. Cinnamic acid, uracil, coumarin, and other compounds are secondary metabolites widely distributed in the plant kingdom; they exhibit excellent environmental compatibility, possess notable biological activities, and are characterized by low toxicity, small molecular weights, ease of synthesis, and structural diversity that lends itself to derivatization. Consequently, using these natural products as templates or intermediates, or employing the precursors used to synthesize them as building blocks, and subjecting them to chemical reactions and modifications to develop biomimetic novel agrochemicals not only enhances bioactivity while addressing challenges such as the limited availability and instability—e.g., photodegradation—of natural products, but also…

    As is well known, conducting optimization studies based on environmentally compatible natural products represents a crucial pathway toward greening agrochemicals. Cinnamic acid, uracil, coumarin, and other secondary metabolites are widely distributed in the plant kingdom; they exhibit excellent environmental compatibility, possess notable biological activities, and are characterized by low toxicity, small molecular weights, ease of synthesis, and structural diversity that lends itself to derivatization. Consequently, using these natural products as templates or intermediates, or employing their synthetic precursors as building blocks, to carry out chemical transformations and modifications for the development of biomimetic novel agrochemicals not only enhances bioactivity while addressing challenges associated with the limited availability and inherent instability—such as photodegradation—of natural products, but also contributes to environmental protection and sustainable development.
     
    The establishment of the intermediate derivatization method
     
    In response to the major scientific and technological challenges of original innovation in green pesticide varieties, after more than two decades of exploration, experimentation, and research, a novel approach—“intermediate derivatization”—has been developed for the molecular design and variety creation of green pesticides. Grounded in both market needs and chemical principles, this method simplifies the complex process of new‑pesticide development. Extensive empirical evidence demonstrates that employing intermediate derivatization in the discovery and formulation of new pesticide candidates can significantly enhance the success rate of new‑pesticide R&D while reducing development costs.
     
    Numerous papers have been published on the “intermediate derivatization method,” and a monograph titled “New Pesticide Discovery and Synthesis” has also been released, including a review article in Chemical Reviews. Recent advances in this approach are now emerging; accordingly, this paper is presented for reference.
     
    The technical approach of the intermediate derivatization method
     
    Pesticide innovation shares similarities with pharmaceutical development: when the three-dimensional structure of a receptor is known, designing novel compounds becomes considerably easier. However, given the vast diversity of pests, diseases, and weeds, coupled with their rapid mutation rates, elucidating receptor structures remains a formidable challenge. Even if such structures are resolved, differences in application methods often mean that compounds predicted by computational models to be effective at the cellular or molecular level fail to deliver in vivo assays. Consequently, as noted earlier, contemporary research on new‑pesticide discovery still operates in an “trial-and-error” phase—akin to searching for a key that fits an unknown lock—requiring extensive experimentation and systematic analysis. The pressing question, then, is how to enhance efficiency: how can we increase the success rate of developing new pesticides that meet market demands? And how can we simplify this complex problem?
     
    First, from a market perspective, to achieve high market share for a new pesticide, it must possess both exclusive patent protection and a favorable cost‑performance profile—characterized by high safety, strong efficacy, and low production costs. The three essential requirements for patentability—novelty (originality), inventive step (advancedness), and industrial applicability—are determined by the chemical structure. Cost‑effectiveness, in turn, depends on both performance and manufacturing costs: performance attributes such as activity and safety are likewise dictated by the chemical structure, while production costs are influenced by the structure itself, as well as by the prices of raw materials (intermediates) and the efficiency of the synthesis process or reaction pathway. In short, a pesticide’s patent status, its performance, and its cost are all closely linked to its chemical structure.
     
    Secondly, from a chemical perspective, most pesticides are small molecules with molecular weights typically ranging from 150 to 500. Based on retrosynthetic analysis, the chemical structures of pesticide compounds are derived through chemical reactions starting from one or several raw materials (intermediates); therefore, selecting appropriate raw materials or intermediates is crucial.
     
    In summary, through more than two decades of research and practice, the “intermediate derivatization method” has been developed.
     
    Key Technologies of the Intermediate Derivatization Method
     
    The intermediate‑derived synthesis approach for developing new agrochemicals differs from conventional methods in that it integrates development considerations at the very outset of green pesticide molecular design, thereby ensuring robust patent protection and delivering significant advantages in performance and cost.
     
    From the outset of the research, we adopted a development strategy that prioritizes inexpensive, readily available, and environmentally safe raw materials (including intermediates), while also considering both cost and safety. We designed novel pesticide molecules or compounds that fall outside the scope of existing patents, ensuring their chemical structures are sufficiently innovative, and employed conventional, easily scalable chemical reactions to synthesize these new compounds, thereby keeping manufacturing costs low. Subsequently, the newly synthesized compounds were evaluated according to standard pesticide‑development protocols—covering bioactivity screening, safety assessments, and more—to identify promising lead candidates. Following multiple rounds of DSTA optimization—“Design–Synthesize–Test–Analyze”—we selected compounds with excellent safety profiles and high biological activity, thus guaranteeing both cutting‑edge innovation and practical utility. Compounds screened using this approach possess the requisite “three characteristics” for patentability, along with a favorable cost‑performance ratio. By leveraging this innovative methodology, we can not only conduct “me‑too” studies but also pursue entirely new structural scaffolds, significantly enhancing the success rate of novel pesticide discovery.
     
     

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