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 their bioactivity while addressing challenges associated with the limited availability and inherent instability—such as 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 reactions and modifications for the development of 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 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, practical application, 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 results demonstrate 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 research on 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 target receptor is known, designing novel compounds becomes considerably easier. However, given the vast diversity of pests, diseases, and weeds, coupled with their rapid evolutionary 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 into new‑pesticide discovery still operates in an “trial-and-error” phase—akin to searching for a key that fits a lock without knowing its exact architecture. The only recourse is extensive experimentation and systematic analysis. But how can we make this process more efficient? In other words, how can we increase the success rate of developing new pesticides that meet market demands? And how can we simplify what is inherently complex?

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, the prices of the raw materials (intermediates) required for synthesis, and the chosen process or reaction conditions. 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 involving one or several starting 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, development was conceived with the following priorities: first, to select inexpensive, readily available, safe, and environmentally friendly raw materials (and intermediates), balancing cost and safety; to design novel pesticide molecules or compounds that fall outside the scope of existing patents, ensuring chemical novelty; and to synthesize these new compounds using conventional, easily scalable chemical reactions, thereby keeping manufacturing costs low. Second, the newly synthesized compounds were evaluated according to standard pesticide‑development protocols, including bioactivity screening and safety assessments, leading to the identification of promising lead candidates. Subsequently, through multiple rounds of DSTA—“Design–Synthesize–Test–Analyze”—optimization studies, compounds with favorable safety profiles and high biological activity were selected, guaranteeing both cutting‑edge innovation and practical utility. Compounds screened using this approach possess the requisite “three characteristics” for patentability, along with a strong cost‑effectiveness advantage. By leveraging this innovative methodology, it is possible not only to conduct “me‑too” research but also to explore entirely new structural scaffolds, significantly enhancing the success rate of novel pesticide discovery.

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