From Imitation to Innovation: Safety-Driven Lead Compound Optimization Strategies and Mode of Action Studies in New Pesticide R&D

Currently, China's pesticide industry is undergoing a significant transformation from traditional "imitation" to "innovation." This transition places higher demands on the scientific evaluation systems for new pesticides, particularly concerning their safety. Specifically, if innovative new pesticides raise doubts at critical safety junctures, such as toxicological and environmental impacts, they may face a "one-vote veto" (i.e., outright rejection) during the registration phase. Therefore, safety-driven lead compound optimization strategies and mode of action studies represent two critical challenges in current new pesticide R&D.

1. Safety-Driven Lead Compound Optimization Strategies in New Pesticide R&D

In the early stages of new pesticide R&D, specifically during the discovery and optimization process from hits to leads, the proactive integration of safety considerations is crucial for mitigating downstream development risks and enhancing R&D efficiency.

a.Leveraging Safety Information from Compounds with Similar Molecular Scaffolds and Targets

For candidate compounds possessing molecular scaffolds similar to known pesticide classes or acting on the same biological targets, a thorough investigation and review of the known toxicological profiles of such compounds are imperative. For instance, 4-hydroxyphenylpyruvate dioxygenase (HPPD) is a common target for HPPD inhibitor herbicides in both target plants and non-target mammals. The typical toxicity manifestation of these herbicides involves interference with tyrosine metabolism, subsequently leading to ocular toxicity. Therefore, if a new pesticide under development shares the same molecular scaffold and target as known pesticides, their established toxic effects should be clearly understood and prioritized for monitoring during the R&D process.

b.Safety Optimization in Chemical Structure Modification

Chemical modification is a primary means of enhancing the efficacy of lead compounds and, concurrently, a critical step where safety risks can be introduced or mitigated. Specific strategies include:

1. Incorporating Known Safe Moieties or Avoiding High-Risk Structures: During molecular design and modification, chemical groups or pharmacophores with proven favorable safety profiles should be purposefully incorporated. For example, employing "intermediate derivatization methods" to introduce moieties with higher safety profiles.

   
   

2. Structural Similarity Analysis and Read-Across: Utilize cheminformatics tools to search newly modified structures and determine if they are substructures or metabolites of compounds that have undergone thorough safety evaluations. If structural similarity is high, methods like "read-across" can be initially employed, leveraging existing safety data from analogous compounds for a preliminary assessment of the lead compound's potential risks.

   
   

3. Early Assessment of Key Ecotoxicological and Environmental Fate Properties: For promising lead compounds, preliminary environmental fate studies (e.g., hydrolysis) and lower-tier ecotoxicological tests (e.g., acute toxicity tests on algae, daphnia, fish, bees) should be conducted as early as possible to assess their environmental persistence and toxicity to representative non-target organisms, thereby enabling timely exclusion of associated risks.

   
   

4. Application of Computational Toxicology: Employ computational toxicology models, such as Quantitative Structure-Activity Relationship ((Q)SAR) models, to predict key toxicity endpoints for lead compounds and their potential metabolites, including genotoxicity, carcinogenicity, and reproductive toxicity. For example, concurrently using expert rule-based and statistic-based models to identify structural alerts, followed by expert review to comprehensively determine if molecular structures within the lead compound necessitate further safety-driven modifications.

   
   

5. High-Throughput/High-Content Screening (HTS/HCS) in Vitro: Utilize HTS/HCS platforms for rapid, multi-dimensional screening of safety-related endpoints for lead compound series at the molecular and cellular levels. Screenable endpoints include genotoxicity, endocrine-disrupting activity, among others. These in vitro data provide a crucial basis for the safety assessment and further optimization of lead compounds.

Through the integrated application of these strategies, a preliminary safety profile of lead compounds can be established in the early R&D stages at a lower cost and in a shorter timeframe, thereby guiding subsequent molecular optimization and increasing the success rate of compounds entering formal development.

2. Safety-Driven Mode of Action (MoA) Studies in New Pesticide R&D

When candidate new pesticides, having undergone initial screening and optimization, enter a more systematic safety evaluation phase, in-depth Mode of Action (MoA) studies become crucial if adverse effects, such as potential carcinogenicity, are observed in formal registration toxicology studies. The core objective of safety-driven MoA research is to elucidate the biological processes, molecular initiating events, and key events underlying these adverse effects, and ultimately to assess their relevance to human health, thereby providing a scientific basis for risk assessment and management decisions.

1. Elucidating Toxicity Mechanisms and Identifying Key Issues: Standard toxicological studies provide phenotypic data on the potential hazards of a compound. When positive results emerge, such as potential carcinogenicity, a comprehensive data analysis is first required to identify the key toxicity endpoints that have the greatest impact on risk assessment.

   
   

2. Human Relevance Assessment: This is one of the core objectives of MoA research. Many toxic effects observed in experimental animals (especially rodents) cannot necessarily be directly extrapolated to humans due to interspecies differences in physiology, metabolic pathways, and molecular regulatory mechanisms. The internationally adopted Human Relevance Framework (HRF) provides a structured methodology for systematically evaluating the predictive value of animal study results for humans.

   
   

3. Weight of Evidence (WoE) Comprehensive Assessment: The elucidation of an MoA often relies on multifaceted, multi-level evidence. The WoE approach requires the integration of all evidence sources—including in vivo and in vitro experimental data, toxicokinetic data, comparative biology data, published literature, and computational model information—for a comprehensive and transparent assessment, ultimately leading to a scientific judgment on the establishment of the MoA and its human relevance.

3. Conclusion and Outlook

The transition from imitation to innovation is an inevitable direction for the transformation and upgrading of China's pesticide industry. In this process, a safety-centric R&D philosophy must be consistently upheld throughout. During pesticide registration, beyond fulfilling data completeness requirements, it is crucial to provide thorough answers to scientific questions. Safety-driven lead compound optimization strategies can effectively identify and mitigate potential risks in the early R&D stages, thereby enhancing R&D efficiency and success rates. When candidate compounds enter later evaluation stages, safety-driven MoA research can scientifically elucidate toxicity mechanisms and accurately assess human relevance, providing critical support for the final safety evaluation and scientific regulation of the product.

In the future, the innovation of new pesticides should place greater emphasis on integrating established platforms and methodologies from the biopharmaceutical industry to refine the feasibility assessment and mechanistic study systems for pesticides. By continuously deepening our understanding of the interaction principles between compounds and biological systems, we can ultimately develop more new pesticide varieties that are highly effective, low in toxicity, and environmentally friendly, thereby safeguarding national food security and promoting sustainable agricultural development.

Article by: REACH24H Consulting Group

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4. References

[1] 张素才, 谷玲玲, 姚大林, 等. 新药非临床安全性评价中啮齿动物致癌试验结果分析要点[J]. 中国新药杂志, 2018, 27(23): 2755-2764.

[2] Botham J, Lewis R W, Travis K Z, et al. Species differences and human relevance of the toxicity of 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors and a new approach method in vitro for investigation[J]. Archives of Toxicology, 2023, 97(4): 991-999.

[3] Dobreniecki S, Mendez E, Lowit A, et al. Integration of toxicodynamic and toxicokinetic new approach methods into a weight-of-evidence analysis for pesticide developmental neurotoxicity assessment: A case-study with dl-and L-glufosinate[J]. Regulatory Toxicology and Pharmacology, 2022, 131: 105167.

[4] Lake B G. Human relevance of rodent liver tumour formation by constitutive androstane receptor (CAR) activators[J]. Toxicology research, 2018, 7(4): 697-717.

[5] Li X, Yang X, Zheng X, et al. Review on structures of pesticide targets[J]. International Journal of Molecular Sciences, 2020, 21(19): 7144.

[6] Peffer R C, Cowie D E, Currie R A, et al. Sedaxane—use of nuclear receptor transactivation assays, toxicogenomics, and toxicokinetics as part of a mode of action framework for rodent liver tumors[J]. Toxicological Sciences, 2018, 162(2): 582-598.

[7] Wolterink G, Zarn J. FLUXAPYROXAD (addendum). EVALUATIONS, 2019: 107

[8] Yozzo K, Perron M. HPPD inhibiting herbicides: state of the science. EPA Memorandum DP Barcode D439367. 2020

This article was published in AgroPages magazine 2025 CROs & CRAOs Manual.