Live Challenges
Escaping fluorine dependency in agrochemical design
Closing Date: September 30, 2024
"Our ambition is to equip the discovery scientists of tomorrow with the right tools to design high-performance agrochemicals that are less reliant on fluorinated substituents, no matter what the requirements of the future will be."
Vlad Pascanu, Principal Scientist Crop Protection Research Chemistry, Syngenta
Description
Syngenta is seeking organisations with capabilities, tools, data and/or platforms that will enable the design of new agrochemical products less dependent on fluorination for their in vivo performance. We aspire to better understand how fluorine substituents impact a molecule’s biokinetic profile and ultimately the in vivo translation. To this end, we must deconvolute the “Fluorine Effect” on individual physicochemical and biokinetic parameters.
The key objective of this challenge is to generate robust models built on high quality data to understand how per- and poly-fluoroalkyl substances (PFAS) can be substituted in Syngenta’s research pipeline. Our goal is to elucidate the fundamental basis for bioisosterism and to enable the development of models that will ultimately empower the design of innovative bioactive molecules fit for the market requirements of the future.
Background
Fluorination is extensively used in both agrochemical and drug design because of the unique ability of fluorine atoms to modulate the biokinetic profile of bioactive molecules. Synthetic methodologies for installing fluorine into complex molecules have also become increasingly precise and affordable, facilitating the wide adoption of fluorinated groups to improve in vivo performance.
However, emerging regulatory trends have led to increased scrutiny of all fluorinated compounds, regardless of their demonstrated properties. For example, a class-based ban of all non-essential PFAS has been recently proposed in the EU, which would compromise the continued use of many fluorinated bioactive molecules.
Key Success Criteria
The success of our strategy relies on 3 pillars defined as individual work packages with interdependent deliverables but funded independently. We are looking for partners that can support Syngenta in completing one or more of the individual work packages.
We are seeking to assemble an extensive physical library of (poly)fluorinated compounds with known biological activity (agro- and drug-like), covering a wide diversity of chemical space. The compounds should be free from functional groups of known toxicological concern. Knowledge of the contribution of the PFAS group to ligand-receptor interactions is preferred, but not essential. For each compound we require access to match pair sets, systematically replacing the fluorinated group with substituents of various stereo-electronic properties. We target a collection of a minimum of 25 PFA bioactive compounds with sets of at least 5 to 10 match pairs each. Synthesis on demand is in scope and partial contributions from multiple sources are also welcome. For each contribution we will negotiate a suitable material transfer agreement to enable evaluation.
We aim to generate homogeneous datasets on key properties for the full collection of compounds. To this end, we are looking to partner with CROs or academic groups who are capable of measuring the properties enumerated below, for all the samples supplied by Syngenta based on the collection assembled in Work Package I. The complete set of experimental values (i.e., not modelled or predicted) is required for all “must-have” properties as a minimum deliverable. Access to data for any of the “desirable” properties outlined below can be a differentiating factor. Assay development or optimization is in scope, to ensure data generated are compatible with existing Syngenta data.
- Physicochemical properties
- must-have: logP, pKa, aqueous solubility
- desirable: ΔLogP(alkane), photostability, hydrolytic stability (acidic / neutral / basic pH)
- Biokinetic properties
- must-have: passive cellular uptake (model system e.g., PAMPA); oxidative metabolism (model system, e.g. p450s)
- desirable: active transport (uptake and efflux in relevant cellular assay), other metabolic pathways and liabilities, distribution and accumulation in planta, nonspecific protein binding.
- Environmental properties
- desirable: Koc (model system, e.g. HPLC, or soil adsorption assay), soil DT50 , root uptake.
We are looking for potential partners with expertise in state-of-the-art computational tools to collaborate with Syngenta scientists for data analysis and model development. We aim to model in vivo parameters based on measured physicochemical and biokinetic parameters, to create a suite of robust QSPR and potentially also predictive models based on matched molecular pair analyses (e.g., cellular uptake in pests, systemic distribution in planta, metabolism in both pest and plant cells, degradation in soil, etc.) that will enable the fluorine-efficient design of high-performance agrochemicals.
Why partner with Syngenta?
We invite proposals for collaborating with Syngenta on individual work packages, from outstanding scientists with diverse expertise, who are equally enthusiastic about our vision to replace per- and polyfluoroalkyl substances in agrochemicals.
This project can set the stage for long-term, ambitious collaborations across organisations, that will advance our fundamental understanding and push the boundaries of chemical design for sustainable agrochemicals.
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