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Total synthesis and structure–activity relationship of alternaric acid delivers an herbicide vector

Nature Synthesis volume 1, pages 987–995 (2022)Cite this article

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Abstract

Global food security is one of the foremost challenges of our time and requires a multifaceted solution. Crop protection strategies are an essential part of this response; however, there is increasing resistance to known modes of action. Since its discovery in 1949, the natural product alternaric acid has been proposed as a starting point for herbicide development. However, this target is undeveloped due to its poor synthetic accessibility and a lack of knowledge of the associated pharmacology. Here we report the discovery of herbicidal compounds from alternaric acid that operate via a potentially unknown mode of action. Development of a total synthesis enabled structure–activity relationship profiling of compound libraries, which, combined with phenotypic screening and molecular modelling data, identified small-molecule lead compounds with enhanced and broader spectrum herbicidal activity than alternaric acid.

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Fig. 1: The use of natural product synthesis as a starting point for herbicide discovery.
Fig. 2: Synthetic strategy and total synthesis of alternaric acid.
Fig. 3: Biological screening of alternaric acid.
Fig. 4: Computational model of HPPD binding of 2.
Fig. 5: Lead development strategy and biological screening data of selected examples from the lead library.
Fig. 6: Advanced biological screening data of compounds from lead series.
Fig. 7: Computational model of HPPD binding of lead series.

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Data availability

All data generated during this study are included in this published article (and its Supplementary Information files). Analytical data generated during the current study are also available in the University of St Andrews repository, https://doi.org/10.17630/c41bcf9c-57cc-46f2-94cf-c9f7559554c5. Crystallographic data for compound 2 are available from the Cambridge Crystallographic Data Centre (CCDC) under deposition number 2169366.

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Acknowledgements

E.M.I and A.J.B.W. thank Syngenta and EPSRC for an iCASE PhD studentship. We thank C. Martin and R. Ellis at the Syngenta Jealott’s Hill Chemistry Automation Platform for their support with reaction optimization and library purification.

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Authors and Affiliations

  1. EaStCHEM, School of Chemistry, University of St Andrews, St Andrews, UK

    Eva M. Israel, Alexandra M. Z. Slawin & Allan J. B. Watson

  2. Syngenta, Jealott’s Hill International Research Centre, Bracknell, UK

    Júlia Comas-Barceló

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  1. Eva M. Israel
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  4. Allan J. B. Watson
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Contributions

E.M.I. conceived and conducted the synthetic chemistry. J.C.-B. guided compound design and coordinated the biological screening. A.M.Z.S performed and analysed X-ray crystallography. E.M.I, J.C-B. and A.J.B.W. wrote the manuscript. A.J.B.W. conceived the chemistry and directed the project.

Corresponding author

Correspondence to Allan J. B. Watson.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Patrick Steel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Alison Stoddart, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Discussion, Figs. 1 and 2, and Tables 1–8.

Supplementary Data 1

Crystallographic data for compound 2; CCDC no. 2169366.

Source data

Source Data Fig. 3

Excel file used to generate chart using data from Tables in SI (pS183-184).

Source Data Fig. 5

Excel file used to generate chart using data from Tables in SI (pS183-184).

Source Data Fig. 6

Excel file used to generate chart using data from Tables in SI (pS183-184).

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Israel, E.M., Comas-Barceló, J., Slawin, A.M.Z. et al. Total synthesis and structure–activity relationship of alternaric acid delivers an herbicide vector. Nat. Synth 1, 987–995 (2022). https://doi.org/10.1038/s44160-022-00169-3

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