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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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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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.
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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 Discussion, Figs. 1 and 2, and Tables 1–8.
Supplementary Data 1
Crystallographic data for compound 2; CCDC no. 2169366.
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Excel file used to generate chart using data from Tables in SI (pS183-184).
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Excel file used to generate chart using data from Tables in SI (pS183-184).
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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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DOI: https://doi.org/10.1038/s44160-022-00169-3
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