Improved herbicide discovery using physico-chemical rules refined by antimalarial library screening.

Kirill V Sukhoverkov,Joel Haywood,Joshua S Mylne,Maxime G Corral,Philipp Johnen,Keith A Stubbs,Trevor Newton,Julie Leroux

doi:10.1039/d1ra00914a

Abstract

Herbicides have physico-chemical properties not unlike orally-delivered human drugs, but are known to diverge in their limits for proton donors, partition coefficients and molecular weight. To further refine rules specific for herbicides, we exploited the close evolutionary relationship between Plasmodium falciparum and plants by screening the entire Malaria Box, a chemical library of novel chemical scaffolds with activity against the blood stage of P. falciparum. Initial screening against Arabidopsis thaliana on agar media and subsequently on soil demonstrated the crucial nature of log P and formal charge are to active molecules. Using this information, a weighted scoring system was applied to a large chemical library of liver-stage effective antimalarial leads, and of the six top-scoring compounds, one had potency comparable to that of commercial herbicides. This novel compound, MMV1206386, has no close structural analogues among commercial herbicides. Physiological profiling suggested that MMV1206386 has a new mode of action and overall demonstrates how weighted rules can help during herbicide discovery programs.

Highlights

The implementation of herbicides in agriculture in the 1940s improved crop productivity, but the emergence of herbicide resistance in the last few decades threatens those gains in yield
To evaluate the overall potential in planta bioavailability of compounds from the Malaria Box library (MMV400) we compared their solubility in water, partition and distribution coefficients, molar mass, proportion of aromatic atoms and polar surface area with the corresponding parameters of 360 commercial herbicides
The physico-chemical properties of commercial herbicides and the MMV400 compounds were similar, the range for each speci c parameter was narrower for the MMV400 compounds

Summary

Introduction

The implementation of herbicides in agriculture in the 1940s improved crop productivity, but the emergence of herbicide resistance in the last few decades threatens those gains in yield. 1) and since the number of weed species resistant to one or more herbicides is 262.2 practices such as herbicide rotation helps avoid the evolution of resistance and extends the life of herbicides, it relies on switching between modes of action.[3] From the 1950s to the 1970s a new mode of action was introduced every two to three years, but this slowed in the 1980s. During the 30 years no new herbicide mode of action was commercialised until tet upyrolimet (inhibitor of plant dihydroorotate dehydrogenase) was announced by FMC Agricultural Solutions in 2019.4,5 Two old herbicides, cinmethylin and aclonifen, were rediscovered as having new modes of action,[6,7] while new compounds with new modes of action have emerged, such as. The screening of this subset against A. thaliana grown on Murashige–Skoog agar medium revealed twenty highly herbicidal compounds.[18,19] Ten of these

Results

Discussion

Conclusion