In search of new herbicidal inhibitors of the non‐mevalonate pathway

The first five steps of the non-mevalonate pathway have been tested in high-throughput screening (HTS) campaigns, using enzymes of plant origin. Hit rates were in general relatively low, which could be attributed to the high polarity and charged nature of substrates and active sites of these enzymes. Still, for all the enzymes, apart from IspF (2-methylerythritol 2,4-cyclodiphosphate synthase), inhibitors could be identified with activities below 100 μM, and these were followed up to identify structure–activity relationships (SARs). For the enzyme IspD (2C-methyl-D-erythritol 4-phosphate cytidyltransferase), inhibitors with IC50 down to 35 nM were identified that also showed herbicidal activity.