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

Abstract

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.

Novel Bioassay for the Discovery of Inhibitors of the 2-C-Methyl-D-erythritol 4-Phosphate (MEP) and Terpenoid Pathways Leading to Carotenoid Biosynthesis

“…Clomazone, 5-hydroxyclomazone and a series of acylated 5-hydroxy derivatives do not inhibit purified plant DXS, whereas ketoclomazone is highly active, with an I 50 value of 80 nM [41]. Additionally, the seco -ketoclomazone analog with a 3-[methyl(hydroxy)amino]-2,2-dimethyl-3-oxopropanoic acid side chain, which is a known plant metabolite of clomazone [60], [62], was recently reported as a potent inhibitor of Haemophilus influenza DXS [65].…”

“…Interest in inhibitors of the MEP pathway has led a research group at BASF-SE (Ludwigshafen, Germany) to screen for new herbicides targeting this pathway in target-based high throughput in vitro assays [41]. Eleven of these experimental compounds were tested in our in vivo bioassay.…”

“…Crop Protection (now Syngenta, Greensboro, NC 27419), and experimental inhibitors for some of the enzymes of the MEP pathway were provided by BASF-SE (Ludwigshafen, Germany) [41].…”

“…In spite of the potential relevance of all other enzymes of this pathway, no herbicide targeting the early steps of carotenoid synthesis, other than clomazone, has been developed [41].…”

(Z)-4-Chloro-N-{3-[(4-chlorophenyl)sulfonyl]-2,3-dihydrobenzo[d]thiazol-2-ylidene}benzenesulfonamide

“…Inhibition of enzymes from this pathway has tremendous potential to generate new anti-infective agents or herbicides (Frank & Groll, 2017; Witschel et al ., 2013). The enzyme 2-methylerythritol 2,4-cyclodiphosphate synthase (IspF) is present in the MEP pathway (Zhang et al ., 2013, Geist et al ., 2010, Crane et al ., 2006).…”