Current Status and Future Prospects in Herbicide Discovery

Abstract

Herbicides represent about 60% of the pesticides (by volume) used worldwide. The success of herbicides can be attributed in part to a relatively steady discovery of one unique mechanisms of action (MOA) every two years from the early 1950s to the mid-1980s. While this situation changed dramatically after the introduction of glyphosate-resistant crops, evolution of resistance to glyphosate has renewed the agrichemical industry interest in new chemistry interacting with novel target sites. This review analyses recent characterization of new herbicide target sites, the chemical classes developed to inhibit these target sites, and where appropriate the innovative technologies used in these discovery programs.

Keywords: amino acid biosynthesis; lipid biosynthesis; mechanism of action; plastoquinone biosynthesis; pyrimidine biosynthesis; target site.

Figure 1

(A) Overview of fatty acid biosynthesis and herbicide targets in plant cells. Inhibition of acetyl-CoA carboxylase (ACCase) by haloxyfopmethyl or tepraloxydim disrupts early fatty acid biosynthesis. Cinmethylin prevents the release of both unsaturated and saturated fatty acids from the plastids through inhibition of fatty acid thioesterase (FAT) A and B, respectively. Inhibitors of very-long-chain fatty acid (VLCFA) biosynthesis act at the endoplasmic reticulum. ACP: acyl carrier protein; CoA: Coenzyme A. From [18] with permission. (B) Structure of cinmethylin.

Figure 2

Overview of the relationship between carotenoid and prenyl quinone biosynthesis. Biosynthesis of carotenoids and plastoquinone requires the MEP, terpenoid and homogentisate pathways. Older chemistry such as clomazone inhibits 1-deoxy-D-xylulose 5-phosphate synthase (DXS), the first step in the MEP pathway; a number of chemical classes inhibit carotenoid biosynthesis by targeting phytoene desaturase (PDS); the newer triketone herbicides inhibit p-hydroxyphenylpyruvate dioxygenase (HPPD) involved in homogentisate biosynthesis. The two newest target sites affect solanyl diphosphate synthase (SPS) responsible for the synthesis of the terpenoid tail of plastoquinone or homogentisate solanesyl transferase (HST), the enzyme combining solanyl diphosphate and homogentisate to form a plastoquinone precursor.

Figure 3

Structure of aclonifen, an inhibitor of chloroplastic solanyl diphosphate synthase (SPS).

Figure 4

Cyclopyrimorate and its bioactive metabolite des-morpholinocarbonyl cyclopyrimorate (DMC).

Figure 5

(A) Key enzymes involved in branched chain amino acid biosynthesis. DHAD is the most recent putative herbicide target site in this pathway. (B) Structure of the microbial metabolite aspterric acid, an inhibitor of DHAD. ALS: acetolactate synthase; KARI: acetohydroxy acid isomeroreductase; DHAD: dihydroxy acid dehydratase.

Figure 6

Shikimate pathway and aromatic amino acid biosynthesis showing the metabolites formed at each step catalyzed by the enzymes abbreviated in bold. The target site of glyphosate is EPSPS (green). The target site of the antimetabolite 7-deoxysedoheptulose (red) is DQS (orange). DAHPS: 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase, DQS: 3-dehydroquinate synthase, DHQD/SD: 3-dehydroquinatede hydratase, SK: shikimate kinase, EPSPS: 5-enolpyruvylshikimate 3-phosphate synthase, CS: chorismate synthase, CM: chorismate mutase, PAT: prephenate aminotransferase.

Figure 7

Structure of endothall, cantharidin and its dicarboxylic acid analog.

Figure 8

Structure of a potent 1-(substituted phenoxyacetoxy)alkylphosphonate that targets pyruvate dehydrogenase complex (PDHc).

Figure 9

Structure of 2-hydroxy-3-(1,2,4-triazol-1-yl) propylphosphonate, an herbicidal inhibitor of imadazoleglycerol phosphate dehydratase (IGPD).

Figure 10

Structure of tetflupyrolimet, an aryl pyrrolidinone anilide targeting Dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis.

Figure 11

Structure of actinonin, a microbial metabolite targeting chloroplastic peptide deformylase.

Figure 12

Structure of the fluoroquinolone ciprofloxacin and structure-optimized analog 44 with increased specificity against plants DNA gyrase and better herbicidal profile.

Figure 13

Simplified biosynthesis of folate in higher plants and structures of herbicidal compounds targeting this pathway. HPPK: 6-hydroxymethyldihydropterin pyrophosphokinase; DHPS: dihydropteroate synthase; DHFS: dihydrofolate synthetase; DHFR: dihydrofolate reductase; FPGS: folylpolyglutamate synthetase; ADCS: aminodeoxychorismate synthase; ADCL: aminodeoxychorismate lyase.

Figure 14

New insight into the mechanisms of action (MOA) of glufosinate. (A) Older leaves are more sensitive to glufosinate than meristematic tissue and younger leaves. (B) Absorption of glufosinate. (C) Inhibition of glutamine synthetase (GS). (D) Ammonia accumulation. (E) Reactive oxygen species (ROS) accumulation. Reproduced from Takano et al. 2019 with permission.

Figure 15

Structure of novel HPPD inhibitor Y13161 (benquitrione).

Figure 16

Structural features of the chemical classes mentioned in Section 4.