Discovery and biological profile of pyridachlometyl

Abstract

Pyridachlometyl is a novel tubulin dynamics modulator fungicide developed by Sumitomo as a new agent designed to tackle fungicide resistance. Pyridachlometyl is being developed as a first-in-class molecule with an anti-tubulin mode of action, the chemical structure of which is characterized by a unique tetrasubstituted pyridazine ring. The first commercial product 'Fuseki flowable' received initial registration in 2023 in Japan. The concepts of the discovery project, optimization of chemical structures, and biological profiles are reviewed herein. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Keywords: bioisostere; fungicide resistance; pyridachlometyl; pyridazine; tubulin.

Figure 1

Chemical structures of experimental tubulin dynamics modulator fungicides., , , , , ,

Figure 2

A related plausible bioisosteric replacement between amide and 1,2,4‐triazole moieties incorporated into or fused with heterocycles.

Figure 3

Hetero‐atoms (red color) of bicyclic and monocyclic pharmacophores as hypothetical hydrogen bond receptors at target sites.

Figure 4

The selection of pyridachlometyl.

Figure 5

The route of pyridachlometyl synthesis., , ,

Figure 6

Binding sites of pyridachlometyl and the benzimidazole fungicide carbendazim (docking model ¹⁷ , ¹⁹ ). A homology model of Zymoseptoria tritici tubulin based on the X‐ray patterns of Bos taurus, Sus barbatus, and Gallus gallus (PDB, 5NJH, and 5C1A1) tubulins.

Figure 7

Close‐up view of the putative binding site of pyridachlometyl (docking model ¹⁷ , ¹⁹ ). A homology model of Zymoseptoria tritici tubulin based on the X‐ray patterns of Bos taurus, Sus barbatus, and Gallus gallus (PDB, 5NJH, and 5C1A1) tubulins. Altered amino acid residues resulting in a change in pyridachlomethyl sensitivity are shown in red.

Figure 8

Circular zones of powdery mildew inhibition around pyridachlometyl‐impregnated plastic disks. Formulation, 60 g L⁻¹ EC; Concentration of pyridachlometyl (active constituent), 1000 mg L⁻¹; Treatment, 20 μL on plastic disk; Inoculum, conidiospores from infected plants.

Figure 9

Translaminar activity of pyridachlometyl against cercospora leaf spot. Adaxial–adaxial: Test plants were inoculated with a conidial suspension of Cercospora beticola on the adaxial surface of the leaves 3 days after a fungicide had been applied to the adaxial surface. Abaxial–adaxial: Test plants were inoculated on the adaxial surface of leaves 3 days after the fungicide had been applied to the abaxial surface. Both tests were conducted in triplicate, with four leaves being assessed for each plant. Statistical differences were assessed using t‐tests. *P < 0.05, **P < 0.01.

Figure 10

Histogram of half maximal effective concentration (EC₅₀) values for pyridachlometyl (A) and carbendazim (B) in Cercospora beticola isolates. A total of 67 isolates collected from sugar beet fields in Hokkaido between 2014 and 2019 were assessed using a microtiter plate assay. EC₅₀ values (mg L⁻¹) were calculated for each fungicide.

Figure 11

Results of field trials (sugar beet leaf spot caused by Cercospora beticola, Japan). In most trials, four to seven ground applications were performed using a water volume of approximately 1500 L ha⁻¹ at intervals of approximately 7 days from the beginning of the primary infection.

Figure 12

Results of field trials (vegetables/fruit, powdery mildews, Korea). For each crop, three ground applications were performed at a water volume of 1500 L ha⁻¹ with a 7 days interval from the beginning of the primary infection.

Figure 13

Results of field trials (wheat snow mold caused by Microdochium spp., Japan). A single ground application was performed prior to snow cover at water volumes of 1500–2500 L ha⁻¹ at each site (n = 3).

Figure 14

Result of a field trial using an unmanned aerial vehicle sprayer (soybean purple stain caused by Cercospora kikuchii, Japan). In a single trial with three replicate plots, a single application was performed using an unmanned aerial vehicle sprayer at 8 L ha⁻¹ water volume after the flowering stage of soybean. The concentrations of the fungicides pyridachlometyl, difenoconazole, azoxystrobin, and iminoctadine‐albesilate in water were 1.09%, 1.56%, 1.25%, and 5%, respectively.