Society Awards 2013
Development of a novel fungicide, penthiopyrad#
2013 Volume 38 Issue 3 Pages 167-168
Details
2013 Volume 38 Issue 3 Pages 167-168
The discovery of the systemic fungicide carboxin greatly encouraged further optimization of the chemical structure. Thus, a number of carboxin-related carboxamides have been synthesized and shown to be effective in the control of plant diseases. Carboxin is a narrow-spectrum fungicide with specific potency against Basidiomycetes. In the 1980s, mepronil and flutolanil, which contain a (3-isopropyloxy)phenyl group, were developed. And in the 1990s, two azole carboxamides—furametpyr and thifluzamide—were launched in the Japanese market to control rice sheath blight.
On the other hand, N-(biphenyl-2-yl)-2-methyl-1,4-thioxolane-3-carboxamide (F427) is unique in that it exhibits a broader spectrum of activity and could control Ascomycetes and Deuteromycetes species as well as Basidiomycetes compared with carboxin. In 1989, Mitsubishi Kasei Corporation discovered that a 2-chloropyridine-3-carboxamide derivative (BC723) exhibited fungicidal activity against Deuteromycetes as well as Basidiomycetes.
In those days, the authors were engaged in a project aimed to discover a broad-spectrum fungicide whose structure was different from that of existing fungicides. We considered BC723 to be a suitable lead compound because it showed the potential for broad-spectrum activity. In the course of our research, we realized the importance of the aromatic rings and N-substituent in the carboxamide compounds and attempted to increase fungicidal activity by structural modification. This led to the identification of penthiopyrad as a potent fungicide for various plant diseases involving Basidiomycetes.
The chemical structure of carboxamide can be divided into two moieties: carboxylic acid moiety and amine moiety. Structural modification of carboxamides was carried out separating carboxylic acid moiety and amine moiety.
In the case of carboxylic acid moiety, considering the structure of BC723 and F427, we estimated that the essential structure for exhibiting antifungal activity against gray mold had the compact hydrophobic substituent in the ortho position of carbonyl group and the proton acceptor in the meta position next to the compact hydrophobic substituent. We synthesized the various heterocyclic carboxamides that satisfied this essential structure. Among these carboxamides, 1-methyl- 3-(trifluoromethyl)pyrazole-4-carboxamide derivatives were found to exhibit high antifungal activity against gray mold.
On the other hand, in the case of amine moiety, because the compounds with the substituent in ortho position of aniline such as phenyl or sec-butyl group showed high activity against gray mold, we estimated that the essential structure for exhibiting antifungal activity against gray mold had the right sized hydrophobic substituent in the ortho position of aniline. Furthermore, the compounds with sec-butyl group showed broader fungicidal spectrum than the compounds with phenyl group. Therefore we thought that alkyl group had more potential than phenyl group. During the process of structural modification, N-(2-substitutent-3-thienyl)heterocyclic carboxamide derivatives were found to exhibit the same activity against various pathogens as N-(2-substituent-phenyl)heterocyclic carboxamide derivatives. Because the 2-substitutent-3-amino thiophene that constituted N-(2-substitutent-3-thienyl)heterocyclic carboxamide had high novelty, we thought that 2-substitutent-3-amino thiophene was a potential structure.
Therefore we intensively synthesized 2-substitutent-3-amino thiophene that had various alkyl groups in 2-position and converted to amide derivatives and then evaluated its fungicidal activity. As a result, we discovered that (RS)-N-[(2-(1,3-dimethylbutyl)-3-thienyl]-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxamide (penthiopyrad) that had 1,3-dimethyl butyl group in the 2-position of thiophene exhibited extremely high activity against various pathogens.
Common name: penthiopyrad
Trade name: Affet® SC, Gaia® WDG
Development code: MTF-753
CAS registry number: 183675-82-3
Chemical name: (RS)-N-[2-(1,3-dimethylbutyl)-3-thienyl]-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxamide
Molecular formula: C16H20F3N3OS
Molecular weight: 359.42
Appearance: White crystalline solid
Melting point: 108.7°C
Vapor pressure: 6.43×10−6 Pa at 25°C
Solubility in water: 7.53 mg/L at 20°C
Partition coefficient: Log PO/W=3.2 at 24°C
Penthiopyrad showed strong inhibitory activity of spore germination in various plant pathogens compared with that of mycelial growth. For example, penthiopyrad has higher antifungal activity against spore germination than mycelial growth of B. cinerea. In the case of the field trials, penthiopyrad showed highly preventive control effects rather than curative effects against gray mold. The strong inhibition effect of penthiopyrad on spore germination seems to be one reason why preventive application brings better results of gray mold control than curative application.
Penthiopyrad has broad spectrum of fungicidal activity on a wide range of fruits and vegetables. It is effective in controlling a range of pathogens including gray mold, powdery mildew, tomato leaf mold, cucumber corynespora leaf spot, rust, southern blight, apple and pear scab, apple blossom blight, and peach and cherry brown rot. On cereals, penthiopyrad has high activity against wheat Septoria diseases, rust and snow mold, and on turf grass, it also has high activity against brown patch, dollar spot, fairly rings, anthracnose and snow mold. Especially against wheat brown rust, cucumber powdery mildew and beans gray mold, penthiopyrad was significantly effective even at the low dosage. No phytotoxicity could be observed in all the tested plants at higher application dosage than practical dosage for efficacy.
Furthermore, penthiopyrad has a different mode of action from that of many commercial fungicides used for these kinds of diseases. No cross resistance has been observed to benzimidazole, dicarboximide, anilinopyrimidine, DMI and strobilurin.
Penthiopyrad showed high inhibitory activity against succinate dehydrogenase (SDH) in the enzyme complex II in mitochondrial respiratory chain. As a result of this effect, the fungus cannot produce vital energy in the form of ATP. Penthiopyrad showed high inhibitory activity against SDH derived from not only Rhizoctonia solani but also Botrytis cinerea and Fusarium oxysporum.
Penthiopyrad has low acute toxicity potential in mammals and avian. In contrast, it has a relatively high acute toxicity in some aqueous species. Its acceptable daily intake (ADI) for human was established to be 0.081 mg/kg b.w./day in Japan from the results of toxicological studies.
