ABSTRACT
Pyraziflumid is a novel succinate dehydrogenase inhibitor (SDHI) fungicide discovered and developed by Nihon Nohyaku Co., Ltd. It exhibits excellent fungicidal activities against a broad range of plant diseases and has a favorable safety profile for the Integrated Pest Management (IPM) program. This compound was found by researching the unique chemical derivatives, 3-(trifluoromethyl)pyrazine-2-carboxamides, and has good biological properties, such as preventive, residual and curative activity, and rain-fastness. Pyraziflumid was registered and launched in Japan in 2018. It was registered in South Korea in 2018 and is now under development in other countries. This paper describes the discovery, synthesis, biological activity, safety profile and mode of action of pyraziflumid.
ABSTRACT
Pyraziflumid was discovered as a novel SDHI fungicide chemically characterized by the 3-(trifluoromethyl)pyrazine-2-carboxamide group. This chemical series showed particularly high fungicidal activities against a broad spectrum of plant diseases in the case of N-(biphenyl-2-yl) as well as N-(1,1,3-trimethylindan-4-yl)carboxamides. Various N-(biphenyl-2-yl)pyrazine-2-carboxamides were synthesized, and their structure-activity relationships were studied. The optimization of the fungicidal performance of the series finally led to the identification of pyraziflumid, which could control a wide range of plant diseases. In this report, details of the structure-activity relationships from the lead compound to pyraziflumid are described.
ABSTRACT
Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 µM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 µM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.
