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Design, Synthesis, and Study of the Dual Action Mode of Novel N-Thienyl-1,5-disubstituted-4-pyrazole Carboxamides against Nigrospora oryzae
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-05-04 , DOI: 10.1021/acs.jafc.3c00269 Chengzhi Zhang 1 , Cailong Zhao 1 , Huanlin Zheng 1 , Longju Li 1 , Ya Zheng 1 , Zhibing Wu 1
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-05-04 , DOI: 10.1021/acs.jafc.3c00269 Chengzhi Zhang 1 , Cailong Zhao 1 , Huanlin Zheng 1 , Longju Li 1 , Ya Zheng 1 , Zhibing Wu 1
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Due to the single target but extensive application of commercialized succinate dehydrogenase inhibitors (SDHIs), resistance problems have gradually become apparent in recent years. To solve this problem, a series of novel N-thienyl-1,5-disubstituted-1H-4-pyrazole carboxamide derivatives were designed and synthesized in this work based on the active skeleton 5-trifluoromethyl-4-pyrazole carboxamide. The bioassay results indicated that some target compounds exhibited excellent in vitro antifungal activities against the eight phytopathogenic fungi tested. Among them, the EC50 values of T4, T6, and T9 against Nigrospora oryzae were 5.8, 1.9, and 5.5 mg/L, respectively. The in vivo protective and curative activities of 40 mg/L T6 against rice infected with N. oryzae were 81.5% and 43.0%, respectively. Further studies revealed that T6 not only significantly inhibited the growth of N. oryzae mycelia but also effectively hindered spore germination and germ tube elongation. Morphological studies using scanning electron microscopy (SEM), fluorescence microscopy (FM), and transmission electron microscopy (TEM) found that T6 could affect the mycelium membrane integrity by increasing cell membrane permeability and causing peroxidation of cellular lipids, and these results were further verified by measuring the malondialdehyde (MDA) content. The IC50 value of T6 against succinate dehydrogenase (SDH) was 7.2 mg/L, lower than that of the commercialized SDHI penthiopyrad (3.4 mg/L). Further, ATP content detection and the results after docking T6 and penthiopyrad suggested that T6 was a potential SDHI. These studies demonstrated that active compound T6 could both inhibit the activity of SDH and affect the integrity of the cell membrane at the same time via a dual action mode, which is different from the mode of action of penthiopyrad. Thus, this study provides a new idea for a strategy to delay resistance and diversify the structures of SDHIs.
中文翻译：
新型 N-噻吩基-1,5-二取代-4-吡唑甲酰胺对米黑孢菌的双重作用模式的设计、合成与研究
由于商业化的琥珀酸脱氢酶抑制剂（SDHIs）靶点单一但应用广泛，近年来耐药性问题逐渐显现。为解决这一问题，本工作基于活性骨架5-三氟甲基-4-吡唑甲酰胺，设计合成了一系列新型N-噻吩基-1,5-二取代-1H -4-吡唑甲酰胺衍生物。生物测定结果表明，一些目标化合物对测试的八种植物病原真菌表现出优异的体外抗真菌活性。其中，T 4、T 6和T 9的EC 50值对米黑孢子菌分别为 5.8、1.9 和 5.5 mg/L。40 mg/L T 6对稻瘟病水稻的体内保护和治疗活性分别为81.5%和43.0%。进一步的研究表明，T 6不仅能显着抑制稻瘟病菌菌丝体的生长，还能有效阻碍孢子萌发和胚芽管伸长。使用扫描电子显微镜 (SEM)、荧光显微镜 (FM) 和透射电子显微镜 (TEM) 进行的形态学研究发现T 6可以通过增加细胞膜通透性和引起细胞脂质过氧化来影响菌丝体膜的完整性，并且通过测量丙二醛（MDA）含量进一步验证了这些结果。T 6对琥珀酸脱氢酶（SDH）的IC 50值为7.2 mg/L，低于商业化的SDHI吡噻菌胺（3.4 mg/L）。此外，ATP含量检测和T 6与吡噻菌胺对接后的结果表明T 6是一种潜在的SDHI。这些研究表明，活性化合物T 6既能抑制SDH的活性又能同时影响细胞膜的完整性，通过双重作用方式，这与吡噻菌胺的作用方式不同。因此，本研究为延迟抵抗和使SDHI结构多样化的策略提供了新思路。
更新日期：2023-05-04
中文翻译：
新型 N-噻吩基-1,5-二取代-4-吡唑甲酰胺对米黑孢菌的双重作用模式的设计、合成与研究
由于商业化的琥珀酸脱氢酶抑制剂（SDHIs）靶点单一但应用广泛，近年来耐药性问题逐渐显现。为解决这一问题，本工作基于活性骨架5-三氟甲基-4-吡唑甲酰胺，设计合成了一系列新型N-噻吩基-1,5-二取代-1H -4-吡唑甲酰胺衍生物。生物测定结果表明，一些目标化合物对测试的八种植物病原真菌表现出优异的体外抗真菌活性。其中，T 4、T 6和T 9的EC 50值对米黑孢子菌分别为 5.8、1.9 和 5.5 mg/L。40 mg/L T 6对稻瘟病水稻的体内保护和治疗活性分别为81.5%和43.0%。进一步的研究表明，T 6不仅能显着抑制稻瘟病菌菌丝体的生长，还能有效阻碍孢子萌发和胚芽管伸长。使用扫描电子显微镜 (SEM)、荧光显微镜 (FM) 和透射电子显微镜 (TEM) 进行的形态学研究发现T 6可以通过增加细胞膜通透性和引起细胞脂质过氧化来影响菌丝体膜的完整性，并且通过测量丙二醛（MDA）含量进一步验证了这些结果。T 6对琥珀酸脱氢酶（SDH）的IC 50值为7.2 mg/L，低于商业化的SDHI吡噻菌胺（3.4 mg/L）。此外，ATP含量检测和T 6与吡噻菌胺对接后的结果表明T 6是一种潜在的SDHI。这些研究表明，活性化合物T 6既能抑制SDH的活性又能同时影响细胞膜的完整性，通过双重作用方式，这与吡噻菌胺的作用方式不同。因此，本研究为延迟抵抗和使SDHI结构多样化的策略提供了新思路。
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