通过活性片段交换和连接方法发现苯并噻唑基吡唑-4-甲酰胺作为有效的琥珀酸脱氢酶抑制剂,Journal of Agricultural and Food Chemistry

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通过活性片段交换和连接方法发现苯并噻唑基吡唑-4-甲酰胺作为有效的琥珀酸脱氢酶抑制剂
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-09-29 , DOI: 10.1021/acs.jafc.3c03646
Yan-Ming Yin ₁ , Zong-Yue Sun ₁ , Da-Wei Wang ₁ , Zhen Xi ₁

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琥珀酸脱氢酶（SDH）是现代农业研究中开发绿色杀菌剂来管理农业病原体的一个有吸引力的目标。在这项工作中，我们报告了使用活性片段交换和连接方法发现苯并噻唑基吡唑-4-甲酰胺I - III作为有效的 SDH 抑制剂。杀菌活性测定结果表明，一些合成的化合物对受试真菌表现出优异的抑制作用。系统的构效关系研究发现了化合物Ip , N -(1-((4,6-二氟苯并[ d ]噻唑-2-基)硫基)丙-2-基)-3-(二氟甲基)- N -甲氧基-1-甲基-1 H -吡唑-4-甲酰胺，对禾谷镰刀菌 ( Fusarium graminearum Schw) 的杀菌活性 (EC ₅₀ = 0.93 μg/mL) 比商业杀菌剂 thifluzamide (EC ₅₀ > 50 μg/mL) 更高，啶酰菌胺 (EC ₅₀ > 50 μg/mL)。分子模拟研究表明疏水相互作用是配体和SDH 之间的主要驱动力。令人欣喜的是，我们发现Ip可以刺激小麦幼苗和拟南芥的生长，并增加处理植物的生物量。初步研究Ip的植物生长促进机制表明，它可以提高植物体内硝酸还原酶的活性，从而刺激植物的生长。

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Discovery of Benzothiazolylpyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors through Active Fragment Exchange and Link Approach

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, in this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides I-III as potent SDH inhibitors using active fragment exchange and link approach. The results of the fungicidal activity assays showed that some of the synthesized compounds exhibited excellent inhibition against the tested fungi. Systematic structure–activity relationship studies led to the discovery of compound Ip, N-(1-((4,6-difluorobenzo[d]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide, which showed higher fungicidal activity against Fusarium graminearum Schw (EC₅₀ = 0.93 μg/mL) than the commercial fungicides thifluzamide (EC₅₀ > 50 μg/mL) and boscalid (EC₅₀ > 50 μg/mL). The molecular simulation studies suggested that hydrophobic interactions were the primary driving forces between ligands and SDH. Promisingly, we found that Ip could stimulate the growth of wheat seedlings and Arabidopsis thaliana and increase the biomass of the treated plants. Preliminary studies on the plant growth promoter mechanism of Ip indicated that it could increase nitrate reductase activity in planta, that, in turn, stimulates the growth of plants.

更新日期：2023-09-29

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