Abstract：
The main challenge in the development of agrochemicals is the lack of new leads and/or targets. It is critical to discover new molecular targets and their corresponding ligands. YZK-C22, which contains a 1,2,3-thiadiazol-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole skeleton, is a fungicide lead compound with broad-spectrum fungicidal activity. Previous studies suggested that the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole scaffold exhibited good antifungal activity. Inspired by this, a series of pyrrolo[2,3-d]thiazole derivatives were designed and synthesized through a bioisosteric strategy. Compounds C1, C9, and C20 were found to be more active against Rhizoctonia solani than the positive control YZK-C22. More than half of the target compounds provided favorable activity against Botrytis cinerea, where the EC50 values of compounds C4, C6, C8, C10, and C20 varied from 1.17 to 1.77 μg/mL. Surface plasmon resonance and molecular docking suggested that in vitro potent compounds C9 and C20 have a new mode of action instead of acting as pyruvate kinase inhibitors. Transcriptome analysis revealed that compound C20 can impact the tryptophan metabolic pathway, cutin, suberin, and wax biosynthesis of B. cinerea. Overall, pyrrolo[2,3-d]thiazole is discovered as a new fungicidal lead structure with a potential new mode of action for further exploration.
摘要：
农用化学品开发的主要挑战是缺乏新的线索和/或目标。发现新的分子靶标及其相应的配体至关重要。YZK-C22，包含1,2,3-噻二唑-[1,2,4]三唑并[3,4-b][1,3,4]噻二唑骨架，是一种具有广谱杀菌活性的杀菌剂先导化合物。先前的研究表明[1,2,4]三唑并[3,4-b][1,3,4]噻二唑支架表现出良好的抗真菌活性。受此启发,通过生物等排策略设计并合成了一系列吡咯并[2,3-d]噻唑衍生物。发现化合物C1、C9和C20比阳性对照YZK-C22更有活性。超过一半的目标化合物对灰葡萄孢菌具有良好的活性，其中化合物C4、C6、C8、C10和C20的EC50值在1.17至1.77μg/mL之间变化。表面等离子体共振和分子对接表明，体外有效的化合物C9和C20具有新的作用方式，而不是作为丙酮酸激酶抑制剂。转录组分析显示，化合物C20可以影响色氨酸代谢途径，角质,suberin,以及灰霉病菌的蜡生物合成。总的来说,吡咯并[2,3-d]噻唑是一种新的杀菌铅结构，具有潜在的新作用方式，可进一步探索。
