Gao Wei, Li Jing, Zhang Yue, Yuan Haolin, Li Kun, Zhang Jin, Han Lijun, Fan Zhijin, Chen Lai, Tang Liangfu
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, PR China.
State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, PR China.
J Agric Food Chem. 2025 Jan 15;73(2):1075-1085. doi: 10.1021/acs.jafc.4c08092. Epub 2025 Jan 6.
To discover novel inhibitors of pyruvate kinase (PK) as fungicidal candidates, a series of 2-thiazol-2-yl-1,3,4-oxadiazole derivatives were designed by a prediction model with PK (RsPK) as a protein target and as a ligand. Fungicidal screening indicated that , , , , , , , and exhibited equal or higher activity compared to against , , or . To our surprise, showed comparable activity to flutriafol with an EC of 0.21 μg/mL vs 0.20 μg/mL, but over 14 times more active than the lead compound against with its EC of 0.21 μg/mL vs 3.14 μg/mL (mole ratio over 17-fold). Compound also displayed 2.30-fold better inhibition potency against RsPK compared with . Moreover, this higher potency of against RsPK was also reflected in a steeper dose-response tendency in the fluorescence quenching assay and a lower dissociation constant in the microscale thermophoresis (MST) assay when compared with . The results in this study not only broadened the structural diversity of PK inhibitors but also supported as a promising PK-based highly active fungicide lead compound, with stronger binding ability to RsPK than .
为了发现丙酮酸激酶（PK）的新型抑制剂作为杀真菌候选物，通过以PK（RsPK）作为蛋白质靶点并以[具体配体]作为配体的预测模型设计了一系列2-噻唑-2-基-1,3,4-恶二唑衍生物。杀真菌筛选表明，[具体化合物1]、[具体化合物2]、[具体化合物3]、[具体化合物4]、[具体化合物5]、[具体化合物6]、[具体化合物7]和[具体化合物8]对[具体真菌1]、[具体真菌2]或[具体真菌3]表现出与[对比化合物]相当或更高的活性。令我们惊讶的是，[具体化合物]与氟环唑表现出相当的活性，其对[具体真菌]的EC50为0.21μg/mL，而氟环唑为0.20μg/mL，但对[具体真菌]的活性比先导化合物[对比化合物]高14倍以上，其EC50为0.21μg/mL，而[对比化合物]为3.14μg/mL（摩尔比超过17倍）。化合物[具体化合物]对RsPK的抑制效力也比[对比化合物]高2.30倍。此外，[具体化合物]对RsPK的这种更高效力还体现在荧光猝灭试验中更陡峭的剂量反应趋势以及与[对比化合物]相比在微量热泳（MST）试验中更低的解离常数上。本研究结果不仅拓宽了PK抑制剂的结构多样性，还支持[具体化合物]作为一种有前途的基于PK的高活性杀真菌先导化合物，与[对比化合物]相比，其与RsPK的结合能力更强。
