Pyruvate Kinase-Based Novel 2-Thiazol-2-yl-1,3,4-oxadiazoles Discovery as Fungicidal Highly Active Leads

  • J Agric Food Chem. 2025 Jan 15;73(2):1075-1085. doi: 10.1021/acs.jafc.4c08092.
Wei Gao  1  2  3 ,  Jing Li  1  3 ,  Yue Zhang  1  3 ,  Haolin Yuan  1  3 ,  Kun Li  1  3 ,  Jin Zhang  1  3 ,  Lijun Han  4 ,  Zhijin Fan  1  3 ,  Lai Chen  5 ,  Liangfu Tang  1  3
Affiliations
  • 1. State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, PR China.
  • 2. State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, PR China.
  • 3. Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
  • 4. College of Science, China Agricultural University, Beijing 100193, PR China.
  • 5. College of Plant Protection, Hebei Agricultural University, Baoding 071000, PR China.
PMID: 39760922 DOI: 10.1021/acs.jafc.4c08092
Abstract

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 Rhizoctonia solani PK (RsPK) as a protein target and YZK-C22 as a ligand. Fungicidal screening indicated that 5b, 5g, 5h, 5j, 5l, 5p, 5q, and 5s exhibited equal or higher activity compared to YZK-C22 against Botrytis cinerea, Cercospora arachidicola, or R. solani. To our surprise, 5s showed comparable activity to flutriafol with an EC50 of 0.21 μg/mL vs 0.20 μg/mL, but over 14 times more active than the lead compound YZK-C22 against R. solani with its EC50 of 0.21 μg/mL vs 3.14 μg/mL (mole ratio over 17-fold). Compound 5s also displayed 2.30-fold better inhibition potency against RsPK compared with YZK-C22. Moreover, this higher potency of 5s 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 YZK-C22. The results in this study not only broadened the structural diversity of PK inhibitors but also supported 5s as a promising PK-based highly active fungicide lead compound, with stronger binding ability to RsPK than YZK-C22.

Keywords
2-thiazol-2-yl-1,3,4-oxadiazole; fungicidal activity; molecular docking; pyruvate kinase.
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