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

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 .