Design, Synthesis, and Biological Evaluation of Novel Psoralen-Based 1,3,4-Oxadiazoles as Potent Fungicide Candidates Targeting Pyruvate Kinase

Pyruvate kinase (PK) has been considered as a promising fungicide target discovered in our previous studies. Natural compounds are important sources for discovery and development of new pesticides. To continue our ongoing studies on the discovery of novel PK-targeted fungicides, a series of novel psoralen derivatives including a 1,3,4-oxadiazole moiety were designed by a computer-aided pesticide molecular design method, synthesized, and evaluated for their fungicidal activity. The bioassay results indicated that compounds 11d, 11e, 11g, 11i, and 12a showed excellent in vitro fungicidal activity against Botrytis cinerea with EC50 values of 4.8, 3.3, 6.3, 5.4, and 3.9 mu g/mL, respectively. They were more active than the corresponding positive control YZK-C22 [3-(4-methyl-1,2,3-thiadiazol-5-yl)-6-(trichloromethyl)-[1,2,4]-triazolo-[3,4-b] [1,3,4]-thiadiazole] (with an EC50 value of 13.4 mu g/mL). Compounds 11g and 11i displayed promising in vivo fungicidal activity against B. cincrea with 80 and 70% inhibition at a concentration of 200 mu g/mL, respectively. They possessed much higher fungicidal activity than the positive control psoralen and comparable activity with the positive control pyrisoxazole. Enzymatic assays indicated that 11i showed good BcPK inhibition with an IC50 value of 39.6 mu mol/L, comparable to the positive control YZK-C22 (32.4 mu mol/L). Molecular docking provided a possible binding mode of 11i in the BcPK active site. Our studies suggested that the psoralen-based 1,3,4-oxadiazole 11i could be used as a new fungicidal lead targeting PK for further structural optimization.

Automated summary

In this study, a series of psoralen-based 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for their fungicidal activity. The results showed that compounds 11d, 11e, 11g, 11i, and 12a exhibited excellent in vitro fungicidal activity against Botrytis cinerea. Compounds 11g and 11i also demonstrated promising in vivo fungicidal activity. Enzymatic assays revealed that compound 11i had good BcPK inhibition, suggesting its potential as a new lead compound targeting PK. Molecular docking provided insights into the binding mode of compound 11i in the BcPK active site. These findings contribute to the further structural optimization of fungicides targeting PK.