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 μg/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 μg/mL). Compounds 11g and 11i displayed promising in vivo fungicidal activity
against B. cinerea with 80 and 70%
inhibition at a concentration of 200 μg/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 μmol/L, comparable
to the positive control YZK-C22 (32.4 μmol/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.