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

Abstract

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 EC 50 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 ,3,4]-thiadiazole] (with an EC 50 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 IC 50 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.

CoMFA Directed Molecular Design for Significantly Improving Fungicidal Activity of Novel [1,2,4]-Triazolo-[3,4-b][1,3,4]-thiadizoles

“…Natural products have many favorable properties such as ecological compatibility, diversity of structures, unique mode of action, good biological performance, and low risk of cross resistance. − Bioactive natural products and their metabolites can be ideal lead compounds for structure optimization. Typical agrochemicals from natural products include derivatives of strobilurins, coumarins, psoralen, pyrethrin, neopeltolide, nicotine, luotonin A, and rotenone − The principle of IDM is to fully consider cost of raw materials and intermediates, sustainability, facile industrialization, and freedom to operate in order to create novel bioactive molecules. Several rounds of “design–synthesis–test–analysis” are usually needed to reach targets with novel structures and reasonable biological performance. ,− Commercial pesticides such as coumoxystrobin, pyraoxystrobin, pyrimidifen, diflumetorim, and flufenerim are examples from IDM strategy. , PFVS is realized through biophysical screening via analyzing interactions between a target protein and its ligand .…”

Design, synthesis and antifungal evaluation of phenylthiazole‐1,3,4‐oxadiazole thione (ketone) derivatives inspired by natural thiasporine A

“…At present, chemical control is still the main method for controlling crop fungal diseases. However, owing to the constant spraying of traditional fungicides, pesticide residues, and the increase in fungal resistance to pesticides, new green, high‐efficiency and low‐toxicity fungicides are urgently needed for the control of these crop pathogenic fungi 5,6 …”

“…However, owing to the constant spraying of traditional fungicides, pesticide residues, and the increase in fungal resistance to pesticides, new green, high-efficiency and low-toxicity fungicides are urgently needed for the control of these crop pathogenic fungi. 5,6 Natural products have high chemical structural diversity, a wide range of biological activities, and are easily degraded by the environment. [7][8][9] Therefore, structural modification or derivation of reported active natural product structures has become an effective way to develop new fungicides or find lead structures.…”

Novel [1,2,4]-Triazolo[3,4-b]-[1,3,4]thiadizoles as Potent Pyruvate Kinase Inhibitors for Fungal Control

“…A fungicidal lead [3-(4-methyl-1,2,3-thiadiazol-5-yl)-6-(trichloromethyl)-[1,2,4]-triazolo­[3,4- b ]-[1,3,4]­thiadiazole] ( YZK-C22 ) targeting pyruvate kinase (PK) was discovered in our previous study using drug affinity reaction target stability (DARTS) against Saccharomyces cerevisiae, and its mode of action was further validated by the corresponding enzymatic studies. , Afterward, its mode of action was further validated in the Botrytis cinerea system . In addition, a few chemical scaffolds such as isothiazopurines, triazolothiadiazines, and psoralen-based 1,3,4-oxadiazoles were successfully discovered as PK inhibitors by computer-aided molecular design technology. − These findings expanded the structural diversity of PK inhibitors and laid a foundation for further structural optimization of PK inhibitors.…”