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.
To search a novel lead structure for antiphytopathogenic fungus agent, a series of novel psoralen derivatives possessing sulfonohydrazide or acylthiourea structure were designed and synthesized, and their fungicidal activity against seven phytopathogens was evaluated. Their structures were confirmed by melting points, 1 H NMR, 13 C NMR and HRMS, and the typical crystal structure was determined by X-ray diffraction for validation. Preliminary fungicidal activity showed that some of the title compounds exhibited certain-to-high fungicidal activity. Compound I-13 exhibited good fungicidal activity against Botrytis cinerea , Cercospora arachidicola and Physalospora piricola with EC 50 values of 12.49, 13.22 and 12.12 μg/mL, respectively. Compounds II-9 and II-15 showed over 90% inhibition against B. cinerea at 50 μg/mL in vitro. In particular, II-9 exhibited significant higher fungicidal activity with a lower EC 50 value of 9.09 μg/mL than the positive control YZK-C22 (13.41 μg/mL). Our studies found that sulfonohydrazide or acylthiourea-containing psoralen derivatives were promising fungicide leads deserve for further study. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10402-y.
The development of new fungicides is vital for safeguarding crops and ensuring sustainable agriculture. Building on our previous finding that 4-(3,4-dichloroisothiazole)-7-hydroxy coumarins can be used as fungicidal leads, 44 novel coumarin ester derivatives were designed and synthesized to evaluate whether esterification could enhance their fungicidal activity. In vitro fungicidal bioassays indicated that compound 2ai displayed good activity against Alternaria solani, Botrytis cinereal, Cercospora arachidicola, Physalospora piricola and Sclerotinia sclerotiorum, with an EC50 value ranging from 2.90 to 5.56 μg/mL, comparable to the lead compound 1a, with its EC50 value ranging from 1.92 to 9.37 μg/mL. In vivo bioassays demonstrated that compounds 1a, 2ar and 2bg showed comparable, excellent efficacy against Pseudoperonospora cubensis at a dose of 25 µg/mL. Our research shows that the esterification of 4-(3,4-dichloroisothiazole) 7-hydroxycoumarins results in a fungicidal activity equivalent to that of its lead compounds. Furthermore, our density functional theory (DFT) calculations and 3D-QSAR modeling provide a rational explanation of the structure–activity relationship and offer valuable insights to guide further molecular design.
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