Design, Synthesis, and Evaluation of Novel Isothiazole-Purines as a Pyruvate Kinase-Based Fungicidal Lead Compound

et al. 2022

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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.

Section: ■ Introductionmentioning

confidence: 99%

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

Dong

et al. 2022

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Chen

et al. 2022

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To discover novel target-based fungicidal candidates, a molecular design model was established with a threedimensional (3D) structure of Rhizoctonia solani pyruvate kinase (RsPK) simulated with the AlphaFold 2 and YZK-C22 as a fungicidal lead. A series of novel [1,2,4]triazolo [3,4-b][1,3,4]thiadiazole derivatives were rationally designed, synthesized, evaluated for their fungicidal performance, and validated for their mode of action. The in vitro bioassays with R. solani indicated that compounds 5g, 5o, and 5z with an EC 50 value ranging from 1.01 to 1.54 μg/mL displayed higher fungicidal activity than the positive control YZK-C22 with its EC 50 of 3.14 μg/mL. Especially, 5o exhibited high potency and a broad spectrum against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Physalospora piricola, R. solani, and Sclerotinia sclerotiorum with its EC 50 value falling between 1.54 and 13.10 μg/mL. Like all positive controls, 5g, 5o, and 5z showed excellent in vivo growth inhibition against Pseudoperonospora cubensis at 200 μg/mL. Even though the PK enzymatic inhibition assay showed that 5o was approximately 2.6 times less active than YZK-C22 (IC 50 : 29.14 vs 11.15 μg/mL, respectively), the similar fluorescence quenching patterns of RsPK by 5o and YZK-C22, and the docking results of interactions between RsPK and 5o or YZK-C22 implied that they might share the similar binding site in the RsPK active pocket. Our studies suggested that 5o could be used as a potent fungicidal lead for further optimization. The results of comparative molecular field analysis (CoMFA) provided a direction for further molecular design.

“…16−20 Based on homology modeling and computer-aided pesticide design techniques, our team successfully designed and synthesized a series of novel isothiazolopurine derivatives; we discovered a highly potent compound [i.e., 8-(3,4dichloroisothiazol-5-yl)-9-ethyl-N-(4-methoxybenzyl)-9Hpurin-6-amine] targeting PK. 21 Previous results described above indicated that PK can be an effective target for further novel fungicide development.…”

Section: ■ Introductionmentioning

confidence: 99%

“…PK is widely present in animals, plants, microorganisms, and cultured cells to catalyze the transformation of phosphoenolpyruvate (PEP) to pyruvate in the last step of glycolysis. It is an essential enzyme for adenosine triphosphate (ATP) production and cell metabolism regulation in all organisms. − Based on homology modeling and computer-aided pesticide design techniques, our team successfully designed and synthesized a series of novel isothiazolopurine derivatives; we discovered a highly potent compound [i.e., 8-(3,4-dichloroisothiazol-5-yl)-9-ethyl- N -(4-methoxybenzyl)-9 H -purin-6-amine] targeting PK . Previous results described above indicated that PK can be an effective target for further novel fungicide development.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Triazolothiadiazines as Fungicidal Leads Targeting Pyruvate Kinase

Zhang

et al. 2022

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Pyruvate kinase (PK) was discovered as a potent new target for novel fungicide development. A series of novel triazolothiadiazine derivatives were rationally designed and synthesized by a ring expansion strategy and computer-aided pesticide design using the 3D structure of Rhizoctonia solani PK (RsPK) obtained by homology modeling as a receptor and our previously discovered lead YZK-C22 as a ligand. The in vitro bioassay results indicated that compounds 4g, 6h, 6m, 6n, 6o, and 6p exhibited good activity against R. solani with the EC 50 values falling between 10.99 and 72.76 μM. Especially, 6m showed similar potency to YZK-C22 (10.99 vs 11.97 μM of the EC 50 value, respectively). The in vivo bioassay results suggested that 6m against R. solani at a concentration of 200 μg/mL displayed a numerically higher inhibition than YZK-C22 (70 vs 60%, respectively). A field experiment validated that 6m at an application rate of 120 g ai/ha showed comparable efficacy against R. solani to thifluzamide at an application rate of 80 g ai/ha (77.80 vs 84.5%, respectively). Enzymatic inhibition suggested that the potency of 6m was about twofold lower than that of YZK-C22 (67.30 vs 32.64 μM of IC 50 , respectively). Fluorescence quenching studies validated that RsPK was quenched by both 6m and YZK-C22, implying that they both might act at the same target site of PK. A possible binding conformation of 6m in the RsPK active site was depicted by molecular docking. Our studies suggest that 6m could be a fungicidal lead targeting PK.