Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors

Journal of Agricultural and Food Chemistry, Год журнала: 2023, Номер 71(24), С. 9255 - 9265

Опубликована: Июнь 7, 2023

A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis structure commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping evaluated for their antifungal activities against five fungi. The bioassay results showed that most target compounds exhibited excellent in vitro activity Rhizoctonia solani some exerted remarkable Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, Alternaria alternate. Particularly, 7d 12b displayed outstanding R. solani, with EC50 value 0.046 μg/mL, far superior to boscalid (EC50 = 0.741 μg/mL) fluxapyroxad 0.103 μg/mL). Meanwhile, compound also presented a broader fungicidal spectrum than other compounds. Moreover, vivo anti-R. could significantly inhibit growth rice leaves protective curative efficacies. In addition, (SDH) enzymatic inhibition assay generated significant SDH inhibition, IC50 3.293 μM, which was about 2 times better (IC50 7.507 μM) 5.991 μM). Furthermore, scanning electron microscopy (SEM) analysis indicated destroyed typical morphology hyphae. molecular docking study revealed embed into binding pocket form hydrogen bond interactions TRP173 TRY58 at site SDH, line fluxapyroxad, indicating they had similar mechanism action. These demonstrated be promising candidates SDHI fungicides, deserved further investigation.

Язык: Английский

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Design, Synthesis, and Fungicidal Activities of Novel N-(Pyrazol-5-yl)benzamide Derivatives Containing a Diphenylamine Moiety

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(12), С. 6691 - 6701

Опубликована: Март 18, 2024

To accelerate the development of novel fungicides, a variety

Язык: Английский

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Discovery of Pyrazole-5-yl-amide Derivatives Containing Cinnamamide Structural Fragments as Potential Succinate Dehydrogenase Inhibitors

Journal of Agricultural and Food Chemistry, Год журнала: 2023, Номер unknown

Опубликована: Ноя. 3, 2023

To promote the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we introduced cinnamamide and nicotinamide structural fragments into structure pyrazol-5-yl-amide by carbon chain extension scaffold hopping, respectively, synthesized a series derivatives. The results biological activity assays indicated that most target compounds exhibited varying degrees inhibitory against tested fungi. Notably, G22, G28, G34, G38, G39 excellent in vitro antifungal activities Valsa mali with EC50 values 0.48, 0.86, 0.57, 0.73, 0.87 mg/L, this result was significantly more potent than boscalid (EC50 = 2.80 mg/L) closer to specialty control drug tebuconazole 0.30 mg/L). Compounds G22 G34 also vivo protective curative effects V. at 40 mg/L. SEM TEM observations may affect normal mycelial morphology as well cellular ultrastructure. Molecular docking analysis possessed similar binding mode SDH, detailed SDH inhibition validated feasibility designed potential inhibitors. G3 were selected for theoretical calculations, terminal carboxylic acid group be key region influencing activity. Furthermore, toxicity tests on Apis mellifera l. revealed low A. populations. above demonstrated these pyrazole-5-yl-amide derivatives are promising low-risk drug-resistance SDHI fungicides.

Язык: Английский

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Novel Pyrazole-4-Carboxamide Derivatives Containing Oxime Ether Group as Potential SDHIs to Control Rhizoctonia solani

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(17), С. 9599 - 9610

Опубликована: Апрель 22, 2024

In the search for novel succinate dehydrogenase inhibitor (SDHI) fungicides to control Rhizoctonia solani, thirty-five pyrazole-4-carboxamides bearing either an oxime ether or ester group were designed and prepared based on strategy of molecular hybridization, their antifungal activities against five plant pathogenic fungi also investigated. The results indicated that majority compounds containing demonstrated outstanding in vitro activity R. some displayed pronounced Sclerotinia sclerotiorum Botrytis cinerea. Particularly, compound 5e exhibited most promising solani with EC50 value 0.039 μg/mL, which was about 20-fold better than boscalid (EC50 = 0.799 μg/mL) 4-fold more potent fluxapyroxad 0.131 μg/mL). Moreover, detached leaf assay showed could suppress growth rice leaves significant protective efficacies (86.8%) at 100 superior (68.1%) (80.6%), indicating application prospects. addition, (SDH) enzymatic inhibition revealed generated remarkable SDH (IC50 2.04 μM), obviously those 7.92 μM) 6.15 μM). Furthermore, SEM analysis caused a disruption characteristic structure morphology hyphae, resulting damage. docking fit into identical binding pocket through hydrogen bond interactions as well fluxapyroxad, they had similar mechanism. density functional theory electrostatic potential calculations provided useful information regarding electron distribution transfer, contributed understanding structural features mechanism lead compound. These findings suggested be candidate SDHI warranting further investigation.

Язык: Английский

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Design, synthesis, antifungal activity and molecular docking of novel pyrazole‐4‐carboxamides containing tertiary alcohol and difluoromethyl moiety as potential succinate dehydrogenase inhibitors

Pest Management Science, Год журнала: 2023, Номер 80(4), С. 2032 - 2041

Опубликована: Дек. 18, 2023

Abstract BACKGROUND Resistance problems with the long‐term and frequent use of existing fungicides, lack structure diversity traditional pyrazole‐4‐carboxamide succinate dehydrogenase inhibitors, it is highly required to design develop new fungicides address resistance issue. RESULTS Different from previous inhibitors by breaking norm difluoromethyl at C‐3 position pyrazole introducing a tertiary alcohol group position, 27 novel derivatives were designed, synthesized characterized proton ( 1 H) nuclear magnetic resonance (NMR), carbon‐13 13 C) NMR, fluorine‐19 19 F) NMR high‐resolution electrospray ionization mass spectrometry (HR‐ESI‐MS). The crystal structures compounds A14 C5 analyzed single X‐ray diffraction. Their in vitro antifungal activities evaluated against phytopathogen Fusarium graminearum , Botrytis cinerea Phytophthora capsica Sclerotinia sclerotiorum Thanatephorus cucumeris . results displayed that most them exhibited significant S 50 mg/L, half maximal effective concentration (EC ) data A8 3.96 2.52 respectively. vivo Pseudoperonospora cubensis Puccinia sorghi Schw, Colletotrichum gloeosporioides F Erysiphe graminis control efficacies A6, B3, C3, C6 E reached 100% 400 mg/L. molecular docking showed binding mode target containing alcohols similar fluxapyroxad dehydrogenase. In addition, involved formation hydrogen bonds. CONCLUSION excellent inhibitory reported for first time, they could be used as potential lead compounds. © 2023 Society Chemical Industry.

Язык: Английский

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Design and development of pyrazol‐5‐ylbenzamide derivatives containing chiral oxazoline moiety as fungicides based on molecular docking

Pest Management Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Development of novel chiral antifungal agents for effective control plant pathogens is urgently needed. In this study, a series pyrazol-5-yl-benzamide derivatives containing oxazoline moiety were rationally designed and developed based on molecular docking. The in vitro assay results indicated that compounds (rac)-4h (R1 = Et), (S)-4 h S-Et) (R)-4 R-Et) exhibited remarkable activities against Valsa mali with median concentration (EC50) values 0.24, 0.06 1.08 mg/L, respectively. Preliminary structure-activity relationships (SARs) revealed the modification substituent group at significantly affected target compounds. Furthermore, (S)-4h (87.5%) (R)-4h (84.3%) vivo protective comparable to tebuconazole V. mali. Subsequent docking analysis, succinate dehydrogenase (SDH) enzyme inhibition assays dynamic (MD) simulations verified potential class could be SDH helped explain large difference (R)-4h. Confocal laser scanning microscopy (CLSM) electron (SEM) observations confirmed these two severely disrupted mycelial morphology Theoretical calculation studies provided some insight into subsequent such derivatives. Resistance frequency showed treatments less likely produce resistant fungal strains than tebuconazole. Meanwhile, no apparent toxicity Apis mellifera L. Therefore, are candidates development fungicides crop protection. © 2025 Society Chemical Industry.

Язык: Английский

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Design, synthesis, crystal structure, fungicidal activity, and mechanism of action of novel thiazole-based hydrazide derivatives containing the 4-aminoquinazoline moiety

Bioorganic Chemistry, Год журнала: 2025, Номер 156, С. 108237 - 108237

Опубликована: Фев. 2, 2025

Язык: Английский

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Asymmetric Synthesis and Bioactivity Evaluation of Chiral Oxazoline Skeleton Molecules

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

The utilization of novel organic synthesis methods is increasingly critical in the development innovative agrochemicals. In this study, we designed and synthesized a series chiral oxazoline derivatives using one-pot method. This method involved first catalyzing asymmetric aldol addition reaction oxazolinyl esters with paraformaldehyde, followed by esterification various pharmacophore-containing carboxylic acids. Unexpectedly, many target compounds exhibited promising antifungal antioomycete activities, their absolute configurations showing pronounced enantioselective activities. Notably, compound (R)-5c demonstrated significant biological activities against Valsa mali Phytophthora capsica (EC50 = 1.023 mg/L EC50 0.149 mg/L, respectively), which were markedly superior to its enantiomer (S)-5c 9.565 0.924 respectively). vivo experiments confirmed that both curative protective effects V. P. capsici. CLSM SEM analyses further indicated 5c had distinct physiological on capsici hyphae. Moreover, acute toxicity tests zebrafish (Danio rerio) revealed significantly lower compared control drugs tebuconazole dimethomorph. Consequently, study provides valuable insights for analogues as potential

Язык: Английский

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Discovery of Novel Quinazolinone-2-carbohydrazide Derivatives as Effective Succinate Dehydrogenase Inhibitors and Biosafety Assessment on Rice and Zebrafish

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер 73(9), С. 5054 - 5066

Опубликована: Фев. 18, 2025

To develop potent and safe antifungal agents in agriculture, a total of 48 novel quinazolinone-2-carbohydrazide derivatives were designed synthesized based on the pharmacophore hybridization method. The bioassay results demonstrated that many compounds exhibited powerful broad-spectrum inhibition activities vitro against tested fungi. For instance, E23 F23 possessed EC50 (half-maximal effective concentration) values 0.41 0.47 μg/mL Rhizoctonia solani, comparable to commercial fungicide Boscalid (EC50 = 0.49 μg/mL). Additionally, compound also pronounced effects Verticillium dahliae, Alternaria Colletotrichum gloeosporioides with 0.27, 1.15, 0.27 μg/mL, respectively. In vivo assays rice plants revealed this at 200 nearly equipotent curative protective R. as compared positive controls Carbendazim. Moreover, had an obvious activity fungal succinate dehydrogenase (SDH) from solani half-maximal concentration (IC50) 11.76 μM, interactions between SDH enzyme further confirmed by molecular docking studies. Furthermore, presence triggered morphological changes mycelia increased conductivity permeability cell membranes. Interestingly, built three-dimensional quantitative structure-activity relationship (3D-QSAR) models showed electrostatic effect played more important role maintaining anti-R. target than other effects. Finally, biosafety assessment its safety toward zebrafish.

Язык: Английский

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Oxazole and Isoxazole-containing Pharmaceuticals: Targets, Pharmacological Activities, and Their SAR Studies

RSC Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Oxazole, a five-membered aromatic heterocycle featuring nitrogen and an oxygen atom separated by carbon atom, its isomer isoxazole, with directly attached atoms, have been pivotal in medicinal chemistry. Over the past few decades, U.S. Food Drug Administration (FDA) has approved more than 20 drugs containing these nuclei for various clinical conditions, including Tafamidis Oxaprozin. Due to their unique physicochemical properties, often exhibit superior pharmacokinetic profiles pharmacological effects compared those similar heterocycles. This review provides comprehensive overview of all FDA-approved oxazole isoxazole nuclei, focusing on activities structure-activity relationships.

Язык: Английский

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