Discovery of Highly Efficient Novel Antifungal Lead Compounds Targeting Succinate Dehydrogenase: Pyrazole-4-carboxamide Derivatives with an N-Phenyl Substituted Amide Fragment

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(49), P. 19312 - 19323

Published: Nov. 29, 2023

Developing environmentally friendly fungicides is crucial to tackle the issue of rising pesticide resistance. In this study, a series novel pyrazole-4-carboxamide derivatives containing N-phenyl substituted amide fragments were designed and synthesized. The structures target compounds confirmed by 1H NMR, 13C HRMS, crystal structure most active compound N-(1-(4-(4-(tert-butyl)benzamido)phenyl)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide (U22) was further determined X-ray single-crystal diffraction. bioassay results indicated that 26 possessed good in vitro antifungal activity against Sclerotinia sclerotiorum with EC50 values for U12, U13, U15, U16, U18, U22, U23 being 4.17 ± 0.46, 8.04 0.71, 7.01 12.77 1.00, 8.11 0.70, 0.94 0.11, 9.48 0.83 μg·mL–1, respectively, which similar controls bixafen (6.70 0.47 μg·mL–1), fluxapyroxad (0.71 0.14 pydiflumetofen (0.06 0.01 μg·mL–1). Furthermore, vivo S. U12 (80.6%) U22 (89.9%) excellent preventative efficacy at 200 same as control (82.4%). Scanning electron microscopy transmission studies found could destroy hyphal morphology damage mitochondria, cell membranes, vacuoles. molecular docking succinate dehydrogenase (SDH) they interact well site SDH. This study validated our approach design strategy produce an enhanced biological compared parent structure.

Language: Английский

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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, Journal Year: 2023, Volume and Issue: 71(24), P. 9255 - 9265

Published: June 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.

Language: Английский

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Discovery of N-Phenylpropiolamide as a Novel Succinate Dehydrogenase Inhibitor Scaffold with Broad-Spectrum Antifungal Activity on Phytopathogenic Fungi

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(8), P. 3681 - 3693

Published: Feb. 15, 2023

Based on the structural features of both succinate dehydrogenase inhibitors (SDHIs) and targeted covalent inhibitors, a series N-phenylpropiolamides containing Michael acceptor moiety were designed to find new antifungal compounds. Nineteen compounds showed potent inhibition activity in vitro nine species plant pathogenic fungi. Compounds 9 13 higher most fungi than standard drug azoxystrobin. Compound could completely inhibit Physalospora piricola infection apples at 200 μg/mL concentration over 7 days high safety seed germination seedling growth plants ≤100 concentration. The action mechanism that is an SDH inhibitor with median inhibitory concentration, IC50, value 0.55 μg/mL, comparable positive boscalid. Molecular docking studies revealed can bind well ubiquinone-binding region by hydrogen bonds undergoes π–alkyl interaction π–cation interaction. At cellular level, 1 as parent compound destruct mycelial structure P. partly dissolve cell wall and/or membrane. Structure–activity relationship analysis acetenyl group should be determinant for activity, substitution pattern phenyl ring significantly impact activity. Thus, N-phenylpropiolamide emerged novel promising lead scaffold development SDHIs protection.

Language: Английский

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Discovery of Terpene-Derived Quaternary Ring Compounds Containing an Oxime Moiety as Potential Fungicides

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(7), P. 3164 - 3172

Published: Feb. 7, 2023

Terpene-derived quaternary ring compounds with an oxime moiety were designed and prepared to create fungicides from natural products. A preliminary assessment of their antifungal activity against seven common pathogenic fungi was conducted, the median effective concentration (EC50) values Rhizoctonia solani obtained. The effects compound 6a19 (3-bromothiophene-containing), which had outstanding EC50 value (1.62 μg/mL), on morphology, ultrastructure, reactive oxygen species production, mitochondrial membrane potential, nuclear defense-related respiration-related enzyme activities mycelia evaluated. test speculated obstruct bio-oxidative process, inhibiting mycelial growth. Compound exhibited a satisfactory in vivo control effect leaf sheath-infected rice plants. After treating plants 50, 100, 200 μg/mL 6a19, protective therapeutic efficacy 48.3 70.3%, 58.6 75.7%, 69.0 81.1%, respectively. Moreover, linear quantitative structure–activity relationship (R2 = 0.932, F 61.3, S2 0.020) established using density functional theory calculations. Four chemical descriptors that crucial analyzed: number occupied electronic levels atoms, minimum atomic orbital population, maximum net atom charge for H atom, charge. In overall consideration experimental results, it target satisfactorily inhibited R. by interfering biological oxidation pathways, provided insight into future intensive systematic action mechanism. This research is promising invention novel terpenes multiple potential targets ecological compatibility.

Language: Английский

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Design, bioactivity and mechanism of N′-phenyl pyridylcarbohydrazides with broad-spectrum antifungal activity

Molecular Diversity, Journal Year: 2024, Volume and Issue: unknown

Published: June 26, 2024

Language: 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, Journal Year: 2024, Volume and Issue: 72(12), P. 6691 - 6701

Published: March 18, 2024

To accelerate the development of novel fungicides, a variety

Language: Английский

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Recent Advances in Design and Development of Diazole and Diazine Based Fungicides (2014–2023)

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(28), P. 15427 - 15448

Published: July 5, 2024

With fungal diseases posing a major threat to agricultural production, the application of fungicides control related is often considered necessary ensure world's food supply. The search for new bioactive agents has long been priority in crop protection due continuous development resistance against currently used types active compounds. Heterocyclic compounds are an inseparable part core structures numerous lead compounds, these rings constitute pharmacophores significant number developed over past decade by agrochemists. Among heterocycles, nitrogen-based play essential role. To date, diazole (imidazole and pyrazole) diazine (pyrimidine, pyridazine, pyrazine) derivatives make up important series synthetic fungicides. In recent years, many reports have published on design, synthesis, study fungicidal activity scaffolds, but there was lack comprehensive classified review nitrogen-containing scaffolds. Regarding this issue, here we reviewed articles families. current review, molecules synthesized so far based size ring.

Language: Английский

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Design, Synthesis, and Study of the Dual Action Mode of Novel N-Thienyl-1,5-disubstituted-4-pyrazole Carboxamides against Nigrospora oryzae

Journal of Agricultural and Food Chemistry, Journal Year: 2023, Volume and Issue: 71(19), P. 7210 - 7220

Published: May 4, 2023

Due to the single target but extensive application of commercialized succinate dehydrogenase inhibitors (SDHIs), resistance problems have gradually become apparent in recent years. To solve this problem, a series novel N-thienyl-1,5-disubstituted-1H-4-pyrazole carboxamide derivatives were designed and synthesized work based on active skeleton 5-trifluoromethyl-4-pyrazole carboxamide. The bioassay results indicated that some compounds exhibited excellent vitro antifungal activities against eight phytopathogenic fungi tested. Among them, EC50 values T4, T6, T9 Nigrospora oryzae 5.8, 1.9, 5.5 mg/L, respectively. vivo protective curative 40 mg/L T6 rice infected with N. 81.5% 43.0%, Further studies revealed not only significantly inhibited growth mycelia also effectively hindered spore germination germ tube elongation. Morphological using scanning electron microscopy (SEM), fluorescence (FM), transmission (TEM) found could affect mycelium membrane integrity by increasing cell permeability causing peroxidation cellular lipids, these further verified measuring malondialdehyde (MDA) content. IC50 value (SDH) was 7.2 lower than SDHI penthiopyrad (3.4 mg/L). Further, ATP content detection after docking suggested potential SDHI. These demonstrated compound both inhibit activity SDH at same time via dual action mode, which is different from mode penthiopyrad. Thus, study provides new idea for strategy delay diversify structures SDHIs.

Language: 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, Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 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.

Language: 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, Journal Year: 2024, Volume and Issue: 72(17), P. 9599 - 9610

Published: April 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.

Language: Английский

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