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, Journal Year: 2025, Volume and Issue: 73(9), P. 5054 - 5066

Published: Feb. 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.

Language: Английский

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Discovery of novel butyrylcholinesterase inhibitors for treating Alzheimer’s disease

Acta Pharmaceutica Sinica B, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Discovery of α-Methylene-γ-Butyrolactone Derivatives with Hydrazide Moieties as Novel Fungicidal Agents

Journal of Agricultural and Food Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

To discover novel fungicides with unique structures, a series of α-methylene-γ-butyrolactone derivatives were designed and synthesized by incorporating flexible amide or hydrazide chain through active substructure splicing linker modification strategies. Bioassay assessments demonstrated that certain hydrazide-containing compounds have potent fungicidal efficacy. Notably, compound 7IIj exhibited broad-spectrum antifungal activity, EC50 values as low 0.179, 0.301, 0.647, 0.549, 0.789 mg/L against Rhizoctonia solani, Physalospora piricola, Botrytis cinerea, Gaeumanomyces graminis, Valsa mali, respectively. In vivo experiments confirmed the effective activity 7IIj, showing an inhibitory rate 69.7% V. mali on apple twigs at 200 mg/L. Additionally, concentration 100 mg/L, significant protective curative effects R. solani rice plants. Research mechanism action revealed could disrupt hyphal morphology, induce reactive oxygen species (ROS) accumulation, affect mitochondrial membrane potential (MMP), interfere respiratory metabolism binding to complex II. Molecular docking analysis showed interactions TRP 173, TYR 58, ARG 43 in succinate dehydrogenase (SDH) site, resembling mode fluxapyroxad. These findings suggest holds SDH inhibitor for agricultural disease control.

Language: Английский

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Discovery of New Benzohydrazide Derivatives Containing 4-Aminoquinazoline as Effective Agricultural Fungicides, the Related Mechanistic Study, and Safety Assessment

Journal of Agricultural and Food Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

A total of 38 new benzohydrazide derivatives bearing the 4-aminoquinazoline moiety were designed and synthesized based on active subunit combination approach tested in detail for their inhibition activities against eight agricultural phytopathogenic fungi. The bioassay results indicated that many compounds exhibited extraordinary fungicidal vitro For example, A5, A6, A11, A17 had EC50 (half-maximal effective concentration) values 0.66, 0.71, 0.40, 0.42 μg/mL Colletotrichum gloeosporioides, respectively, comparable to boscalid (0.36 μg/mL) much superior carbendazim (6.96 μg/mL). Of particular importance was compound A6 with a 3,4-difluorophenyl group found possess good broad-spectrum antifungal effects, ranging from 0.63 3.82 In vivo assays also revealed curative protective efficacies 72.6% 78.9% at 200 Rhizoctonia solani-caused rice sheath blight, higher than those (70.7 65.2%, respectively). Moreover, mechanism-of-action studies disrupted cell membrane integrity R. solani, as proved by relative conductivity measurements, leakage cellular contents, fluorescence microscopy, scanning electron microscopy observations. Significantly, this an succinate dehydrogenase (SDH) solani inhibitory concentration/IC50 = 11.02 μM), slightly weaker SDH inhibitor (5.17 μM). Further molecular docking analysis could form strong interactions key residues enzyme via hydrogen bond, electrostatic, π-cation interactions, holding promise acting fungicide leads targeting SDH. Finally, safety assessments safe honeybees.

Language: Английский

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Catalyst-free synthesis of 1,2,3-triazole-N-oxide derivatives using tert-butyl nitrite: a novel strategy and synthetic applications

RSC Advances, Journal Year: 2025, Volume and Issue: 15(14), P. 10574 - 10581

Published: Jan. 1, 2025

t BuONO-mediated synthesis of triazole-N-oxide using BuONO as an NO source. EtOH/H 2 O serves a green solvent and additive. Triazole N-oxide is used in various synthetic transformations.

Language: Английский

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Design, synthesis, evaluation, pharmacophore modeling, and 3D‐QSAR of lappaconitine analogs as potential analgesic agents

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Abstract Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate active fragments were innovatively introduced at multiple sites on benzene ring lappaconitine. A total 53 lappaconitine analogs synthesized and evaluated. Compounds 5a , 5c 5e 6 15j addressed narrow therapeutic window enhancing drug safety. Notably, exhibited significantly enhanced activity, compounds having ED 50 values 1.2 1.6 mg/kg, respectively, indicating higher potency than (3.5 mg/kg). metabolic analysis compound was conducted in mice, revealing its primary processes metabolites, providing preliminary exploration druggability. Given targets mechanism remains inconclusive. study, first time, analyzed pharmacological activity characteristics using pharmacophore model established three‐dimensional quantitative structure–activity relationship (3D‐QSAR) elucidate between structures their activities. These findings provide valuable guidance future modification optimization drugs.

Language: Английский

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Targeting Cancer with Novel Tetra-1,2,3-Triazole hybrids: Synthesis, Biological Evaluation, and Molecular Dynamics

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: unknown, P. 140245 - 140245

Published: Oct. 1, 2024

Language: Английский

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l-Isoleucine-Derived Amide-hydrazide Compounds Evaluated as a Novel Potential Agricultural Fungicide

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Building upon previous structure–activity relationships about the fungicidal amide and hydrazide lead structures, 24 novel amide-hydrazide compounds were designed synthesized with L-isoleucine as initial skeleton to explore impact of substituents in bridge on activity. Among these compounds, A5 exhibited excellent broad spectrum inhibitory activity, along satisfactory vivo protective efficiency against R. solani at concentrations 200 50 μg·mL–1. Scanning electron microscopy (SEM) transmission (TEM) observations revealed that compound induced significant morphological changes mycelium coupled vacuole rupture cytoplasmic inhomogeneity cellular structures. Transcriptomic metabolomic analyses indicated that, following treatment, differentially expressed genes metabolites significantly enriched carbohydrate metabolism-related pathways well lipid metabolism-associated pathways, including glycerophospholipid metabolism, steroid biosynthesis, arachidonic acid sphingolipid metabolism. Additionally, demonstrated low toxicity zebrafish, survival rates 100% 60% 1 10 μg·mL–1, respectively, over a period 7 days. The above results provide theoretical guidance for development green candidates.

Language: Английский

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Design, Synthesis, and Herbicidal Activity Study of Novel Pyrazole-Carboxamides as Potential Transketolase Inhibitors

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 21, 2024

Transketolase (TKL; EC 2.2.1.1) has been identified as a potential new herbicide target. In order to discover highly herbicidal active compounds targeting TKL and improve their structural diversity for lead compounds, series of pyrazole-carboxamides 7a–7v were designed synthesized through optimization pyrazole-containing phenoxy amide compound 4u. Among the 7r possessed excellent efficacy against Digitaria sanguinalis (Ds) Amaranthus retroflexus (Ar) by small cup method (the inhibition about 95%, 100 mg/L) foliar spray over 90%, 150 g ai/ha) in greenhouse, which superior that positive control nicosulfuron. More significantly, displayed good crop selectivity toward both maize wheat even at 375 ai/ha. The studies on mode action (MOA) high including enzyme activity, fluorescent quenching experiments, molecular docking analysis between Setaria viridis (Sv)TKL ligand, suggested acts typical inhibitor, benzothiazole ring is an important motif SvTKL activity. Above all, could be candidate development herbicides with MOA weed field.

Language: Английский

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