BACKGROUND:Pesticides are an irreplaceable means of guaranteeing food security. The development of new types of highly efficient, low-toxicity and low-residue pesticides, together with the promotion of pesticide reduction and green developments are important directions of research. Based on this, novel cyanoacrylate derivatives bearing a phosphate or fluoro fragment were synthesized as potential myosin-5 inhibitors using an efficient screening method, namely a stepwise optimization strategy. RESULTS:A single crystal of compound D11 as a structural representative was scanned using an X-ray diffractometer to further determine its structure. The optimized compound D6 had an excellent half-maximal effective concentration (EC50; 0.40 μg mL-1) in vitro against Fusarium graminearum that was very close to that of the fungicide phenamacril (0.17 μg mL-1). In vivo tests on wheat leaves revealed that compound D6 had outstanding antifungal efficacy. The effect of treatment with optimized compound D6 (25 μg mL-1) on mycelium morphology was demonstrated in a scanning electron microscope experiment, and was consistent with the cell membrane permeability results. Comparisons of the molecular structure and density functional theory calculations revealed that compound D6 had similar thermodynamic and geometrical structure parameters to phenamacril. Furthermore, molecular docking verified that the binding mode between compound D6 and myosin-5 was consistent with phenamacril. The complexes 6UI4-D6 and 6UI4-phenamacril had similar trajectories and close values for total energy and hydrogen bonding. CONCLUSION:This research constructing novel cyanoacrylate derivatives bearing a phosphate or fluoro fragment as potential myosin-5 inhibitors provides a valuable antifungal lead for development of an efficient fungicide. © 2026 Society of Chemical Industry.

Succinate dehydrogenase (SDH), also termed complex II or succinate-ubiquinone oxidoreductase, is a crucial biological enzyme in the process of mitochondrial oxidative phosphorylation. Succinate dehydrogenase inhibitors (SDHIs) are a promising class of fungicides targeting the energy production pathway of pathogenic fungi. However, overuse has resulted in the emergence of resistance, underscoring the need for novel and effective SDHIs. This study utilized the Transformer model to generate a customized virtual library of potential SDHIs. These candidates were then meticulously screened based on expert knowledge and synthetic feasibility, ultimately yielding several pyrazole carboxamide derivatives as the promising leads. Subsequent synthesis, antifungal activity assessment, and structural optimization further refined these leads into potent SDHI candidates. This work represents the first application of a generative model to SDHI design, establishing a robust workflow encompassing virtual library generation, screening, activity evaluation, and structure optimization. This study paves the way for the rational design of future SDHIs, not only against fungi, but potentially other agricultural pathogens as well.

BACKGROUND:4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD), as a key enzyme for tyrosine decomposition, is a highly regarded herbicide target. In this work, a series of cyclohexenone derivatives containing a substituted pyrazole group were designed and synthesized by active fragment splicing method for screening new HPPD inhibitors. RESULTS:The bioassay results indicated that some target compounds exhibited noticeable inhibitory activity against Capsella bursa-pastoris (CB), Portulaca oleracea (PO), Echinochloa crus-galli (EC) and Setaria viridis (SV). As an outstanding representative, compound 8n showed excellent inhibitory activity against four tested weeds with the rates more than 90% at 225 active ingredient per hectare (a.i./ha) dosage, especially with a rate more than 90% against CB at 75 a.i./ha dosage, comparable to the control herbicide mesotrione. Compound 8n also demonstrated satisfactory safety for the crops wheat, maize, sorghum and rice. Furthermore, the molecular docking, molecular dynamics (MD) simulations and frontier molecular orbital analysis revealed that compound 8n had strong interaction with the target protein AtHPPD, which could tightly bind with amino acid residues in the active pocket to generate its herbicidal activity. CONCLUSION:This study suggested that compound 8n could be used as a valuable lead molecular structure for the design of novel HPPD inhibitors, while providing an important foundation for the development of new herbicides. © 2025 Society of Chemical Industry.

A systematic optimization strategy, as an effective screening approach for new antifungal compounds, was implemented to rationally construct novel naphthyl and phenyl maleimide derivatives. The structures of molecules A32 and B6 were further confirmed by single-crystal X-ray diffraction. The in vitro antifungal activity evaluation showed that the target compound A32 obtained by the structure optimization exhibited excellent inhibition (EC50 = 0.59 μg/mL) against Rhizoctonia solani, which was better than the control agent dimethachlone (1.21 μg/mL). Further evaluation by in vivo experiments on rice leaves and potted rice plants against R. solani at 200 μg/mL showed that A32 possessed an outstanding protective efficiency compared to dimethachlone. The mycelium morphology observation by SEM indicated that A32 (25 μg/mL) severely damaged the surface structure of the mycelium, which was in accordance with the increased result of the cell membrane permeability assay. MD simulations and molecular docking analysis revealed that compounds A1 and A32 have a similar binding mode in the active pocket of plasma membrane H+-ATPases (PMA1) as the reference fungicide fluoroimide. In particular, there were more hydrogen bonds in the protein complex of A32 than in the protein complexes of A1 and fluoroimide. This research on constructing novel naphthyl and phenyl maleimide derivatives by a systematic optimization strategy provides a practical way to find new antifungal leads, thereby developing novel fungicides.

To discover novel compounds with high inhibitory activity and broad-spectrum activity against phytopathogenic fungi, a series of 2-cyanoacrylate derivatives incorporating various types of arylamide moieties were designed and synthesized according to the active substructure splicing principle. The target compounds were structurally characterized by 1H NMR, 13C NMR, HRMS, and X-ray diffraction. Antifungal bioassay revealed that most compounds exhibited significant inhibitory activity against Fusarium graminearum (Fg). The introduction of arylamide groups significantly enhanced antifungal activity against other phytopathogenic fungi while maintaining an excellent inhibition rate against Fg compared to phenamacril. For example, the inhibitory activity of compound G22 against Botrytis cinerea (Bc) and the inhibitory activity of compound G26 against Alternaria solani (As) were significantly better than those of phenamacril. As the most prominent representative, compound G19 presented an EC50 value of 0.326 μg/mL against Fg. Its in vivo curative efficacy on inoculated wheat leaves at 200 μg/mL was comparable to that of the positive control phenamacril. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and fluorescence microscopy (FM) revealed that compound G19 severely damaged the surface integrity of mycelial cells and induced cytoplasmic leakage. Molecular docking and molecular dynamics (MD) simulation demonstrated that compound G19 could stably bind to the target protein Myosin-5 in a mode similar to that of phenamacril. This study provides a new idea for the development of novel 2-cyanoacrylate derivatives with antifungal activity.

Oxathiapiprolin (OXTP), a highly effective fungicide against oomycete pathogens, represents a novel class of fungicides. In this study, a series of novel OXTP derivatives were synthesized and evaluated for their antifungal activity. Several compounds exhibited potent inhibitory effects, with B12 and B13 demonstrating particularly strong efficacy against plant diseases caused by Phytophthora species. In addition, select derivatives showed significant in vivo activity against fungal pathogens, expanding their potential application beyond oomycetes. These compounds also displayed excellent photostability, suggesting their suitability for use under high UV exposure conditions. Mechanistic studies confirmed that oxysterol-binding protein 1 (ORP1) serves as the molecular target of OXTP derivatives in oomycetes, and that point mutations in ORP1 confer resistance. These findings highlight the potential of optimized OXTP derivatives as effective and sustainable fungicides for controlling both oomycete and fungal pathogens.

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 μg/mL that was superior to that of the agricultural fungicide boscalid (2.2 μg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 μM that was superior to that of boscalid (7.9 μM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.

In search of innovative antifungal solutions for the control of plant diseases, a series of cyanoacrylate derivatives containing naphthalene groups were designed and synthesized, and their inhibition activity against four plant pathogenic fungi was evaluated. The results of in vitro bioassay revealed that some target compounds possessed obvious antifungal effect against Fusarium graminearum. As the most prominent one, compound A2 showed a inhibition rate of 98.46 % at 10 µg/mL and an EC50 value of 0.26 µg/mL, which was close to that of the positive control phenamacril (with a inhibition rate of 100 % at 10 µg/mL and EC50 value of 0.14 µg/mL). The compound A2 also markedly inhibited the growth of F. graminearum inoculated on rice leaves at 200 μg/mL with the protective and curative efficiencies of 89.03 % and 90.91 %, respectively, which were close to that of the positive control phenamacril (with the protective and curative efficiencies of 94.54 % and 96.36 %, respectively). The observation under scanning electron microscopy and measurement of relative conductivity revealed that compound A2 caused the hyphal surface become shrunken and rough, and made the cell membrane permeability increased. Molecular docking and molecular dynamics simulation analyses showed that compound A2 interacted with the key residues in the active site of myosin-5 in a similar mode as phenamacril. These results suggested that target compounds were potential myosin-5 inhibitors, they could serve as the lead compounds for further structural optimization to develop new fungicides against F. graminearum.

To address the urgent need for new antifungal agents, a collection of novel pyrazole carboxamide derivatives incorporating a benzimidazole group were innovatively designed, synthesized, and evaluated for their efficacy against fungal pathogens. The bioassay results revealed that the EC50 values for the compounds A7 (3-(difluoromethyl)-1-methyl-N-(1-propyl-1H-benzo[d]imidazol-2-yl)-1H-pyrazole-4-carboxamide) and B11 (N-(1-(4-chlorobenzyl)-1H-benzo[d]imidazol-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide) against B. cinerea were notably low to 0.79 µg/mL and 0.56 µg/mL, respectively, demonstrating the potency comparable to that of the control fungicide boscalid, which has an EC50 value of 0.60 µg/mL. Noteworthy is the fact that in vivo tests demonstrated that A7 and B11 showed superior protective effects on tomatoes and strawberries against B. cinerea infection when juxtaposed with the commercial fungicide carbendazim. The examination through scanning electron microscopy revealed that B11 notably alters the morphology of the fungal mycelium, inducing shrinkage and roughening of the hyphal surfaces. To elucidate the mechanism of action, the study on molecular docking and molecular dynamics simulations was conducted, which suggested that B11 effectively interacts with crucial amino acid residues within the active site of succinate dehydrogenase (SDH). This investigation contributes a novel perspective for the structural design and diversification of potential SDH inhibitors, offering a promising avenue for the development of antifungal therapeutics.

BACKGROUND: The development of fungicides with low cross resistance, high efficacy and low resistance plays a central role in protecting crops, reducing yield losses, improving quality and maintaining global food security. Based on this important role, after a systematic optimization strategy, novel heterocyclic amide derivatives bearing diphenylmethyl fragment were screened, synthesized and verified with the spectrographic and x-ray diffraction analysis. RESULTS: In this study, the aforementioned optimization obtained compound B19 that was measured for antifungal activity against Rhizoctonia solani (median effective concentration, EC50 = 1.11 mu g mL(-1)). Meanwhile, the anti-R. solani protective effect (79.34%) of compound B19 was evaluated in vivo at 100 mu g mL(-1), which is comparable to that of the control agent fluxapyroxad (80.67%). Thence, morphological observations revealed that compound B19 induced mycelium disruption and shrinking, mitochondrial number reduction and apoptosis acceleration, consistent with the results of the mitochondrial membrane potential and cell membrane permeability. Further investigations found that the potential target enzyme of compound B19 was SDH, which exerted fluorescence quenching dynamic curves similar to that of the commercialized SDHI fluxapyroxad. Additionally, research by molecular docking and MD simulations demonstrated that compound B19 had a similar binding mode acting on the surrounding residues in the SDH active pocket to that offluxapyroxad. CONCLUSION: The above results demonstrated that heterocyclic amide derivatives containing a diphenylmethyl moiety are promising scaffolds for targeting SDH of fungi and provide valuable antifungal leads with the potential to develop new SDH inhibitors. (c) 2024 Society of Chemical Industry.

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27; HPPD) is one of the important target enzymes in the development of herbicides. To discover novel HPPD inhibitors with unique molecular, 39 cyclohexanedione derivations containing pyrazole and pyridine groups were designed and synthesized. The preliminary herbicidal activity test results showed that some compounds had obvious inhibitory effects on monocotyledon and dicotyledonous weeds. The herbicidal spectrums of the highly active compounds were further determined, and the compound G31 exhibited the best inhibitory rate over 90

Novel antifungal phenylethanol derivatives containing a trifluoromethyl pyrazole pharmacophore were designed and synthesized. The effects of compound 6i with strong anti-B. cinerea activity on cell membrane permeability and mycelial morphology were further investigated.

Inspired by the highly effective and broad-spectrum antifungal activity of ergosterol biosynthesis inhibitions, a series of novel 1,2,4-triazole derivatives containing oxime ether moiety were constructed for screening the bioactivity against phytopathogenic fungi. The (Z)- and (E)-isomers of target compounds were successfully separated and identified by the spectroscopy and single crystal X-ray diffraction analyses. The bioassay results showed that the (Z)-isomers of target compounds possessed higher antifungal activity than the (E)-isomers. Strikingly, the compound (Z)-5o exhibited excellent antifungal activity against Rhizoctonia solani with the EC50 value of 0.41 μg/mL in vitro and preventive effect of 94.58

Aiming to develop novel antifungal agents with a distinctive molecular scaffold targeting succinate dehydrogenase (SDH), 24 N'-phenyl-1H-pyrazole-4-sulfonohydrazide derivatives were first devised, synthesized, and verified by 1H NMR, 13C NMR, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction analysis. The bioassays revealed that the target compounds possessed highly efficient and broad-spectrum antifungal activities against four tested plant pathogenic fungi Rhizoctonia solani (R. solani), Botrytis cinerea, Fusarium graminearum, and Alternaria sonali. Strikingly, compound B6 was assessed as the selective inhibitor against R. solani, with an in vitro EC50 value (0.23 μg/mL) that was similar to that of thifluzamide (0.20 μg/mL). The in vivo preventative effect of compound B6 (75.76%) at 200 μg/mL against R. solani was roughly comparable to thifluzamide (84.31%) under the same conditions. The exploration of morphological observations indicated that compound B6 could strongly damage the mycelium morphology, obviously increase the permeability of the cell membrane, and dramatically increase the number of mitochondria. Compound B6 also significantly inhibited SDH enzyme activity with an IC50 value of 0.28 μg/mL, and its fluorescence quenching dynamic curves were similar to that of thifluzamide. Molecular docking and molecular dynamics simulations demonstrated that compound B6 could strongly interact with similar residues around the SDH active pocket as thifluzamide. The present study revealed that the novel N'-phenyl-1H-pyrazole pyrazole-4-sulfonohydrazide derivatives are worthy of being further investigated as the promising replacements of traditional carboxamide derivatives targeting SDH of fungi.

The ever-increasing resistance of Fusarium graminearum has emerged as a pressing agricultural issue that could be settled by developing novel fungicides owning inimitable action mechanisms. With the aim of discovering novel antifungal leads inhibiting F. graminearum, a tryptanthrin structure was dexterously optimized to generate 30 novel quinazolin-4(3H)-one derivatives. The aforementioned optimization generated the molecule C17 that owned exhilarating in vitro anti-F. graminearum effect (EC50 value = 0.76 μg/mL). Whereafter, the in vivo anti-F. graminearum preventative efficacy of the molecule C17 was measured to be 59.5% at 200 μg/mL, which was approximately comparable with that of carbendazim (64.9%). Furthermore, morphological observations indicated that the molecule C17 could cause the hypha to become slender and dense, distort the outline of cell walls, induce an increase in liposome numbers, and cause the reduction of mitochondria numbers. The above results have emerged as an obbligato complement for developing novel antifungal leads that could effectively control Fusarium head blight.

A series of pyrrolidine-2,4-dione derivatives incorporating a chainlike alkoxyalkyl moiety or substituted phenoxyethyl moiety were designed and synthesized based on natural tetramic acids. Some target compounds showed obvious herbicidal activities.

Developing novel fungicide candidates are intensively promoted by the rapid emergences of resistant fungi that outbreak on agricultural production. Aiming to discovery novel antifungal leads, a series of 1,3,4-oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment were constructed for evaluating their inhibition effects against phytopathogenic fungi in vitro and in vivo. Systematically structural optimizations generated the bioactive molecule I32 that was identified as a promising inhibitor against Rhizoctonia solani with the in vivo preventative effect of 58.63% at 200 μg/mL. The observations that were captured by scanning electron microscopy and transmission electron microscopy demonstrated that the bioactive molecule I32 could induce the sprawling growth of hyphae, the local shrinkage and rupture on hyphal surfaces, the extreme swelling of vacuoles, the striking distortions on cell walls, and the reduction of mitochondria numbers. The above results provided an indispensable complement for the discovery of antifungal lead bearing a quinazolin-4(3H)-one and 1,3,4-oxadiazole fragment.

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea. Strikingly, the in vitro EC50 values of constructed pyrazole-4-acetohydrazides 6w against R. solani, 6c against F. graminearum, and 6f against B. cinerea were, respectively, determined as 0.27, 1.94, and 1.93 μg/mL, which were obviously superior to that of boscalid against R. solani (0.94 μg/mL), fluopyram against F. graminearum (9.37 μg/mL), and B. cinerea (1.94 μg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative 6w as a potential SDHI was ascertained by the relative surveys on the in vivo anti-R. solani preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.

A series of novel triazole derivatives containing oxime ether and cyclopropyl moieties were designed and synthesized. Some compounds exhibited remarkable antifungal activities. The molecular docking of compound 5k with Fg CYP51 was investigated.

Main observation and conclusionTo screen novel antifungal agents targeting the succinate dehydrogenase (SDH), a series of pyrazole‐4‐carbohydrazides were rationally designed, synthesized, and characterized under the guidance of the structures of succinate dehydrogenase inhibitors (SDHIs). Bioassay resultsin vitroindicated that most of the target compounds exhibited excellent activity againstRhizoctonia solani(R. solani),Fusarium graminearum(F. graminearum),Botrytis cinerea(B. cinerea) andColletotrichum capsica(C. cinerea). Compounds 7d, 7l, 7t and 7x were identified as the most promoting candidates, and their anti‐F. graminearumEC50values were as low as 0.56, 0.47, 0.46 and 0.49 μg/mL, respectively, presenting the similar antifungal activity as that of the commonly used fungicide carbendazim (0.43 μg/mL). The 3D‐QSAR models were built for a systematic structure‐activity relationship profile to explore more potent pyrazole‐4‐carbohydrazides as novel fungicides. Molecular docking of 7d, 7l and 7r with SDH was performed to reveal the binding modes in active pocket and analyze the interactions between the molecules and the SDH protein.