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Azo-incorporating was reported to be an effective strategy for increasing SDH inhibitory activity but for poor in vivo control effects. Herein, the azo-incorporated compounds were structurally optimized to retain a preferential conformation by replacing the azo bond with their bioisosteres. Interestingly, the 1,2,4-oxadiazole compound D2 displayed a broad fungicidal spectrum as well as fluxapyroxad. More excitedly, compound D2 showed excellent antifungal activities against rice sheath blight disease both in vitro (EC 50 = 0.001 μg/mL) and in vivo (EC 50 = 1.08 μg/mL, EC 95 = 4.67 μg/mL). In addition, an extra π-π interaction was found between the 1,2,4-oxadiazole ring of compound D2 and the phenyl ring of residue D_Y586, which might interpret the enhanced potency of compound D2 against Rhizoctonia solani . Further structural optimizations of the 1,2,4-oxadiazole compounds gave several analogues that made a breakthrough in controlling rice blast disease. These 1,2,4-oxadiazole compounds, derived from azobenzene derivatives, could be antifungal leads especially against R. solani and Magnaporthe grisea , exemplifying an interesting mode of pesticide discovery and providing theoretical guidance for innovation of the SDHI fungicide.

Background: Utilizing fungicides to protect crops from diseases is an effective method, and novel eco-friendly plant-derived fungicides with high efficiency and low toxicity are urgent requirements for sustainable crop protection., Result: Two series of rosin-based fungicides (totally 35) were designed and synthesized. In vitro fungicidal activity revealed that Compound 6a (Co. 6a) effectively inhibited the growth of Valsa mali [median effective concentration (EC 50 ) = 0.627 μg mL -1 ], and in vivo fungicidal activity suggested a significant protective efficacy of Co. 6a in protecting both apple branches (35.12% to 75.20%) and apples (75.86% to 90.82%). Quantum chemical calculations (via density functional theory) results indicated that the primary active site of Co. 6a lies in its amide structure. Mycelial morphology and physiology were investigated to elucidate the mode-of-action of Co. 6a, and suggested that Co. 6a produced significant cell membrane damage, accelerated electrolyte leakage, decreased succinate dehydrogenase (SDH) protein activity, and impaired physiological and biochemical functions, culminating in mycelial mortality. Molecular docking analysis revealed a robust binding energy (ΔE = -7.29 kcal mol -1 ) between Co. 6a and SDH. Subsequently, biosafety evaluations confirmed the environmentally-friendly nature of Co. 6a via the zebrafish model, yet toxicological results indicated that Co. 6a at median lethal concentration [LC 50(96) ] damaged the gills, liver and intestines of zebrafish., Conclusion: The above research offers a theoretical foundation for exploiting eco-friendly rosin-based fungicidal candidates in sustainable crop protection. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: The natural product paeonol is a rich and sustainable natural bioresource, and its derivatives have various unique biological efficacy. As is well known, Schiff bases are a class of organic compounds with a wide range of biological activities, including anti-fungal, insecticidal, anti-viral, and nematicidal., Results: To discover biorational natural product-based pesticides, nine intermediates (2-10), 12 sulfonylhydrazones (11a-11c, 12a-12c, 13a-13c, and 14a-14c) and 20 benzylidene hydrazones (18a-18r, 19a, and 20a) were synthesized by structural modification of paeonol, and their structures were characterized by proton nuclear magnetic resonance ( 1 H NMR), carbon-13 ( 13 C) NMR, and high-resolution mass spectrometry (HRMS). The stereochemical configurations of compounds 14a, 18d, and 18r were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete, anti-fungal, and nematicidal agents against three serious agricultural pests, Phytophthora capsici, Fusarium graminearum, and Heterodera glycines were evaluated. Among all tested compounds: (i) compound 7 exhibited promising anti-oomycete against Phytophthora capsici, with a half maximal effective concentration (EC 50 ) value of 15.81 mg L -1 ; (ii) compounds 2, 7, 10, and 19a displayed promising anti-fungal against F. graminearum, with EC 50 values of 12.22, 14.72, 23.39, and 33.10 mg L -1 , respectively; (iii) ten compounds (12a-12c, 14c, 18g-18j, 18m, and 19a) showed significant nematicidal activity against H. glycines, with median lethal concentration (LC 50 ) values all less than 30.00 mg L -1 . Especially for compound 18g, its LC 50 value is the smallest, at 12.65 mg L -1 ., Conclusion: The research results indicate that introducing nitro groups at the C5 position of paeonol, or introducing halogens at both C5 and C3 positions, can significantly enhance its biological activity against Phytophthora capsici, F. graminearum, and H. glycines. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

In this study, 12 pairs of tautomeric flavonol derivatives containing quinoxaline were synthesized. The results of antifungal activity showed that in the enol-keto tautomerism, the target compounds containing keto ( Y B series) had better inhibitory activity against Sclerotinia sclerotiorum ( S.s .) than compounds containing enol ( Y A series). Y B9 showed the strongest antifungal activity against S.s., and the median effective concentration (EC 50 ) value was 1.0 μg/mL, which was better than azoxystrobin ( Az , 35.3 μg/mL). In vivo fungal inhibition experiments showed that the protective activity of Y B9 against rape leaves was 83.4% at 200 μg/mL, which was superior to that of Az (70.2%). The activity of succinate dehydrogenase and molecular docking results showed that Y B9 had a stronger antifungal effect than Y A9 . The results of oxalic acid content determination showed that Y B9 could reduce the pathogenic ability of S.s. Then, the inhibitory effect of Y B9 against S.s. was further verified by scanning electron microscopy, fluorescence microscopy, cell membrane permeability, cell content leakage, and malondialdehyde content.

To develop novel succinate dehydrogenase (SDH) inhibitors for sustainable crop protection, a series of dehydroabietyl-diamide-based fungicides (a total of 21) were designed. In vitro fungicidal activity measurement showed that compound 3u exhibited excellent fungicidal activity against Valsa mali (half-maximal effective concentration, EC 50 = 0.195 μg/mL), surpassing that of the positive control carbendazim (EC 50 = 1.35 μg/mL). The in vivo fungicidal activity assessment suggested that 3u exhibited a protective effect on apple branches (69.7-48.1%) and apples (94.6-56.6%). Furthermore, biosafety evaluation indicated that 3u was significantly environmentally friendly toward zebrafish. Subsequently, morphology, physiology, and molecular docking were investigated to elucidate the mode of action of 3u against V. mali . Results demonstrated a strong binding between 3u and SDH, resulting in decreased SDH activity (half-maximal inhibitory concentration, IC 50 = 11.7 μg/mL). Moreover, 3u disrupted the mycelial cell membrane and accelerated electrolyte leakage, ultimately resulting in the death of V. mali . These findings suggest that 3u could serve as a potent SDH inhibitor for sustainable crop protection.

To develop further novel environmentally friendly antifungal agents with high efficacy, a series of pyrazole-5-sulfonamide derivatives were designed and synthesized by using the active molecules synthesized in previous works as lead compounds. Their antifungal activities were evaluated in vitro against ten highly destructive plant pathogenic fungi. The bioassay results indicated that more than half of the target compounds displayed potent antifungal activities (inhibition rate ≥85%) against Valsa mali and Sclerotinia sclerotiorum at 20 mg/L. Among them, compound C22 exhibited significant broad-spectrum antifungal activities against V. mali , S. sclerotiorum , Rhizoctonia solani , Botrytis cinerea , and Trichoderma viride , with EC 50 values of 0.45, 0.49, 3.06, 0.57, and 1.43 mg/L, respectively. Moreover, compounds C21 and C22 exhibited remarkable protective effects on apple Valsa canker similar to tebuconazole (89.5%) at 50 mg/L. Preliminary antifungal mechanism investigations demonstrated that compound C22 may have inhibited V. mali mycelial growth by inducing oxidative damage to the mycelium and compromising the integrity of the cell membrane. Meanwhile, compounds C21 and C22 exhibited no obvious toxicity to worker bees ( Apis mellifera ligustica). Taken together, these pyrazole-5-sulfonamide derivatives, particularly compound C22 , possess huge potential to be developed as novel environmentally friendly fungicides with high efficacy.

As part of continuous work to explore novel and efficient fungicides originating from natural products, a series of cyclobutyl oxime ester derivatives containing an α,β-unsaturated carbonyl moiety were designed and synthesized. In line with the primary evaluation of the inhibitory effect on common pathogenic fungi causing crop failure, a systematic study on the antifungal activity of target compounds against Rhizoctonia solani was carried out. Most target compounds exhibited satisfactory antifungal activity, and 10 of them were superior to the positive control trifloxystrobin. The most notable median effective concentration (EC 50 ) of compound 6b was 1.70 μg/mL, which was considerable for an intensive study. The control efficacy of compound 6b on potted rice against R. solani was superior to trifloxystrobin at identical concentration. The mycelial morphology and cell membrane permeability of the treated fungi were disrupted, and the meaningful enzyme activities of SDH and POD were also restrained. The reactive oxygen species, nuclear morphology, and mitochondrial membrane potential of the treated hypha reflected an apparent difference compared with the normal morphology, which represented mitochondrial function damage. In addition, chemical features essential for the activity and docking mode within the compound and cytochrome bc 1 complex were accessed by computer-aided technology. This study provided insights into the development of new green and efficient fungicides targeting the mitochondria.

The discovery of natural product-derived novel nanopesticide systems can effectively address the adverse effects caused by the improper use of traditional fungicides. In this research, 33 novel 3-carene-derived amide-thiourea derivatives 5a - 5zg were designed using laccase as the biological target, synthesized from natural renewable forest biomass resource 3-carene as the starting material, and structurally confirmed by Fourier-transform infrared spectroscopy, nuclear magnetic resonance, high-resolution mass spectrometry, and single crystal X-ray diffraction. The antifungal activity of the target compounds against eight plant pathogenic fungi was evaluated, and the results presented that target compound 5g exhibited excellent and broad-spectrum antifungal activity against the eight tested phytopathogenic fungi. Furthermore, the important contribution of the gem -dimethylcyclopropane structure in the antifungal activity of compound 5g was revealed through two negative controls without the gem -dimethylcyclopropane structure. Besides, compound 5g also demonstrated a prominent laccase inhibitory activity. The fluorescence quenching of the laccase with compound 5g , the chelating characteristics of compound 5g , and the interaction mode between the laccase and compound 5g presented that the target compound 5g probably exhibited excellent antifungal activity by acting on the laccase target. Cytotoxicity assay revealed that compound 5g had a low cytotoxicity for LO2 and HEK293T cell lines. On the other hand, to further improve the application potential of compound 5g , the 3-carene molecular skeleton containing gem -dimethylcyclopropane ring was grafted onto chitosan, and two nanopesticide carriers CACS and CATCS with sustained releasing performance were synthesized for loading compound 5g . 3-Carene-derived nanochitosan carrier CATCS showed a relatively regular, loose, and porous reticular structure, which displayed high dispersibility and good thermostability. In addition, this carrier had a higher drug-loading capacity and sustained releasing performance than that of the unmodified chitosan. This research identified that the target compound 5g could be used as a promising lead compound for fungicide against the laccase target, meanwhile, the complex 5g /CATCS deserved further study as a nanopesticide candidate.

Penicillium expansum is the major fungus that causes blue mold and produces patulin, threatening human health. Due to health and environmental pollution concerns, chitosan (CS) has attracted more and more attention as a safer alternative to synthetic fungicides for the control of blue mold. In the present study, four different benzimidazole groups were introduced onto CS by the acylation reaction to obtain benzimidazole-based chitosan derivatives (R1b-R4b). After being well-characterized with Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-vis spectra), and nuclear magnetic resonance (NMR), their antifungal activities against P. expansum were screened. Results showed that the inhibitory effects of chitosan derivatives against the pathogen were significantly correlated with chitosan derivatives' concentration and their structures. R4b was shown as optimum with good solubility and antifungal activity with a minimum inhibitory concentration (MIC) value of 0.5 mg/mL and a minimum fungicidal concentration (MFC) value of 2.0 mg/mL. The remarkable antifungal efficiency of R4b against P. expansum was further demonstrated in terms of spore germination, mycelial growth, patulin production, and the preliminary antifungal mechanism. R4b exhibited significant inhibition of patulin production, while its antifungal mechanism was revealed by destroying cell membrane integrity and inducing membrane depolarization. Furthermore, R4b treatment could significantly reduce the incidence of blue mold rot in apple fruit, and the MTT assay showed the nontoxicity of R4b against Raw 264.7, HBZY-1, and Caco-2 cells. Altogether, these results indicate that it is promising to be used as a fruit preservative in the future.

Flutriafol, a globally utilized triazole fungicide in agriculture, is typically applied as a racemic mixture, but its enantiomers differ in bioactivity and environmental impact. The synthesis of flutriafol enantiomers is critically dependent on chiral precursors: 2,2-bisaryl-substituted oxirane [(2-fluorophenyl)-2-(4-fluorophenyl)oxirane, 1a ] and 1,2-diol [1-(2-fluorophenyl)-1-(4-fluorophenyl)ethane-1,2-diol, 1b ]. Here, we engineered a Rhodotorula paludigensis epoxide hydrolase ( Rp EH), obtaining mutant Escherichia coli / Rpeh H336W/L360F with a 6.4-fold enhanced enantiomeric ratio ( E ) from 5.5 to 35.4. This enabled a gram-scale resolution of rac - 1a by E. coli / Rpeh H336W/L360F , producing ( S )- 1a (98.2% ee s ) and ( R )- 1b (75.0% ee p ) with 44.3 and 55.7% analytical yields, respectively. As follows, chiral ( S )-flutriafol (98.2% ee ) and ( R )-flutriafol (75.0% ee ) were easily synthesized by a one-step chemocatalytic process from ( S )- 1a and a two-step chemocatalytic process from ( R )- 1b , respectively. This chemoenzymatic approach offers a superior alternative for the asymmetric synthesis of flutriafol enantiomers. Furthermore, molecular dynamics simulations revealed insight into the enantioselectivity improvement of Rp EH toward bulky 2,2-bisaryl-substituted oxirane 1a .

Based on previous research, this study synthesized 24 compounds by splicing the substructures of the indolyl group and the isothiocyanate group. Alternaria alternata , Phytophthora capsici , Botrytis cinerea, and Valsa mali were used to test the activity of the target compounds. At 100 μg/mL, compounds 8 , 13 , 14 , and 17 exhibited excellent inhibitory effects of more than 80% on P. capsici , B. cinerea, and V. mail . The EC 50 values of compounds 13 and 14 were 0.64 and 2.08 μg/mL, respectively. Potted antifungal activity demonstrated that compounds 13 and 14 had a protective effect of around 80% against B. cinerea at 200 μg/mL. Further physiological and biochemical studies on B. cinerea revealed that compound 13 thickened cell walls and caused mitochondrial vacuolization. Moreover, theoretical calculations indicated that the charge distribution of indolyl isothiocyanate compounds played a crucial role in the observed fungicidal activity. In summary, this study provided fundamental reference data for the derivative synthesis of these indolyl isothiocyanate compounds.

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against Botrytis cinerea ( B. cinerea ), Alternaria solani ( A. solani ), Rhizoctorzia solani ( R. solani ), Fusarium graminearum ( F. graminearum ), and Colletotrichum orbiculare ( C. orbiculare ). Specifically, the EC 50 values of 38 target compounds against R. solani were below 4 μg/mL, among which the compounds C13 (EC 50 = 0.49 μg/mL), C15 (EC 50 = 0.37 μg/mL), and C19 (EC 50 = 0.37 μg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC 50 = 0.52 μg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of R. solani mycelia and cells after treatment with the compound C19 revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.

Brown rot of stone fruit, a disease caused by the ascomycete fungus Monilinia fructicola, has caused significant losses to the agricultural industry. In order to explore and discover potential fungicides against M. fructicola, thirty-one novel mandelic acid derivatives containing piperazine moieties were designed and synthesized based on the amide skeleton. Among them, target compound Z 31 exhibited obvious in vitro antifungal activity with the EC 50 value of 11.8 mg/L, and significant effects for the postharvest pears (79.4 % protective activity and 70.5 % curative activity) at a concentration of 200 mg/L. Antifungal activity for the target compounds was found to be significantly improved by the large steric hindrance of the R 1 groups and the electronegative of the piperazines in the molecular structure, according to a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. Further mechanism studies have demonstrated that the compound Z 31 can disrupt cell membrane integrity, resulting in increased membrane permeability, release of intracellular electrolytes, and affect the normal growth of hyphae. Additional, morphological study also indicated that Z 31 may disrupt the integrity of the membrane by inducing generate excess endogenous reactive oxygen species (ROS) and resulting in the peroxidation of cellular lipids, which was further verified by the detection of malondialdehyde (MDA) content. These studies have provided the basis for the creation of novel fungicides to prevent brown rot in stone fruits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cationic antimicrobial peptides (AMPs) possess broad-spectrum biological activities with less inclination to inducing antibiotic resistance. Herein a battery of amphiphilic amidines were designed by mimicking the characteristics of AMPs. The antifungal activities and the effects to the hyphal morphology and membrane permeability were investigated., Results: The results indicated the inhibitory rates of ten compounds were over 80% to Botrytis cinerea and ten compounds over 90% to Valsa mali Miyabe et Yamada at 50 mg L -1 . The half maximal effective concentration (EC 50 ) values of compound 5g and 6g to V. mali were 1.21 and 1.90 mg L -1 respectively. The protective rate against apple canker of compound 5g reached 93.4% at 100 mg L -1 on twigs, superior to carbendazim (53.3%). When treated with 5g, the cell membrane permeability and leakage of content of V. mali increased, accompanied with the decrease of superoxide dismutase (SOD) and catalase (CAT) level. Concurrently, the mycelial hyphae contracted, wrinkled, and collapsed, providing evidence of membrane perturbation. A three-dimensional quantitative structure-activity relationship (3D-QSAR) between the topic compounds and the EC 50 to V. mali was established showing good predictability (r 2  = 0.971)., Conclusion: Amphiphilic amidines can acquire antifungal activities by acting on the plasmic membrane. Compound 5g could be a promising lead in discovering novel fungicidal candidates. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: Plant pathogens cause substantial crop losses annually, posing a grave threat to global food security. Fungicides have usually been used for their control, but the rapid development of pesticide resistance renders many ineffective, therefore the search for novel and efficient green pesticides to prevent and control plant diseases has become the top priority in crop planting., Results: The results of bioassay studies indicated that most of the target compounds showed certain antimicrobial activity in vitro. In particular, compound X7 showed high inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC 50 value of 27.47 μg mL -1 , surpassing conventional control agents such as thiazole zinc (41.55 μg mL -1 ) and thiodiazole copper (53.39 μg mL -1 ). Further studies on molecular docking showed that X7 had a strong binding affinity with 2FBW. The morphological change observed by scanning electron microscopy indicated that the surface of Xoo appears wrinkled and cracked under X7 treatment and a total of 2662 proteins were identified by label-free proteomic analysis. Three experiments have elucidated the mechanism whereby X7 induced considerable changes in the physiological and biochemical properties of Xoo, which in turn affected the reproduction and growth of bacteria., Conclusion: This work represents a pivotal advancement, offering important reference for the research and development therapeutics in combating plant pathogens. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: To discover more efficient agricultural antimicrobial agents, a series of new quinazoline derivatives containing both a piperazine linker and the N-acetyl moiety were prepared and assessed for their antibacterial and antifungal activities., Results: All the target compounds were characterized by 1 H and 13 C NMR as well as high-resolution mass spectrometry (HRMS), and the chemical structure of the most potent compound E19 incorporating a 4-trifluoromethoxy substituent was clearly confirmed via single crystal X-ray diffraction measurements. The bioassay results indicated that some compounds possessed notable inhibitory effects in vitro against the bacterium Xanthomonas oryzae pv. oryzicola (Xoc). For example, compound E19 had an EC 50 (effective concentration for 50% activity) value of 7.1 μg/mL towards this pathogen, approximately 15- and 10-fold more effective than the commercial bactericides thiodiazole copper and bismerthiazol (EC 50  = 110.2 and 72.4 μg/mL, respectively). Subsequently, the mechanistic studies showed that compound E19 likely exerted its antibacterial efficacies by altering the cell morphology, increasing the permeability of bacterial cytoplasmic membrane, suppressing the production of bacterial extracellular polysaccharides and the extracellular enzyme activities (amylase and cellulase), and blocking the swimming motility of Xoc. Moreover, the proteomic analysis revealed that compound E19 could reduce the bacterial flagellar biosynthesis and decrease the flagellar motility by down-regulating the expression of the related differential proteins., Conclusion: Compound E19 exhibited good potential for further development as a bactericide candidate for control of Xoc. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Replacing old pesticides with new pesticide varieties has been the main means to solve pesticide resistance. Therefore, it is necessary to research and develop new antifungal agents for plant protection. In this study, a series of pyridinecarbaldehyde phenylhydrazone derivatives were designed and evaluated for their inhibition activity on plant pathogenic fungi to search for novel fungicide candidates. Picolinaldehyde phenylhydrazone ( 1 ) and nicotinaldehyde phenylhydrazone ( 2 ) were identified as promising antifungal lead scaffolds. The 4-fluorophenylhydrazone derivatives ( 1a and 2a ) of 1 and 2 showed highly effective and broad-spectrum inhibition activity in vitro on 11 phytopathogenic fungi with EC 50 values of 0.870-3.26 μg/mL, superior to the positive control carbendazim in most cases. The presence of the 4-fluorine atom on the phenyl showed a remarkable activity enhancement effect. Compound 1a at 300 μg/mL provided almost complete protection against infection of Alternaria solani on tomatoes over the post-treatment 9 days and high safety to germination of plant seeds. Furthermore, 1a showed strong inhibition activity with an IC 50 value of 0.506 μg/mL on succinate dehydrogenase in A. solani . Molecular docking showed that both 1a and 2a can well bind to the ubiquinone-binding region of SDH by the conventional hydrogen bond, carbon-hydrogen bond, π-π or π-amide interaction, π-alkyl interaction, X---F (X = N, C, or H) interaction, and van der Waal forces. Meanwhile, scanning and transmission electron analysis displayed that 1a destroyed the morphology of mycelium and the structure of the cell membrane of A. solani . Fluorescent staining analysis revealed that 1a changed the mitochondrial membrane potential and cell membrane permeability. Thus, pyridinecarbaldehyde phenylhydrazone compounds emerged as novel antifungal lead scaffolds, and 1a and 2a can be considered promising candidates for the development of new agricultural fungicides.

This research adopted the Fischer indole synthesis method to continue constructing a novel drug-like chemical entity based on the guidance of isocryptolepine and obtained four series of derivatives: Y , Da , Db , and Dc . The antimicrobial activity of these derivatives against plant pathogens was further evaluated. The results showed that Dc-2 had the best antifungal effect against Botrytis cinerea , and its EC 50 value was up to 1.29 μg/mL. In addition, an in vivo activity test showed that the protective effect of Dc-2 on apples was 82.2% at 200 μg/mL, which was better than that of Pyrimethanil (45.4%). Meanwhile, it was found by scanning electron microscopy and transmission electron microscopy that the compound Dc-2 affected the morphology of mycelia. The compound Dc-2 was found to damage the cell membrane by PI and ROS staining. Through experiments such as leakage of cell contents, it was found that the compound Dc-2 changed the permeability of the cell membrane and caused the leakage of substances in the cell. According to the above studies, compound Dc-2 can be used as a candidate lead compound for further structural optimization and development.

Sulfur-containing compounds have diverse biological functions and are crucial in crop protection chemistry. In this study, a series of novel 1-methyl-1 H -pyrazol-5-amine derivatives incorporating disulfide moieties were synthesized and evaluated for their antimicrobial properties. In vitro bioassays demonstrated that compound 7f displayed potent antifungal activity against Valsa mali , with an EC 50 value of 0.64 mg/L, outperforming allicin (EC 50 = 26.0 mg/L) but lower than tebuconazole (EC 50 = 0.33 mg/L). In vivo experiments confirmed that compound 7f could effectively inhibit V. mali infection on apples at a concentration of 100 mg/L, similar to the positive control tebuconazole. Mechanistic studies revealed that compound 7f could induce hyphal shrinkage and collapse, trigger intracellular reactive oxygen species accumulation, modulate antioxidant enzyme activities, initiate lipid peroxidation, and ultimately cause irreversible oxidative damage to the cells of V. mali . Additionally, compound 7b exhibited notable antibacterial activity, particularly against Pseudomonas syringae pv. actinidiae , with a MIC 90 value of 1.56 mg/L, surpassing the positive controls allicin, bismerthiazol, and streptomycin sulfate. These findings suggest that 1-methyl-1 H -pyrazol-5-amine derivatives containing disulfide moieties hold promise as potent candidates for the development of novel antimicrobial agents.

Using antifungal agrochemicals as the most economical solution might reduce plant diseases caused by pathogenic fungi, which have a significant negative impact on the quality and yield of food worldwide. In this work, 33 compounds ( G ) containing 1,2,3-triazole and malononitrile structures were synthesized. When the compounds were tested in vitro against six fungal species, they exhibited significant fungicidal activity toward Botrytis cinerea and Rhizoctonia solani . Compounds G17 and G30 displayed promising in vivo efficacy, with an EC 50 of 0.19 and 0.27 mg/L respectively against R. solani . Fungal ergosterol production was suppressed by compounds G17 and G30 , according to a preliminary analysis of their mechanism of action on R. solani using transcriptomics and scanning electron microscopy. It has been shown through experimentation that compounds G17 and G30 prevent R. solani from synthesizing ergosterol. Ultimately, it was anticipated that compounds G17 and G30 would be discovered to be low-toxic.

Background: Rice sheath blight caused by Rhizoctonia solani is a severe threat to the yield and quality of rice. Due to the unscientific abuse of common fungicides causing resistance and environmental issues, the development of new fungicides is necessary. In this study, we used citral as the lead compound, designed and synthesized a series of novel citral amide derivatives, and evaluated their antifungal activity and mode of action against R. solani., Result: Bioassay results indicated that the antifungal activities of most citral amide derivatives against R. solani were significantly improved compared to citral, with EC 50 values ranging from 9.50-27.12 mg L -1 . Among them, compound d21 containing the N-(pyridin-4-yl)carboxamide group exhibited in vitro and in vivo fungicidal activities, with curative effects at 500 mg L -1 as effectively as the commercial fungicide validamycin·bacillus. Furthermore, d21 prolonged the lag phase of the growth curve of R. solani, reduced the amount of growth, and inhibited sclerotium germination and formation. Mechanistically, d21 deformed the mycelia, increased cell membrane permeability, and inhibited the activities of antioxidant and tricarboxylic acid cycle (TCA)-related enzymes. Metabolome analysis showed the abundance of some energy-related metabolites within R. solani increased, and simultaneously the antifungal substances secreted by itself reduced. Transcriptome analysis showed that most genes encoding ATP-binding cassette (ABC) transporters and peroxisomes upregulated after the treatment of d21 and cell membrane destruction., Conclusion: This study indicates that novel citral amide derivatives possess antifungal activity against R. solani and are expected to develop an alternative option for chemical control of rice sheath blight. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens., Results: In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC 50 ) of 0.17 mg L -1 , substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC 50 ) of 1.02 μM, much stronger than that of positive control cysteine (IC 50  = 35.50 μM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking., Conclusion: This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Southern root-knot nematodes are among the most pernicious phytoparasites; they are responsible for substantial yield losses in agricultural crops worldwide. The limited availability of nematicides for the prevention and control of plant-parasitic nematodes necessitates the urgent development of novel nematicides. Natural products have always been a key source for the discovery of pesticides. Waltherione A, an alkaloid, exhibits potent nematocidal activity. In this study, we designed and synthesized a series of quinoline and quinolone derivatives from Waltherione A, leveraging a strategy of structural simplification. Bioassays have revealed that the quinoline derivatives exhibit better activity than quinolone derivatives in terms of both nematocidal and fungicidal activities. Notably, compound D1 demonstrated strong nematocidal activity, with a 72 h LC 50 of 23.06 μg/mL, and it effectively controlled the infection of root-knot nematodes on cucumbers. The structure-activity relationship suggests that the quinoline moiety is essential for the nematocidal efficacy of Waltherione A. Additionally, compound D1 exhibited broad-spectrum fungicidal activity, with an EC 50 of 2.98 μg/mL against Botrytis cinerea . At a concentration of 200 μg/mL, it significantly inhibited the occurrence of B. cinerea on tomato fruits, with an inhibitory effect of 96.65%, which is slightly better than the positive control (90.30%).

Succinate dehydrogenase (SDH) has been considered an ideal target for discovering fungicides. To develop novel SDH inhibitors, in this work, 31 novel benzothiazol-2-ylthiophenylpyrazole-4-carboxamides were designed and synthesized using active fragment exchange and a link approach as promising SDH inhibitors. The findings from the tests on antifungal activity indicated that most of the synthesized compounds displayed remarkable inhibition against the fungi tested. Compound Ig N -(2-(((5-chlorobenzo[ d ]thiazol-2-yl)thio)methyl)phenyl)-3-(difluoromethyl)-1-methyl-1 H -yrazole-4-carboxamide, with EC 50 values against four kinds of fungi tested below 10 μg/mL and against Cercospora arachidicola even below 2 μg/mL, showed superior antifungal activity than that of commercial fungicide thifluzamide, and specifically compounds Ig and Im were found to show preventative potency of 90.6% and 81.3% against Rhizoctonia solani Kühn , respectively, similar to the positive fungicide thifluzamide. The molecular simulation studies suggested that hydrophobic interactions were the main driving forces between ligands and SDH. Encouragingly, we found that compound Ig can effectively promote the wheat seedlings and the growth of Arabidopsis thaliana . Our further studies indicated that compound Ig could stimulate nitrate reductase activity in planta and increase the biomass of plants.

In this study, a series of novel hydrazide-containing flavonol derivatives was designed, synthesized, and evaluated for antifungal activity. In the in vitro antifungal assay, most of the target compounds exhibited potent antifungal activity against seven tested phytopathogenic fungi. In particular, compound C32 showed the best antifungal activity against Rhizoctonia solani (EC 50 = 0.170 μg/mL), outperforming carbendazim (EC 50 = 0.360 μg/mL) and boscalid (EC 50 = 1.36 μg/mL). Compound C24 exhibited excellent antifungal activity against Valsa mali , Botrytis cinerea , and Alternaria alternata with EC 50 values of 0.590, 0.870, and 1.71 μg/mL, respectively. The in vivo experiments revealed that compounds C32 and C24 were potential novel agricultural antifungals. 3D quantitative structure-activity relationship (3D-QSAR) models were used to analyze the structure-activity relationships of these compounds. The analysis results indicated that introducing appropriate electronegative groups at position 4 of a benzene ring could effectively improve the anti- R. solani activity. In the antifungal mechanism study, scanning electron microscopy and transmission electron microscopy analyses revealed that C32 disrupted the normal growth of hyphae by affecting the structural integrity of the cell membrane and cellular respiration. Furthermore, compound C32 exhibited potent succinate dehydrogenase (SDH) inhibitory activity (IC 50 = 8.42 μM), surpassing that of the SDH fungicide boscalid (IC 50 = 15.6 μM). The molecular dynamics simulations and docking experiments suggested that compound C32 can occupy the active site and form strong interactions with the key residues of SDH. Our findings have great potential for aiding future research on plant disease control in agriculture.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali , Gaeumannomyces graminis , and Botrytis cinerea , with EC 50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC 50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC 50 = 0.82 mg/L) and Rhizoctonia solani (EC 50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC 50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum , respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (Δ G cal = -46.8 kcal/mol, IC 50 = 1.22 mg/L, compared to Δ G cal = -41.1 kcal/mol, IC 50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

A series of new piperidine-4-carbohydrazide derivatives bearing a quinazolinyl moiety were prepared and evaluated for their fungicidal activities against agriculturally important fungi. Among these derivatives, the chemical structure of compound A45 was clearly verified by X-ray crystallographic analysis. The antifungal bioassays revealed that many compounds in this series possessed good to excellent inhibition effects toward the tested fungi. For example, compounds A13 and A41 had EC 50 values of 0.83 and 0.88 μg/mL against Rhizoctonia solani in vitro , respectively, superior to those of positive controls Chlorothalonil and Boscalid (1.64 and 0.96 μg/mL, respectively). Additionally, the above two compounds also exhibited notable inhibitory activities against Verticillium dahliae (with EC 50 values of 1.12 and 3.20 μg/mL, respectively), far better than the positive controls Carbendazim and Chlorothalonil (19.3 and 11.0 μg/mL, respectively). More importantly, compound A13 could potently inhibit the proliferation of R. solani in the potted rice plants, showing good in vivo curative and protective efficiencies of 76.9% and 76.6% at 200 μg/mL, respectively. Furthermore, compound A13 demonstrated an effective inhibition of succinate dehydrogenase (SDH) activity in vitro with an IC 50 value of 6.07 μM. Finally, the molecular docking study revealed that this compound could be well embedded into the active pocket of SDH via multiple noncovalent interactions, involving residues like SER39, ARG43, and GLY46.

Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a , 3e , 4l, and 4o possessing appropriate c log P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani , Sclerotinia sclerotiorum , Botrytis cinerea , and Fusarium graminearum at 10 mg/L in vitro, and the EC 50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum , respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC 50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC 50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.

Background: The discovery of agricultural fungicide candidates from natural products is one of the key strategies for developing environment friendly agricultural fungicides with high efficiency, high selectivity and unique modes-of-action. Based on previous work, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing benzothiophene moiety were designed and synthesized., Results: The majority of the proposed compounds displayed moderate to considerable antifungal efficacy against the tested pathogenic fungi and oomycetes, some exhibiting broad spectrum antifungal activity. Notably, compounds 2 (3-F-Ph) and 7 (4-Cl-Ph) showed excellent antifungal activity against Rhizoctonia with half maximal effective concentration (EC 50 ) values of 0.94 and 0.99 mg L -1 , respectively, comparable to the commercial fungicide tebuconazole (EC 50  = 0.96 mg L -1 ), and also displayed significant inhibitory effects against V alsa mali with EC 50 values of 2.26 and 1.67 mg L -1 , respectively - better than famoxadone and carabrone. The in vivo protective and curative effects against R. solani of compound 2 were 57.2% and 53.7% at 100 mg L -1 , respectively, which were equivalent to tebuconazole (51.6% and 52.4%). Further investigations found that compound 2 altered the ultrastructure of R. solani cell, significantly increased the relative conductivity of the cells, and reduced the activity of complex III in a dose-dependent manner. Molecular docking results showed that compound 2 matched well with the Qo pocket., Conclusion: The results revealed that MBL derivatives containing benzothiophene moiety are promising antifungal candidates and provide a new backbone structure for further optimization of novel fungicides. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC 50 values of 3.26 and 1.52 μg/mL respectively, and also exhibited excellent efficacy against R. solani with EC 50 values of 0.27 and 0.06 μg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 μg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Carbamate is a key structural motif in the development of fungicidal compounds, which is still promising and robust in the discovery of green pesticides. Herein, we report the synthesis and evaluation of the fungicidal activity of 35 carbamate derivatives, among which 19 compounds were synthesized in our previous report. These derivatives were synthesized from aromatic amides in a single step, which was a green oxidation process for Hofmann rearrangement using oxone, KCl and NaOH. Their chemical structures were characterized by 1 H NMR, 13 C NMR and high-resolution mass spectrometry. Their antifungal activity was tested against seven plant fungal pathogens. Many of the compounds exhibited good antifungal activity in vitro (inhibitory rate > 60% at 50 μg/mL). Compound 1ag exhibited excellent broad-spectrum antifungal activities with inhibition rates close to or higher than 70% at 50 μg/mL. Notably, compound 1af demonstrated the most potent inhibition against F. graminearum , with an EC 50 value of 12.50 μg/mL, while compound 1z was the most promising candidate fungicide against F. oxysporum (EC 50 = 16.65 μg/mL). The structure-activity relationships are also discussed in this paper. These results suggest that the N -aryl carbamate derivatives secured by our green protocol warrant further investigation as potential lead compounds for novel antifungal agents.

The active splicing strategy has witnessed improvement in bioactivity and antifungal spectra in pesticide discovery. Herein, a series of simple-structured molecules ( Y1 - Y53 ) containing chloro-substituted benzyl esters were designed using the above strategy. The structure-activity relationship (SAR) analysis demonstrated that the fatty acid fragment-structured esters were more effective than those containing an aromatic acid moiety or naphthenic acid part. Compounds Y36 and Y41 , which featured a thiazole-4-acid moiety and trifluoromethyl aliphatic acid part, respectively, exhibited excellent in vivo curative activity (89.4%, 100 mg/L Y36 ) and in vitro fungicidal activity (EC 50 = 0.708 mg/L, Y41 ) against Botrytis cinerea . Determination of antifungal spectra and analysis of scanning electron microscopy (SEM), membrane permeability, cell peroxidation, ergosterol content, oxalic acid pathways, and enzymatic assays were performed separately here. Compound Y41 is cost effective due to its simple structure and shows promise as a disease control candidate. In addition, Y41 might act on a novel target through a new pathway that disrupts the cell membrane integrity by inducing cell peroxidation.

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

Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site of action have hindered their wider application in agriculture. In order to extend the structural diversity of tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing the attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1 H -benzo[ d ]imidazole ( A 25 ) exhibited optimal antifungal activity against Sclerotinia sclerotiorum ( S. s. ), affording an excellent half-maximal effective concentration (EC 50 ) of 0.158 μg/mL, which was higher than that of the reference agent carbendazim (EC 50 = 0.594 μg/mL). Pot experiments revealed that compound A 25 (200 μg/mL) had acceptable protective activity (84.7%) and curative activity (78.1%), which were comparable with that of carbendazim (protective activity: 90.8%; curative activity: 69.9%). Molecular docking displayed that multiple hydrogen bonds and π-π interactions could be formed between A 25 and β-tubulin, resulting in a stronger bonding effect than carbendazim. Fluorescence imaging revealed that the structure of intracellular microtubules can be changed significantly after A 25 treatment. Overall, these remarkable antifungal profiles of constructed novel benzimidazole derivatives could facilitate the application of novel microtubule-targeting agents.

Corn ear rot and fumonisin caused by Fusarium verticillioides pose a serious threat to food security. To find more highly active fungicidal and antitoxic candidates with structure diversity based on naturally occurring lead xanthatin, a series of novel spiropiperidinyl-α-methylene-γ-butyrolactones were rationally designed and synthesized. The in vitro bioassay results indicated that compound 7c showed broad-spectrum in vitro activity with EC 50 values falling from 3.51 to 24.10 μg/mL against Rhizoctonia solani and Alternaria solani , which was more active than the positive controls xanthatin and oxathiapiprolin. In addition, compound 7c also showed good antitoxic efficacy against fumonisin with a 48% inhibition rate even at a concentration of 20 μg/mL. Fluorescence quenching and the molecular docking validated both 7c and oxathiapiprolin targeting at FvoshC. RNA sequencing analysis discovered that FUM gene cluster and protein processing in endoplasmic reticulum were downregulated. Our studies have discovered spiropiperidinyl-α-methylene-γ-butyrolactone as a novel FvoshC target-based scaffold for fungicide lead with antitoxin activity.

The development of new fungicide molecules is a crucial task for agricultural chemists to enhance the effectiveness of fungicides in agricultural production. In this study, a series of novel fluoroalkenyl modified succinate dehydrogenase inhibitors were synthesized and evaluated for their antifungal activities against eight fungi. The results from the in vitro antifungal assay demonstrated that compound 34 exhibited superior activity against Rhizoctonia solani with an EC 50 value of 0.04 μM, outperforming commercial fluxapyroxad (EC 50 = 0.18 μM) and boscalid (EC 50 = 3.07 μM). Furthermore, compound 34 showed similar effects to fluxapyroxad on other pathogenic fungi such as Sclerotinia sclerotiorum (EC 50 = 1.13 μM), Monilinia fructicola (EC 50 = 1.61 μM), Botrytis cinerea (EC 50 = 1.21 μM), and also demonstrated protective and curative efficacies in vivo on rapeseed leaves and tomato fruits. Enzyme activity experiments and protein-ligand interaction analysis by surface plasmon resonance revealed that compound 34 had a stronger inhibitory effect on succinate dehydrogenase compared to fluxapyroxad. Additionally, molecular docking and DFT calculation confirmed that the fluoroalkenyl unit in compound 34 could enhance its binding capacity with the target protein through p-π conjugation and hydrogen bond interactions.

Scaffold hopping and structural fine-tuning are important strategies for agrochemical innovation. Multidimensional optimization of the prevalidated antifungal lead R -LE001 was conducted via the design, synthesis, and bioevaluation of 53 new compounds differing in either scaffold or substituent. The antifungal structure-activity relationship (SAR) revealed that a number of amides containing 2-(2-oxazolinyl) aniline (NHPhOx) or 2-(2-thiazolinyl) aniline (NHPhthiOx) demonstrated a more promising antifungal effect than both R -LE001 and the positive control boscalid. Specifically, compound 10 (encoded LEX-K01 ) shows an excellent antifungal effect against Botrytis cinerea with an EC 50 value lower than 0.11 μM. This small change leads to a significant improvement (over 1 order of magnitude) in bioactivity compared to that of either R -LE001 (EC 50 = 1.41 μM) or boscalid (EC 50 = 2.01 μM) and fluxapyroxad (EC 50 = 4.35 μM). With much lower resistance factors, LEX-K01 ( 10 ) was more efficacious against the two boscalid-resistant strains of B. cinerea TZ01 and NJBH2017. A combination of LEX-K01 ( 10 ) and boscalid in a ratio of 1:3 showed synergistic effects against resistant B. cinerea TZ01 and NJBH2017, with SR values of 3.01 and 2.55, respectively. LEX-K01 ( 10 ) has a curative efficacy (70.3%) more prominent than that of boscalid (51.2%) in controlling disease caused by B. cinerea . The molecular docking simulation of LEX-K01 ( 10 ) with the SDH protein of B. cinerea displayed four hydrogen bonds with amino acid residues TYR144, ARG88, TRP81, and SER84, rationalizing a stronger affinity than boscalid. The scanning electron microscopy (SEM) characteristic revealed that it could cause an obvious collapse of B. cinerea mycelium. This work indicates that LEX-K01 ( 10 ) has the potential to be further explored as a new antifungal agent.

Phthalide, benzoxazole, and chromene are important heterocyclic skeletons with extensive biological activities. In order to develop novel potential antifungal agents, twenty-two benzoxazole/chromene-containing phthalide derivatives were prepared, and their fungicidal activity against nine common plants pathogenic fungi were evaluated in vitro . The EC 50 values indicated that compound Z-4b displayed superior antifungal activity against P. oryza e (11.0  μ g/mL), F. solani (8.5  μ g/mL), P. capsici (27.8  μ g/mL), V. mali (3.1  μ g/mL) and A. brassicae (4.3  μ g/mL) strains, which was more potent than the two commercialized fungicides hymexazol and chlorothalonil. In addition, the structure-activity relationship analysis demonstrated that the combination site of oxazolamide with phthalide has an important effect on antifungal activity. This research offers a potential compound for the development of novel agricultural fungicides.

Background: Peanut southern blight disease, caused by Sclerotium rolfsii, is a destructive soil-borne fungal disease. The current control measures, which mainly employ succinate dehydrogenase inhibitors, are prone to resistance and toxicity to non-target organisms. As a result, it is necessary to explore the potential of eco-friendly fungicides for this disease., Results: Fourteen novel phthalide compounds incorporating amino acid moieties were designed and synthesized. The in vitro activity of analog A1 [half maximal effective concentration (EC 50 ) = 332.21 mg L -1 ] was slightly lower than that of polyoxin (EC 50  = 284.32 mg L -1 ). It was observed that on the seventh day, the curative activity of A1 at a concentration of 600.00 mg L -1 was 57.75%, while the curative activity of polyoxin at a concentration of 300.00 mg L -1 was 42.55%. These results suggested that our compound exhibited in vivo activity. Peanut plants treated with A1 showed significant agronomic improvements compared to the untreated control. Several compounds in this series exhibited superior root absorption and conduction in comparison to the endothermic fungicide thifluzamide. The growth promotion and absorption-conduction experiments demonstrated the reason for the superior in vivo activity of the target compound. Cytotoxic assays have demonstrated that this series of targeted compounds exhibit low toxicity levels toward human lo2 liver cells., Conclusion: Our results provide a new strategy for the design and synthesis of novel green compounds. Furthermore, the target compound A1 can serve as a lead for further development of green fungicides. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

The extensive and repeated application of chemical fungicides results in the rapid development of fungicide resistance. Novel antifungal pesticides are urgently required. Natural products have been considered precious sources of pesticides. It is necessary to discover antifungal pesticides by using natural products. Herein, 42 various griseofulvin derivatives were synthesized. Their antifungal activities were evaluated in vitro. Most of them showed good antifungal activity, especially 3d exhibited a very broad antifungal spectrum and the most significant activities against 7 phytopathogenic fungi. In vivo activity results suggested that 3d protected apples and tomatoes from serious infection by phytopathogenic fungi. These proved that 3d had the potential to be a natural product-derived antiphytopathogenic fungi agent. Furthermore, docking analysis suggested that tubulin might be one of the action sites of 3d . It is reasonable to believe that griseofulvin derivatives are worth further development for the discovery of new pesticides.

Plant pathogenic fungi pose a significant threat to agricultural production, necessitating the development of new and more effective fungicides. The ring replacement strategy has emerged as a highly successful approach in molecular design. In this study, we employed the ring replacement strategy to successfully design and synthesize 32 novel hydrazide derivatives containing diverse heterocycles, such as thiazole, isoxazole, pyrazole, thiadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, thiophene, pyridine, and pyrazine. Their antifungal activities were evaluated in vitro and in vivo . Bioassay results revealed that most of the title compounds displayed remarkable antifungal activities in vitro against four tested phytopathogenic fungi, including Fusarium graminearum , Botrytis cinerea , Sclerotinia sclerotiorum , and Rhizoctonia solani . Especially, compound 5aa displayed a broad spectrum of antifungal activity against F. graminearum , B. cinerea , S. sclerotiorum , and R. solani , with the corresponding EC 50 values of 0.12, 4.48, 0.33, and 0.15 μg/mL, respectively. In the antifungal growth assay, compound 5aa displayed a protection efficacy of 75.5% against Fusarium head blight (FHB) at a concentration of 200 μg/mL. In another in vivo antifungal activity evaluation, compound 5aa exhibited a noteworthy protective efficacy of 92.0% against rape Sclerotinia rot (RSR) at a concentration of 100 μg/mL, which was comparable to the positive control tebuconazole (97.5%). The existing results suggest that compound 5aa has a broad-spectrum antifungal activity. Electron microscopy observations showed that compound 5aa might cause mycelial abnormalities and organelle damage in F. graminearum . Moreover, in the in vitro enzyme assay, we found that the target compounds 5aa , 5ab , and 5ca displayed significant inhibitory effects toward succinate dehydrogenase, with the corresponding IC 50 values of 1.62, 1.74, and 1.96 μM, respectively, which were superior to that of boscalid (IC 50 = 2.38 μM). Additionally, molecular docking and molecular dynamics simulation results revealed that compounds 5aa , 5ab , and 5ca have the capacity to bind in the active pocket of succinate dehydrogenase (SDH), establishing hydrogen-bonding interactions with neighboring amino acid residues.

A series of novel 2-Ar-1,2,3-triazole derivatives were designed and synthesized based on our previously discovered active compound 6d against Rhizoctonia solani . Most of these compounds exhibited good antifungal activity against R. solani at a concentration of 25 μg/mL. Based on the results of biological activity, we established a three-dimensional quantitative structure-activity relationship (3D-QSAR) model that guided the synthesis of compound 7y . Compound 7y exhibited superior activity against R. solani (EC 50 = 0.47 μg/mL) compared to the positive controls hymexazol (EC 50 = 12.80 μg/mL) and tebuconazole (EC 50 = 0.87 μg/mL). Furthermore, compound 7y demonstrated better protective activity than the aforementioned two commercial fungicides in both detached leaf assays and greenhouse experiments, achieving 56.21% and 65.75% protective efficacy, respectively, at a concentration of 100 μg/mL. The ergosterol content was determined and molecular docking was performed to explore the mechanism of these active molecules. DFT calculation and MEP analysis were performed to illustrate the results of this study. These results suggest that compound 7y could serve as a novel 2-Ar-1,2,3-triazole lead compound for controlling R. solani.

A series of 19 novel eugenol derivatives containing a 1,2,3-triazole moiety was synthesized via a two-step process, with the key step being a copper(I)-catalyzed azide-alkyne cycloaddition reaction. The compounds were assessed for their antifungal activities against Colletotrichum gloeosporioides , the causative agent of papaya anthracnose. Triazoles 2k , 2m , 2l , and 2n , at 100 ppm, were the most effective, reducing mycelial growth by 88.3, 85.5, 82.4, and 81.4%, respectively. Molecular docking calculations allowed us to elucidate the binding mode of these derivatives in the catalytic pocket of C. gloeosporioides CYP51. The best-docked compounds bind closely to the heme cofactor and within the channel access of the lanosterol ( LAN ) substrate, with crucial interactions involving residues Tyr102, Ile355, Met485, and Phe486. From such studies, the antifungal activity is likely attributed to the prevention of substrate LAN entry by the 1,2,3-triazole derivatives. The triazoles derived from natural eugenol represent a novel lead in the search for environmentally safe agents for controlling C. gloeosporioides .

To explore more potential fungicides with new scaffolds, thirty-seven norbornene carboxamide/sulfonamide derivatives were designed, synthesized, and assayed for inhibitory activity against six plant pathogenic fungi and oomycetes. The preliminary antifungal assay suggested that the title derivatives showed moderate to good antifungal activity against six plant pathogens. Especially, compound 6 e presented excellent in vitro antifungal activity against Sclerotinia sclerotiorum (EC 50 =0.71 mg/L), which was substantially stronger than pydiflumetofen. In vivo antifungal assay indicated 6 e displayed prominent protective and curative effects on rape leaves infected by S. sclerotiorum. The preliminary mechanism research displayed that 6 e could damage the surface morphology and inhibit the sclerotia formation of S. sclerotiorum. In addition, the in vitro enzyme inhibition bioassay indicated that 6 e displayed pronounced laccase inhibition activity (IC 50 =0.63 μM), much stronger than positive control cysteine. Molecular docking elucidated the binding modes between 6 e and laccase. The bioassay results and mechanism investigation demonstrated that this class of norbornene carboxamide/sulfonamide derivatives could be promising laccase inhibitors for novel fungicide development., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The pursuit of new succinate dehydrogenase (SDH) inhibitors is a leading edge in fungicide research and development. The use of 3D quantitative structure-activity relationship (3D-QSAR) models significantly enhances the development of compounds with potent antifungal properties. In this study, we leveraged the natural product coumarin as a molecular scaffold to synthesize 74 novel 3-coumarin hydrazide derivatives. Notably, compounds 4ap (0.28 μg/mL), 6ae (0.32 μg/mL), and 6ah (0.48 μg/mL) exhibited exceptional in vitro effectiveness against Rhizoctonia solani , outperforming the commonly used fungicide boscalid (0.52 μg/mL). Furthermore, compounds 4ak (0.88 μg/mL), 6ae (0.61 μg/mL), 6ah (0.65 μg/mL), and 6ak (1.11 μg/mL) showed significant activity against Colletotrichum orbiculare , surpassing both the SDHI fungicide boscalid (43.45 μg/mL) and the broad-spectrum fungicide carbendazim (2.15 μg/mL). Molecular docking studies and SDH enzyme assays indicate that compound 4ah may serve as a promising SDHI fungicide. Our ongoing research aims to refine this 3D-QSAR model further, enhance molecular design, and conduct additional bioactivity assays.

Thirty-four new pyrido[4,3- d ]pyrimidine analogs were designed, synthesized, and characterized. The crystal structures for compounds 2c and 4f were measured by means of X-ray diffraction of single crystals. The bioassay results showed that most target compounds exhibited good fungicidal activities against Pyricularia oryzae , Rhizoctonia cerealis , Sclerotinia sclerotiorum , Botrytis cinerea, and Penicillium italicum at 16 μg/mL. Compounds 2l , 2m , 4f , and 4g possessed better fungicidal activities than the commercial fungicide epoxiconazole against B. cinerea . Their half maximal effective concentration (EC 50 ) values were 0.191, 0.487, 0.369, 0.586, and 0.670 μg/mL, respectively. Furthermore, the inhibitory activities of the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results displayed that they had prominent activities. Compounds 2l , 2m , 4f , and 4g also showed better inhibitory activities than epoxiconazole against CYP51. Their half maximal inhibitory concentration (IC 50 ) values were 0.219, 0.602, 0.422, 0.726, and 0.802 μg/mL, respectively. The results of molecular dynamics (MD) simulations exhibited that compounds 2l and 4f possessed a stronger affinity to CYP51 than epoxiconazole.

The main challenge in the development of agrochemicals is the lack of new leads and/or targets. It is critical to discover new molecular targets and their corresponding ligands. YZK-C22 , which contains a 1,2,3-thiadiazol-[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazole skeleton, is a fungicide lead compound with broad-spectrum fungicidal activity. Previous studies suggested that the [1,2,4]triazolo[3,4- b ][1,3,4]thiadiazole scaffold exhibited good antifungal activity. Inspired by this, a series of pyrrolo[2,3- d ]thiazole derivatives were designed and synthesized through a bioisosteric strategy. Compounds C1 , C9 , and C20 were found to be more active against Rhizoctonia solani than the positive control YZK-C22. More than half of the target compounds provided favorable activity against Botrytis cinerea , where the EC 50 values of compounds C4 , C6 , C8 , C10 , and C20 varied from 1.17 to 1.77 μg/mL. Surface plasmon resonance and molecular docking suggested that in vitro potent compounds C9 and C20 have a new mode of action instead of acting as pyruvate kinase inhibitors. Transcriptome analysis revealed that compound C20 can impact the tryptophan metabolic pathway, cutin, suberin, and wax biosynthesis of B. cinerea . Overall, pyrrolo[2,3- d ]thiazole is discovered as a new fungicidal lead structure with a potential new mode of action for further exploration.

The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl heteroaryl ketone was drawn as a common model intriguing the design and divergent synthesis of 14 kinds of heteroaryl ketones aligned with their oxime derivatives. Antifungal function-oriented phenotypical screen protruded benzothiazolyl-phenyl oxime 5a as a promising model, and the concomitant modification led to benzothiazolyl oxime 5am (EC 50 = 5.17 μM) as a superior lead than fluoxastrobin (EC 50 = 7.54 μM) against Sclerotinia sclerotiorum . Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime 5bm with remarkable activity (EC 50 = 3.57 μM) against Pyricularia oryzae . Molecular docking showed that candidate 5am could form more hydrogen bonds with the amino acid residues of actin than metrafenone. This compound also demonstrated better curative efficacy than that of fluoxastrobin and metrafenone in controlling the plant disease caused by S. sclerotiorum . These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.

A total of 32 novel sulfoximines bearing cyanoguanidine and nitroguanidine moieties were designed and synthesized by a rational molecule design strategy. The bioactivities of the title compounds were evaluated and the results revealed that some of the target compounds possessed excellent antifungal activities against six agricultural fungi, including Sclerotinia sclerotiorum , Fusarium graminearum , Phytophthora capsici , Botrytis cinerea , Rhizoctonia solani , and Pyricularia grisea . Among them, compounds 8e 1 and 8e 4 exhibited significant efficacy against P. grisea with EC 50 values of 2.72 and 2.98 μg/mL, respectively, which were much higher than that of commercial fungicides boscalid (47.95 μg/mL). Interestingly, in vivo assays determined compound 8e 1 possessed outstanding activity against S. sclerotiorum with protective and curative effectiveness of 98 and 95.6% at 50 μg/mL, which were comparable to those of boscalid (93.2, 91.9%). The further preliminary mechanism investigation disclosed that compound 8e 1 could damage the structure of the cell membrane of S. sclerotiorum , increase its permeability, and suppress its growth. Overall, the findings enhanced that these novel sulfoximine derivatives could be potential lead compounds for the development of new fungicides.

In this study, a series of acrylamide derivatives containing trifluoromethylpyridine or piperazine fragments were rationally designed and synthesized. Subsequently, the in vitro antifungal activities of all of the synthesized compounds were evaluated. The findings revealed that compounds 6b , 6c , and 7e exhibited >80% antifungal activity against Phomopsis sp. ( Ps ) at the concentration of 50 μg/mL. Furthermore, the EC 50 values for compounds 6b , 6c , and 7e against Ps were determined to be 4.49, 6.47, and 8.68 μg/mL, respectively, which were better than the positive control with azoxystrobin (24.83 μg/mL). At the concentration of 200 μg/mL, the protective activity of compound 6b against Ps reached 65%, which was comparable to that of azoxystrobin (60.9%). Comprehensive mechanistic studies, including morphological studies with fluorescence microscopy (FM), cytoplasmic leakage, and enzyme activity assays, indicated that compound 6b disrupts cell membrane integrity and induces the accumulation of defense enzyme activity, thereby inhibiting mycelial growth. Therefore, compound 6b serves as a valuable candidate for the development of novel fungicides for plant protection.