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On the basis of the structures of natural methylxanthines and chalcone, a series of novel chalcone analogues containing a methylxanthine moiety, Ia - Ig , and their N -acyl pyrazoline derivatives IIa - IIz and IIaa - IIaf were synthesized and identified through melting points, 1 H NMR, 13 C NMR, and HRMS. The single crystal of compound IId was obtained, which further illustrated the structural characteristics of the methylxanthine-acylpyrazoline compounds. The biological tests showed that some of them displayed favorable insecticidal activities toward Plutella xylostella L. and were superior to the natural methylxanthine compound caffeine while being comparable with the insecticide triflumuron (e.g., compound Ic : LC 50 = 16.8508 mg/L, IIf : LC 50 = 1.5721 mg/L, against P. xylostella ). Of these compounds, Ic , IIf, and IIu could serve as novel insecticidal leading structures for further study. Some of the compounds showed good fungicidal activities (e.g., compound Ig : EC 50 = 14.74 μg/mL, against Rhizoctonia cerealis ; IIf : EC 50 = 7.06 μg/mL, against Physalospora piricola ; IIac : EC 50 = 5.37 and 8.19 μg/mL, against Phytophthora capsici and Sclerotinia sclerotiorum , respectively); Ic , Ig , IIa , IIf , IIr , IIs , IIv , IIac , and IIaf could be novel fungicidal leading compounds for further exploration. Furthermore, most of the tested compounds exhibited apparent herbicidal activities against Brassica campestris at a concentration of 100 μg/mL; among others, compound IIa was the best one both toward Brassica campestris and Echinochloa crusgalli and deserves further investigation. The structure-activity relationships of these compounds were also summarized and discussed in detail. The contrast experiment results of compounds C-1 and C-2 showed a positive effect on the biological activity enhancement from the combination of the methylxanthine moiety with the N -dichloroacetyl phenylpyrazoline skeleton. In addition, two 3D-QSAR models with predictive capability were constructed based on the insecticidal and fungicidal activities to afford deep insight into the bioactivity profiles of these compounds. This research provides useful guidance and reference for the discovery and development of novel xanthine natural product-based pesticides.

Background: Plant diseases caused by phytopathogenic fungi and oomycetes pose a serious threat to ensuring crop yield and quality. Finding novel fungicidal candidates based on natural products is one of the critical methods for developing effective and environmentally friendly pesticides. In this study, a series of salicylaldehyde derivatives containing an α-methylene-γ-butyrolactone moiety were designed, synthesized, and their fungicidal activities were evaluated., Results: The bioassay studies indicated that compound C3 displayed an excellent in vitro activity against Rhizoctonia solani with a half-maximal effective concentration (EC 50 ) value of 0.65 μg/mL, higher than that of pyraclostrobin (EC 50  = 1.44 μg/mL) and comparable to that of carbendazim (EC 50  = 0.33 μg/mL). For Valsa mali and Phytophthora capsici, compound C3 also showed good fungicidal activities with EC 50 values of 0.91 and 1.33 μg/mL, respectively. In addition, compound C3 exhibited promising protective in vivo activity against R. solani (84.1%) at 100 μg/mL, which was better than that of pyraclostrobin (78.4%). The pot experiment displayed that compound C3 had 74.8% protective efficacy against R. solani at 200 μg/mL, which was comparable to that of validamycin (78.2%). The antifungal mode of action research indicated that compound C3 could change the mycelial morphology and ultrastructure, increase cell membrane permeability, affect respiratory metabolism by binding to complex III, and inhibit the germination and formation of sclerotia, thereby effectively controlling the disease., Conclusion: The present study provides support for the application of these salicylaldehyde derivatives as promising potential pesticides with remarkable and broad-spectrum fungicidal activities against phytopathogenic fungi and oomycetes in crop protection. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Tebuconazole is a triazole fungicide widely used in agricultural crops for control of multiple fungal, mainly foliar and soil-borne diseases. Due to its intense use, this pesticide has been detected on aquatic matrices in different countries, which makes it necessary to identify metabolites capable to be used in its exposure monitoring. The aim of this work was to evaluate tebuconazole metabolites in zebrafish water tanks using liquid chromatography coupled to a high-resolution mass spectrometer (LCHRMS) to highlight analytical targets to monitor tebuconazole exposure in aquatic environments. Two Phase I metabolites, TEB-OH and TEB-COOH, and one Phase II metabolite, TEB-S, were identified. Target metabolomics pointed TEB-S as the most important metabolite for discrimination between treatment and negative control group and potential surrogate for detection and monitoring of tebuconazole exposure in aquatic environments. To the best of our knowledge, this is the first study to suggest the sulphation of tebuconazole (TEB-S) by zebrafish metabolism. Moreover, the use of water samples proved to be a promising approach when compared to the usual biological matrices (e.g. plasma) for evaluating the exposure of aquatic animals to tebuconazole because it is a clean and easy to obtain matrix. Water samples presented a higher concentration of metabolites when compared to plasma samples. The results suggest the applicability of this assay model for the identification of potential biomarkers for monitoring the presence of xenobiotics in water., 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 © 2023. Published by Elsevier B.V.)

Selective oxidative C-O coupling of hydrazones with diacetyliminoxyl is demonstrated, in which diacetyliminoxyl plays a dual role. It is an oxidant (hydrogen atom acceptor) and an O-partner for the oxidative coupling. The reaction is completed within 15-30 min at room temperature, is compatible with a broad scope of hydrazones, provides high yields in most cases, and requires no additives, which makes it robust and practical. The proposed reaction leads to the novel structural family of azo compounds, azo oxime ethers, which were discovered to be highly potent fungicides against a broad spectrum of phytopathogenic fungi ( Venturia inaequalis , Rhizoctonia solani , Fusarium oxysporum , Fusarium moniliforme , Bipolaris sorokiniana , Sclerotinia sclerotiorum ).

Scaffold hopping strategy has become one of the most successful methods in the process of molecular design. Seeking to develop novel succinate dehydrogenase inhibitors (SDHIs), we employed a scaffold hopping strategy to design compounds featuring geminate dichloralkenes ( gem -dichloralkenes) fragment. After stepwise modifications, a series of N -cyclopropyl-dichloralkenes-pyrazole-carboxamide derivatives was synthesized. Among them, compounds G28 (IC 50 = 26.00 nM) and G40 (IC 50 = 27.00 nM) were identified as the best inhibitory activity against porcine SDH, with IC 50 values reaching the nanomolar range, outperforming the lead compound pydiflumetofen. Additionally, the greenhouse assay indicated that compounds G37 (EC 90 = 0.031 mg/L) and G34 (EC 90 = 1.67 mg/L) displayed extremely high activities against wheat powdery mildew (WPM) and cucumber powdery mildew (CPM), respectively. Computational results further revealed that the gem -dichloralkene fragment and fluorine substituted pyrazole form an extra hydrophobic interaction and dipolar-dipolar interaction with SDH. In summary, our study provides a novel gem -dichloralkene scaffold with outstanding fungicidal properties, obtained through scaffold hopping, that holds great potential for future research on PM control.

In an effort to promote the development of new fungicides, a series of 48 novel N -(1-methyl-4-thiocyanato-1 H -pyrazol-5-yl)-benzamide derivatives A1 - A36 and B1 - B12 were designed and synthesized by incorporating a thiocyanato group into the pyrazole ring, and their fungicidal activities were evaluated against Sclerotinia sclerotiorum , Valsa mali , Botrytis cinerea , Rhizoctonia solani , and Phytophthora capsici . In the in vitro antifungal/antioomycete assay, many of the target compounds exhibited good broad-spectrum fungicidal activities. Among them, compound A36 displayed the best antifungal activity against V. mali with an EC 50 value of 0.37 mg/L, which was significantly higher than that of the positive controls fluxapyroxad (13.3 mg/L) and dimethomorph (10.3 mg/L). Meanwhile, compound B6 exhibited the best antioomycete activity against P. capsici with an EC 50 value of 0.41 mg/L, which was higher than that of azoxystrobin (29.2 mg/L) but lower than that of dimethomorph (0.13 mg/L). Notably, compound A27 displayed broad-spectrum inhibitory activities against V. mali , B. cinerea , R. solani , S. sclerotiorum , and P. capsici with respective EC 50 values of 0.71, 1.44, 1.78, 0.87, and 1.61 mg/L. The in vivo experiments revealed that compounds A27 and B6 presented excellent protective and curative efficacies against P. capsici , similar to that of the positive control dimethomorph . Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed that compound B6 could change the mycelial morphology and severely damage the ultrastructure of P. capsici . The results of the in vitro SDH enzymatic inhibition experiments indicated that compounds A27 and B6 could effectively inhibit the activity of P. capsici SDH ( Pc SDH). Furthermore, molecular docking analysis demonstrated significant hydrogen bonds and Pi-S bonding between the target compounds and the key amino acid residues of Pc SDH, which could explain the probable mechanism of action. Collectively, these studies provide a valuable approach to expanding the fungicidal spectrum of pyrazol-5-yl-benzamide derivatives.

Structure optimization based on natural products has become an effective way to develop new green fungicides. In this project, thirty-two novel NPs-derived hydrazide compounds were designed and synthesized by introducing the bioactive hydrazide substructure into sinapic acid and mycophenolic acid. The fungicidal bioassays indicated that the obtained hydrazide compounds showed excellent and selective fungicidal activity against specific pathogens, especially compounds C8 , D7 , and D8 with EC 50 values of 0.63, 0.56, and 0.43 μg mL -1 against M. oryzae , respectively. SAR indicated that the introduction of 4-fluoro, 4-chloro, and 2,4-difluoro groups was conducive to improving the fungicidal activity, while the extension of the hydrazide bridge would affect the selectivity for inhibitory activity. Subsequently, the effects of hydrazide compounds on rice seedling and zebrafish growth were also investigated. The fungicidal mechanism implied that treatment with compound B4 would cause significant changes in metabolites of plasma membrane-related linolenic acid metabolism, arachidonic acid metabolism, and α-linolenic acid metabolism pathways, which further led to the wrinkled hyphae and the blurred plasma membrane and cytoplasm. Finally, the frontier molecular orbitals and charge distribution were calculated to analyze the differences in bioactivity from a structural perspective. These results provide important guidance for the development and practical application of novel fungicides.

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, in this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides I - III as potent SDH inhibitors using active fragment exchange and link approach. The results of the fungicidal activity assays showed that some of the synthesized compounds exhibited excellent inhibition against the tested fungi. Systematic structure-activity relationship studies led to the discovery of compound Ip , N -(1-((4,6-difluorobenzo[ d ]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)- N -methoxy-1-methyl-1 H -pyrazole-4-carboxamide, which showed higher fungicidal activity against Fusarium graminearum Schw (EC 50 = 0.93 μg/mL) than the commercial fungicides thifluzamide (EC 50 > 50 μg/mL) and boscalid (EC 50 > 50 μg/mL). The molecular simulation studies suggested that hydrophobic interactions were the primary driving forces between ligands and SDH. Promisingly, we found that Ip could stimulate the growth of wheat seedlings and Arabidopsis thaliana and increase the biomass of the treated plants. Preliminary studies on the plant growth promoter mechanism of Ip indicated that it could increase nitrate reductase activity in planta , that, in turn, stimulates the growth of plants.

Considering that humans are unavoidably exposed to triazole fungicides through the esophagus, respiratory tract, and skin contact, revealing the developmental toxicity of triazole fungicides is vital for health risk assessment. This study aimed to screen and discriminate neural developmental disorder chemicals in commonly used triazole fungicides, and explore the underlying harmful impacts on neurogenesis associated with histone modification abnormality in mouse embryonic stem cells (mESCs). The triploblastic and neural differentiation models were constructed based on mESCs to expose six typical triazole fungicides (myclobutanil, tebuconazole, hexaconazole, propiconazole, difenoconazole, and flusilazole). The result demonstrated that although no cytotoxicity was observed, different triazole fungicides exhibited varying degrees of alterations in neural differentiation, including increased ectodermal differentiation, promoted neurogenesis, increased intracellular calcium ion levels, and disturbance of neurotransmitters. Molecular docking, cluster analysis, and multiple linear regressions demonstrated that the binding affinities between triazole fungicides and the Kdm6b-ligand binding domain were the dominant determinants of the neurodevelopmental response. This partially resulted in the reduced enrichment of H3K27me3 at the promoter region of the serotonin receptor 2 C gene, finally leading to disturbed neural differentiation. The data suggested potential adverse outcomes of triazole fungicides on embryonic neurogenesis even under sublethal doses through interfering histone modification, providing substantial evidence on the safety control of fungicides., 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 © 2023 Elsevier B.V. All rights reserved.)

Target based molecular design via the aid of computation is one of the most efficient methods in the discovery of novel pesticides. Here, a combination of the comparative molecular field analysis (CoMFA) and molecular docking was applied for discovery of potent fungicidal [1,2,4]-triazolo-[3,4- b ][1,3,4]-thiadiazoles. Bioassay results indicated that the synthesized target compounds 3a , 3b , and 3c exhibited good activity against Alternaria solani , Botrytis cinerea , Cercospora arachidicola , Fusarium graminearum , Physalospora piricola , Rhizoctonia solani , and Sclerotinia sclerotiorum with an EC 50 value falling between 0.64 and 16.10 μg/mL. Specially, 3c displayed excellent fungicidal activity against C. arachidicola and R. solani, which was 5 times more potent than the lead YZK-C22 . The enzymatic inhibition assay and fluorescence quenching analysis with R. solani pyruvate kinase (RsPK) showed a weaker binding affinity between RsPK and 3a , 3b , or 3c . Transcriptomic analyses showed that 3c exerted its fungicidal activity by disrupting steroid biosynthesis and ribosome biogenesis in eukaryotes. These findings support that 3c is a promising fungicide candidate, and a fine modification from a lead may lead to a totally different mode of action.

Background: Succinate dehydrogenase inhibitors (SDHIs) emerging in fungicide markets are widely used in crop protection. Currently, the structural modification focusing on a structurally diverse 'core' moiety (aryl) of SDHIs is being gradually identified as one of the innovative strategies for developing novel, highly effective and low resistant fungicides., Results: By optimization of lead compound SCU2028, 30 novel aromatic carboxamides Ia-o and IIa-o without a pyrazol group were designed, synthesized and characterized by 1 H NMR, 13 C NMR and high resolution mass spectrum (HRMS). In vitro antifungal activities showed that most of the compounds Ia-o and IIa-o exhibited good antifungal activities against Rhizoctonia solani. Among them, compounds Ic and IIc (EC 50  = 0.02 mg/L), with the 2-chloro-3-pyridyl moiety, and compounds Io (EC 50  = 0.03 mg/L) and IIo (EC 50  = 0.02 mg/L), with the 4-methyl-2-trifluoromethylthiazolyl moiety, all exhibited the equivalent antifungal activities against R. solani with compound SCU2028 (EC 50  = 0.03 mg/L) and bixafen (EC 50  = 0.04 mg/L). Additionally, in pot tests, compound IIc (EC 50  = 3.63 mg/L) also had higher antifungal activity against R. solani than compound SCU2028 (EC 50  = 7.63 mg/L). Furthermore, in vitro inhibitory activity against fungal SDH showed the inhibitory ability of compound IIc was equivalent with that of compound SCU2028, and molecular dynamics simulation of the SDH-compound IIc complex suggested that compound IIc could strongly bind to and interact with the binding site of SDH., Conclusion: Novel aromatic carboxamides without a pyrazol group have potential as a class of SDHIs, and the strategy of replacing the pyrazol group with another aryl in the 'core' moiety might offer an alternative option in discovery of SDHI fungicides. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Background: Succinate dehydrogenase is an important target of fungicides. Succinate dehydrogenase inhibitors (SDHIs) have widely been used to combat destructive plant pathogenic fungi because they possess efficient and broad-spectrum antifungal activities and as well as unique mode of action. The research and development of novel SDHIs have been ongoing., Results: Thirty-six novel quinolin-2(1H)-one derivatives were designed, synthesized and characterized. The single crystal structure of compound 3c was determined through the X-ray diffraction of single crystals. The bioassay results displayed that most compounds had good antifungal activities at 16 μg mL -1 against Rhizoctonia cerealis, Erysiphe graminis, Botrytis cinerea, Penicillium italicum and Phytophthora infestans. Compounds 6o, 6p and 6r had better antifungal activities than the commercialized fungicide pyraziflumid against Botrytis cinerea. Their half maximal effective concentration (EC 50 ) values were 0.398, 0.513, 0.205 and 0.706 μg mL -1 , respectively. Moreover, the inhibiting activities of the bioactive compounds were tested against succinate dehydrogenase. The results indicated that they possessed outstanding activities. Compounds 6o, 6p and 6r also exhibited better inhibiting activities than pyraziflumid against succinate dehydrogenase. Their half maximal inhibitory concentration (IC 50 ) values were 0.450, 0.672, 0.232 and 0.858 μg mL -1 , respectively. The results of molecular dynamic (MD) simulations indicated that compound 6r displayed stronger affinity to succinate dehydrogenase than pyraziflumid., Conclusion: The results of the present study displayed that quinolin-2(1H)-one derivative could be one scaffold of potential SDHIs and will provide some valuable information for the research and development of new SDHIs. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Background: Plant pathogenic fungal infections have become a severe threat to the yield and quality of agricultural products, and new green antifungal agents with high efficiency and low toxicity are needed. In this study, a series of thiasporine A derivatives containing phenylthiazole-1,3,4-oxadiazole thione (ketone) structures were designed and synthesized, and their antifungal activities against six invasive and highly destructive phytopathogenic fungi were evaluated., Results: The results found that all compounds showed moderate to potent antifungal activity against six phytopathogenic fungi, and most of the E series compounds showed remarkable antifungal activity against Sclerotinia sclerotiorum and Colletotrichum camelliaet. In particular, compounds E1-E5, E7, E8, E13, E14, E17, and E22 showed more significant antifungal activity against S. sclerotiorum, with half-maximal effective concentration (EC 50 ) values of 0.22, 0.48, 0.56, 0.65, 0.51, 0.39, 0.60, 0.56, 0.60, 0.63, and 0.45 μg mL -1 , respectively, which were superior to that of carbendazim (0.70 μg mL -1 ). Further activity studies showed that compound E1 possessed superior curative activities against S. sclerotiorum in vivo and better inhibitory effects on sclerotia germination and the formation of S. sclerotiorum compared with those of carbendazim., Conclusions: This study indicates that these thiasporine A derivatives containing phenylthiazole-1,3,4-oxadiazole thione structures might be used as antifungal agents against S. sclerotiorum. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

For the purpose of screening high-efficiency and low-risk green pesticides, a systematic study on fungicide penthiopyrad was conducted at the enantiomeric level. The bioactivity of S-(+)-penthiopyrad (median effective concentration (EC 50 ), 0.035 mg/L) against Rhizoctonia solani was 988 times higher than R-(-)-penthiopyrad (EC 50 , 34.6 mg/L), which would reduce 75% usage of rac-penthiopyrad under the same efficacy. Furthermore, their antagonistic interaction (toxic unit (TU rac ), 2.07) indicated the existence of R-(-)-penthiopyrad would reduce the fungicidal activity of S-(+)-penthiopyrad. AlphaFold2 modeling and molecular docking illustrated that S-(+)-penthiopyrad had the higher binding ability with the target protein than R-(-)-penthiopyrad, showing higher bioactivity. For model organism Danio rerio, S-(+)-penthiopyrad (median lethal concentrations (LC 50 ), 3.02 mg/L) and R-(-)-penthiopyrad (LC 50 , 4.89 mg/L) were both less toxic than rac-penthiopyrad (LC 50 , 2.73 mg/L), and the existence of R-(-)-penthiopyrad could synergistically enhance the toxicity of S-(+)-penthiopyrad (TU rac , 0.73), using S-(+)-penthiopyrad would reduce at least 23% toxicity to fish. The enantioselective dissipation and residues of rac-penthiopyrad were tested in three kinds of fruits, and their dissipation half-lives ranged from 1.91 to 23.7 d. S-(+)-penthiopyrad was dissipated preferentially in grapes, which was R-(-)-penthiopyrad in pears. On the 60th d, the residue concentrations of rac-penthiopyrad in grapes were still higher than its maximum residue limit (MRL), but the initial concentrations were lower than their MRL values in watermelons and pears. Thus, more tests in different cultivars of grapes and planting environments should be encouraged. Based on the acute and chronic dietary intake risk assessments, the risks in the three fruits were all acceptable. In conclusion, S-(+)-penthiopyrad is a high-efficiency and low-risk alternative to rac-penthiopyrad., 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 © 2023 Elsevier Ltd. All rights reserved.)

Derivatives of morpholine are biologically active organic compounds with special structures discovered in multiple drugs. As a result of the terminal pharmacophore of action and extraordinary activity, they attracted fair attention with regard to pesticide innovation and development. Analysis of brief structure-activity relationships and the summarization of the characteristics of pesticides containing morpholine fragments with efficient activity are key steps in the development of novel pesticides. This review primarily overviews morpholine compounds with insecticidal, fungicidal, herbicidal, antiviral, and plant growth regulation properties to provide educational insight for the creation of new morpholine-containing compounds.

To explore more efficient and less toxic antibacterial and antifungal pesticides, we utilized 2,6-difluorobenzamide as a starting material and ultimately synthesized 23 novel benzoylurea derivatives containing a pyrimidine moiety. Their structures were characterized and confirmed by 1 H NMR, 13 C NMR, 19 F NMR, and HRMS. The bioassay results demonstrated that some of the title compounds exhibited moderate to good in vitro antifungal activities against Botrytis cinerea in cucumber, Botrytis cinerea in tobacco, Botrytis cinerea in blueberry, Phomopsis sp., and Rhizoctonia solani . Notably, compounds 4j and 4l displayed EC 50 values of 6.72 and 5.21 μg/mL against Rhizoctonia solani , respectively, which were comparable to that of hymexazol (6.11 μg/mL). Meanwhile, at 200 and 100 concentrations, the target compounds 4a - 4w exhibited lower in vitro antibacterial activities against Xanthomonas oryzae pv. oryzicola and Xanthomonas citri subsp. citri , respectively, compared to those of thiodiazole copper. Furthermore, the molecular docking simulation demonstrated that compound 4l formed hydrogen bonds with SER-17 and SER-39 of succinate dehydrogenase (SDH), providing a possible explanation for the mechanism of action between the target compounds and SDH. This study represents the first report on the antifungal and antibacterial activities of novel benzoylurea derivatives containing a pyrimidine moiety.

The roles of soil and earthworm gut microorganisms in the degradation of the chiral fungicide imazalil (IMA) enantiomers were systemically studied in soil-earthworm systems. S-IMA degraded slower than R-IMA in soil without earthworms. After the addition of earthworms, S-IMA degraded faster than R-IMA. Methylibium was the potential degradative bacterium likely related to the preferential degradation of R-IMA in soil. However, the addition of earthworms significantly decreased the relative abundance of Methylibium, especially in R-IMA-treated soil. Meanwhile, a new potential degradative bacterium Aeromonas first appeared in soil-earthworm systems. Compared with enantiomer-treated soil, the relative abundance of indigenous soil bacterium Kaistobacter significantly boomed in enantiomer-treated soil with earthworms. Interestingly, Kaistobacter in the earthworm gut also obviously increased after exposure to enantiomers, particularly in S-IMA-treated soil, which was associated with the significant increase in Kaistobacter in soil. More importantly, the relative abundances of Aeromonas and Kaistobacter in S-IMA-treated soil were obviously higher than those in R-IMA-treated soil after the addition of earthworms. Moreover, these two potential degradative bacteria were also potential bacterial hosts of the biodegradation genes p450 and bph. Collectively, gut microorganisms are important helpers in soil pollution remediation by participating in the preferential degradation of S-IMA mediated by indigenous soil microorganisms., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Fungal diseases remain important causes of crop failure and economic losses. As the resistance toward current selective fungicides becomes increasingly problematic, it is necessary to develop efficient fungicides with novel chemotypes., Results: A series of novel quinazolin-6-ylcarboxylates which combined the structures of pyridine or heterocyclic motif and the N-(3-chloro-4-fluorophenyl)quinazolin-4-amine moiety, a binding group of ATP-binding site of gefitinib, were evaluated for their fungicidal activity on different phytopathogenic fungi. Most of these compounds showed excellent fungicidal activities against Botrytis cinerea and Exserohilum rostratum, especially compound F17 displayed the highest activity with EC 50 values as 3.79 μg mL -1 against B. cinerea and 2.90 μg mL -1 against E. rostratum, which was similar to or even better than those of the commercial fungicides, such as pyraclostrobin (EC 50 , 3.68, 17.38 μg mL -1 ) and hymexazol (EC 50 , 4.56, 2.13 μg mL -1 ). Moreover, compound F17 significantly arrested the lesion expansion of B. cinerea infection on tomato detached leaves and strongly suppressed grey mold disease on tomato seedlings in greenhouse. The abilities of compound F17 to induce cell apoptosis of the non-germinated spores, to limit oxalic acid production, to reduce malate dehydrogenase (MDH) expression, and to block the active pocket of MDH protein were demonstrated in B. cinerea., Conclusion: The novel quinazolin-6-ylcarboxylates containing ATP-binding site-directed moiety, especially compound F17, could be developed as a potential fungicidal candidate for further study. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

In this project, quinoline and quinolone-containing hydrazide compounds were designed and synthesized by introducing a bioactive hydrazide group into the skeleton of waltherione F. The fungicidal activity revealed that some hydrazide compounds exhibited excellent and broad-spectrum fungicidal activity; especially, compounds E8 , E12 , and E16 showed more than 90% or even 100% inhibition rates against most pathogens at 50 μg·mL -1 . The fungicidal mechanism indicated that compound E8 may affect the normal function of the plasma membrane, further generating changes in the morphology and subcellular structure of mycelia. Simultaneously, Fusarium graminearum may resist the E8 -treated stress through the metabolic pathways related to l-glutamate, l-glutamine, and glutathione. Finally, the effect of compound E8 on wheat seedling's growth and the toxicity to zebrafish were accomplished. These results will provide important guidance to discover novel fungicidal lead compounds and explore new targets, which are effective ways to alleviate the increasingly severe drug resistance.

Agricultural production is seriously threatened by plant pathogens. The development of new fungicides with high efficacy and low toxicity is urgently needed. In this study, a series of pyrazole carboxamide thiazole derivatives were designed, synthesized, and evaluated for their antifungal activities against nine plant pathogens in vitro . Bioassay results showed that most compounds ( 3i , 5i , 6i , 7i , 9i , 12i , 16i , 19i , and 23i ) exhibited good antifungal activities against Valsa mali . In particular, compounds 6i and 19i exhibited better antifungal activities against Valsa mali with EC 50 values of 1.77 and 1.97 mg/L, respectively, than the control drug boscalid (EC 50 = 9.19 mg/L). Additionally, compound 23i exhibited excellent inhibitory activity against Rhizoctonia solani , with an EC 50 value of 3.79 mg/L. Compound 6i at 40 mg/L showed a satisfactory in vivo protective effect against Valsa mali . Scanning electron microscopy analyses revealed that compound 6i could significantly damage the surface morphology to interfere with the growth of Valsa mali . In molecular docking, the results showed that compound 6i interacts with TRP O: 173, SER P: 39, TYR Q: 58, and ARG P: 43 of succinate dehydrogenase (SDH) through hydrogen bonding and σ-π interaction, and its binding mode is similar to that of boscalid and SDH. The enzyme activity experiment also further verified its action mode. Our studies suggested that pyrazole carboxamide thiazole derivative 6i provided a valuable reference for the further development of succinate dehydrogenase inhibitors.

The discovery of novel and easily available leads provides a convincing solution to agrochemical innovation. A bioassay-guided scaffold subtraction of the previous "Chem-Bio Model" isoquinoline-3-oxazoline MIQOX was conducted for identifying the easily available isoquinoline-3-hydrazide as a novel antifungal scaffold. The special and practical potential of this model was demonstrated by a phenotypic antifungal bioassay, molecular docking, and cross-resistance evaluation. A panel of antifungal leads ( LW2 , LW3 , and LW11 ) was acquired, showing much better antifungal performance than the positive controls. Specifically, compound LW3 exhibited a broad antifungal spectrum holding EC 50 values as low as 0.54, 0.09, 1.52, and 2.65 mg/L against B. cinerea , R. solani , S. sclerotiorum , and F. graminearum , respectively. It demonstrated a curative efficacy better than that of boscalid in controlling the plant disease caused by B. cinerea . The candidate LW3 did not show cross-resistance to the extensively used succinate dehydrogenase inhibitor (SDHI) fungicides and can efficiently inhibit resistant B. cinerea strains. The molecular docking of compound LW3 is quite different from that of the positive controls boscalid and fluopyram. This progress highlights the practicality of isoquinoline hydrazide as a novel model in fungicide innovation.

In recent decades, natural products have been considered important resources for developing of new agrochemicals because of their novel architectures and multibioactivities. Consequently, herein, 1- O -acetylbritannilactone (ABL), a natural sesquiterpene lactone from Inula britannica L., was used as a lead for further modification to discover fungicidal candidates. Six series of ABL-based derivatives containing an oxadiazole, triazole, or imidazole moiety were designed and synthesized, and their antifungal activities were also evaluated in vitro and in vivo . Bioassay results revealed that compounds 8d , 8h , and 8j (EC 50 = 61.4, 30.9, and 12.4 μg/mL, respectively) exhibited more pronounced inhibitory activity against Fusarium oxysporum than their precursor ABL (EC 50 > 500 μg/mL) and positive control hymexazol (EC 50 = 77.2 μg/mL). Derivatives 8d and 11j (EC 50 = 19.6 and 41.5 μg/mL, respectively) exhibited more potent antifungal activity toward Cytospora mandshurica than ABL (EC 50 = 68.3 μg/mL). Compound 10 exhibited excellent and broad-spectrum antifungal activity against seven phytopathogenic fungal mycelia. Particularly, the inhibitory activity of compound 10 against the mycelium of Botrytis cinerea was more than 10.8- and 2.3-fold those of ABL and hymexazol, respectively. Meanwhile, derivative 10 (IC 50 = 47.7 μg/mL) displayed more pronounced inhibitory activity against the spore of B. cinerea than ABL (IC 50 > 500 μg/mL) and difenoconazole (IC 50 = 80.8 μg/mL). Additionally, the in vivo control efficacy of compound 10 against B. cinerea was further studied using infected tomatoes (protective effect = 58.4%; therapeutic effect = 48.7%). The preliminary structure-activity relationship analysis suggested that the introduction of the 1,3,4-oxadiazole moiety (especially the 1,3,4-oxadiazole heterocycle containing the 4-chlorophenyl, 2-furyl, or 2-pyridinyl group) on the skeleton of ABL was more likely to produce potential antifungal compounds. These findings pave the way for further design and development of ABL-based derivatives as potential antifungal agents.

Background: Succinate dehydrogenase inhibitors (SDHIs) are the fastest growing agricultural fungicides at present, but their rapidly growing resistance is a serious problem for their application. Previously, we screened out a fungicidal lead compound CBUA-TPP (1) through triphenylphosphonium (TPP)-driven mitochondrial-targeting strategy. The targeting led to the rapid accumulation of 1 in mitochondria and the saturation inhibition of complex II in a short time, resulting in electron leakage and the explosion of reactive oxygen species (ROS). However, the contribution of biphenyl-2-amines to the activity of these compounds and their structure-activity relationship are still unknown., Results: Two series of CBUA-TPP (1) analogues (series 2 and 3) were designed and synthesized. The bioassay results indicated that series 2 compounds generally showed much higher fungicidal activities than series 3, suggesting the crucial contribution of the biarylamine module in these targeted molecules and the pyridinyl substitution of phenyl is unfavorable to their activities. Interestingly, these two series of compounds displayed almost opposite substituent effects. Several compounds showed excellent fungicidal activities in vitro, among which compound 2-1 exhibited excellent field control efficacy on potato late blight., Conclusion: By optimizing the lead compound, the contribution of biarylamine in CBUA-TPP (1) analogs to the fungicidal activity is clarified. Several compounds, represented by 2-1, have great potential as fungicide candidates. They exhibit high and broad-spectrum fungicidal activities and are highly effective against common pathogenic fungi infecting vegetables and fruits both in vitro and field control. It not only provided a new choice for controlling these diseases, but its low resistance tendency also provided a better scheme for resistance management. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

The element sulfur has an outstanding role in the crop protection chemistry because it is used in its elemental form as a multisite fungicide, but is also part of agrochemicals in the form of aromatic or aliphatic sulfur-containing rings or sulfur-based functional groups. This review gives an exhaustive overview over the latter category. Several fundamental agrochemical compound classes are named after a sulfur-based functionality, such as the dithiocarbamate fungicides and sulfonylurea herbicides. Altogether, 16 different sulfur-based functional groups are presented with their typical synthesis approaches and most important representatives in crop protection. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Triadimefon is ubiquitous in various environmental media. Although toxicity of triadimefon to individual of aquatic organisms has been confirmed, its effect on organisms at population level remain poorly understood. In this study the long-term effect of triadimefon on individual and population of Daphnia magna were studied using multi-generational experiments and matrix model. Development and reproduction of three generations of F1 and F2 were significantly inhibited with the triadimefon concentration of 0.1 mg/L (p < 0.01). Toxicity of triadimefon to the offspring was stronger than to the parent (p < 0.05). When triadimefon concentration was higher than 0.1 mg/L, both population number and intrinsic rate of increase showed a decreasing trend with the increasing exposure concentration. Age structure of the population also tended to decline. Toxicity threshold derived on population-level was between mortality-based LC 50 and reproduction-based NOEC of Daphnia magna, and also between acute toxicity and chronic toxicity derived from species sensitivity distribution (SSD). The risk of population level derived from risk quotient was low for most areas, and the results derived from probability risk showed that the expected loss of intrinsic rate of increase of population was 0.0039 without considering other factors. Compared to the individual-level, the ecological risks at the population level were closer to the actual situation of the ecosystem response to the chemical pollution., 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 © 2023 Elsevier Ltd. All rights reserved.)

Biomimetic oxidation using synthetic iron-porphyrin (F 20 TPPFeCl) as a catalyst eliminated a xylene moiety of the fungicide mandestrobin, uniformly labeled with carbon-14 at the benzyl ring, to produce the corresponding radiolabeled metabolite 1. This reaction mechanism was investigated by identifying chemical structures of intermediate 5 and p-xyloquinone derivatives 6 and 7, as by-products. Optimization of reaction factors based on the mechanism improved the yield of 1 from mandestrobin up to 87%. Finally, various carbon-14 labeled metabolites of mandestrobin were prepared from 1., (© 2023 John Wiley & Sons Ltd.)

Background: The unreasonable use of chemical fungicides causes common adverse consequences that not only affect the environment, but also cause resistance and resurgence problems of plant pathogens, which are extremely harmful to human health, the economy, and the environment. Based on the rich biological activities of boron-based compounds, 82 phenylboronic acid derivatives were selected and their antifungal activities against six agricultural plant pathogens were determined. Combined with transcriptomics tools, the mechanism of action of compound A49 (2-chloro-5-trifluoromethoxybenzeneboronic acid) against Botrytis cinerea Pers (B. cinerea) was studied., Results: The EC 50 values of compounds A24, A25, A30, A31, A36, A41, A49 and B23 against all six fungi were under 10 μg/mL. Compound A49 displayed significant activity against B. cinerea (EC 50  = 0.39 μg/mL), which was better than that of commercial fungicide boscalid (EC 50  = 0.55 μg/mL). A49 not only inhibited the germination of B. cinerea spores, but also caused abnormal cell morphology, loss of cell membrane integrity, enhanced cell membrane permeability, and accumulation of intracellular reactive oxygen species. Further findings showed that A49 reduced cellular antioxidant activity, and peroxidase and catalase activities. Transcriptomic results indicated that A49 could degrade intracellular redox processes and alter the metabolism of some amino acids. Meanwhile, A49 showed obvious activity in vivo and low cytotoxicity to mammal cells., Conclusion: The boron-containing small molecule compounds had high efficiency and broad-spectrum antifungal activities against six plant pathogens, and are expected to be candidate compounds for a new class of antifungal drugs. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Background: Phytopathogenic fungi can cause a direct loss in economic value of agriculture. Especially Valsa mali Miyabe et Yamada, a devastating phytopathogenic disease especially threatening global apple production, is very difficult to control and manage. To discover new potential antifungal agents, a series of thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles were prepared. Their antifungal activities were first tested against six typically phytopathogenic fungi including Curvularia lunata, Valsa mali, Alternaria alternate, Fusarium graminearum, Botrytis cinerea and Fusarium solani. Then their mechanism of action against V. mali was investigated., Results: Derivatives displayed potent antifungal activity against V. mali. Notably, 3-acetyl-N-benzylindole thiosemicarbazone (IV-1: EC 50 : 0.59 μg mL -1 ), whose activity was comparable to that of a commercial fungicide carbendazim (EC 50 : 0.33 μg mL -1 ), showed greater than 98-fold antifungal activity of the precursor indole. Moreover, compound IV-1 displayed good protective and therapeutic effects on apple Valsa canker disease. By scanning electron microscope (SEM) and RNA-Seq analysis, it was demonstrated that compound IV-1 can destroy the hyphal structure and regulate the homeostasis of metabolism of V. mali via the ergosterol biosynthesis and autophagy pathways., Conclusion: 3-Acetyl-N-(un)substituted benzylindoles thiosemicarbazones (IV-1-IV-5) can be studied as leads for further structural modification as antifungal agents against V. mali. Particularly, these ergosterol biosynthesis and autophagy pathways can be used as target receptors for design of novel green pesticides for management of congeneric phytopathogenic fungi. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

As part of our ongoing efforts to discover novel agricultural fungicidal candidates from natural sesquiterpene lactones, in the present work, sixty-three xanthatin-based derivatives containing a arylpyrazole, arylimine, thio-acylamino, oxime, oxime ether, or oxime ester moiety were synthesized. Their structures were well characterized by 1 H and 13 C nuclear magnetic resonance and high-resolution mass spectrometry, while the absolute configurations of compounds 5' and 6a were further determined by single-crystal X-ray diffraction. Meanwhile, the antifungal activities of the prepared compounds against several phytopathogenic fungi were investigated using the spore germination method and the mycelium growth rate method in vitro . The bioassay results illustrated that compounds 5 , 5' , and 15 exhibited excellent inhibitory activity against the tested fungal spores and displayed remarkable inhibitory effects on fungal mycelia. Compounds 5 and 5' exhibited more potent inhibitory activity (IC 50 = 1.1 and 24.8 μg/mL, respectively) against the spore of Botrytis cinerea than their precursor xanthatin (IC 50 = 37.6 μg/mL), wherein the antifungal activity of compound 5 was 34-fold higher than that of xanthatin and 71-fold higher than that of the positive control, difenoconazole (IC 50 = 78.5 μg/mL). Notably, compound 6'a also demonstrated broad-spectrum inhibitory activity against the four tested fungal spores. Meanwhile, compounds 2 , 5 , 8 , and 15 showed prominent inhibitory activity against the mycelia of Cytospora mandshurica with the EC 50 values of 2.3, 11.7, 11.1, and 3.0 μg/mL, respectively, whereas the EC 50 value of xanthatin was 14.8 μg/mL. Additionally, compounds 5' and 15 exhibited good in vivo therapeutic and protective effects against B. cinerea with values of 55.4 and 62.8%, respectively. The preliminary structure-activity relationship analysis revealed that the introduction of oxime, oxime ether, or oxime ester structural fragment at the C-4 position of xanthatin or the introduction of a chlorine atom at the C-3 position of xanthatin might be significantly beneficial to antifungal activity. In conclusion, the comprehensive investigation indicated that partial xanthatin-based derivatives from this study could be considered for further exploration as potential lead structures toward developing novel fungicidal candidates for crop protection.

Developing fungicides from active botanical skeletons is one of the effective methods to tackle the resistance of plant pathogens. Based on our previous discoveries, a series of novel α-methylene-γ-butyrolactone (MBL) derivatives containing heterocycles and phenyl rings were designed according to the antifungal molecule carabrone first discovered in plant Carpesium macrocephalum . The target compounds were synthesized, and the inhibitory activity against pathogenic fungi as well as the mechanism of action were then systematically investigated. Several compounds showed promising inhibitory activities against a variety of fungi. The most potent compound 38 exhibited the EC 50 value of 0.50 mg/L against Valsa mali ( V. mali ), which was more effective than that of commercial fungicide famoxadone. The protective effect of compound 38 against V. mali on apple twigs was superior to that of famoxadone, with an inhibition rate of 47.9% at 50 mg/L. The physiological and biochemical results showed that compound 38 inhibits V. mali by causing cell deformation and contraction, reducing the number of intracellular mitochondria, thickening the cell wall, as well as increasing the permeability of the cell membrane. Based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, it was shown that the introduction of the bulky and negatively charged groups favored the antifungal activity of the novel MBL derivatives. These findings suggest that compound 38 can be a potential candidate for novel fungicides worthy of further investigation further.

Severe plant virus diseases lead to poor harvests and poor crop quality, and the lack of effective suppressive drugs makes plant disease control a huge challenge. Natural product-based structural simplification is an important strategy for finding novel pesticide candidates. According to our previous research on the antiviral activities of harmine and tetrahydroharmine derivatives, a series of chiral diamine compounds were designed and synthesized by means of structural simplification using diamines in natural products as the core structure in this work, and the antiviral and fungicidal activities were investigated. Most of these compounds displayed higher antiviral activities than those of ribavirin. Compounds 1a and 4g displayed higher antiviral activities than ningnanmycin at 500 μg/mL. The antiviral mechanism research revealed that compounds 1a and 4g could inhibit virus assembly by binding to tobacco mosaic virus (TMV) CP and interfere with the assembly process of TMV CP and RNA via transmission electron microscopy and molecular docking. Further fungicidal activity tests showed that these compounds displayed broad-spectrum fungicidal activities. Compounds 3a , 3i , 5c , and 5d with excellent fungicidal activities against Fusarium oxysporum f.sp. cucumerinum can be considered as new fungicidal candidates for further research. The current work provides a reference to the development of agricultural active ingredients in crop protection.

To discover fungicides with novel targets, a series of N -acyl-1,2,3,4-tetrahydroquinoline (NATHQ) derivatives were designed and synthesized by linking the active substructure NATHQ moiety in aspernigerin with the O -benzyl oxime-ether scaffold in commercial agrochemicals. Target compound structures were identified using proton and carbon-13 nuclear magnetic resonance spectroscopies and high-resolution mass spectrometry. Preliminary bioassays indicated that at 40 mg/L, some target compounds exhibited moderate to considerable in vitro fungicidal activities against Rhizoctonia solani and Botrytis cinerea . In particular, compound 3j exhibited higher fungicidal activities both in vitro (EC 50 = 0.733 mg/L) and in vivo (EC 50 = 15.2 mg/L) against R. solani than the commercial fungicide prochloraz; therefore, it should be a promising fungicide candidate against rice sheath blight. Additionally, compound 3j exhibited good laccase inhibitory activity (73.2% at 200 mg/L). Molecular docking revealed that the bis-cyano-oxime-ether moiety of compound 3j exhibited an excellent binding mode with the laccase target protein and could be used as a lead compound for developing laccase inhibitors. The structural features of these NATHQ derivatives will provide inspiration for developing laccase inhibitors and discovering more effective fungicides to control agricultural diseases.

The conformational restriction switch concept has been adopted as a major tool for structural optimization of pharmaceuticals in order to expand the chemical structure scope and improve therapeutic activity against specific proteins. Several of the 1-aminocyclobutanecarboxylic acid derivatives produced in this way exhibited satisfactory antifungal activity in vitro compared with positive control boscalid. In vitro antifungal tests revealed that compound A21 had comparable, even higher antifungal activity against Rhizoctonia solani ( R . s ., EC 50 = 0.03 mg/L) and Botrytis cinerea ( B . c ., EC 50 = 0.04 mg/L) than fluxapyroxad ( R . s ., EC 50 = 0.02 mg/L; B . c ., EC 50 = 0.20 mg/L) and boscalid ( R . s ., EC 50 = 0.29 mg/L; B . c ., EC 50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity against porcine SDH, its IC 50 value was 3.73 μM, which has considerable potency compared with fluxapyroxad (IC 50 = 3.76 μM). The mode of action was determined using SEM and membrane potential research. The effects of the substituent steric hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable models of comparative molecular field analysis and comparative molecular similarity index analysis. Furthermore, density functional theory simulations, molecule electrostatic potential, and molecular docking were also used to study the probable binding mode of target compounds with flexible fragments. The results showed that the scaffold of 1-aminocyclobutanecarboxylic acid derivatives could be used as lead for discovering new succinate dehydrogenase inhibitors.

In this report, two polymeric matrix systems at macro and nanoscales were prepared for efficacious fungicide delivery. The macroscale delivery systems used millimeter-scale, spherical beads composed of cellulose nanocrystals and poly(lactic acid). The nanoscale delivery system involved micelle-type nanoparticles, composed of methoxylated sucrose soyate polyols. Sclerotinia sclerotiorum (Lib.), a destructive fungus affecting high-value industrial crops, was used as a model pathogen against which the efficacy of these polymeric formulations was demonstrated. Commercial fungicides are applied on plants frequently to overcome the transmission of fungal infection. However, fungicides alone do not persist on the plants for a prolonged period due to environmental factors such as rain and airflow. There is a need to apply fungicides multiple times. As such, standard application practices generate a significant environmental footprint due to fungicide accumulation in soil and runoff in surface water. Thus, approaches are needed that can either increase the efficacy of commercially active fungicides or prolong their residence time on plants for sustained antifungal coverage. Using azoxystrobin (AZ) as a model fungicide and canola as a model crop host, we hypothesized that the AZ-loaded macroscale beads, when placed in contact with plants, will act as a depot to release the fungicide at a controlled rate to protect plants against fungal infection. The nanoparticle-based fungicide delivery approach, on the other hand, can be realized via spray or foliar applications. The release rate of AZ from macro- and nanoscale systems was evaluated and analyzed using different kinetic models to understand the mechanism of AZ delivery. We observed that, for macroscopic beads, porosity, tortuosity, and surface roughness governed the efficiency of AZ delivery, and for nanoparticles, contact angle and surface adhesion energy were directing the efficacy of the encapsulated fungicide. The technology reported here can also be translated to a wide variety of industrial crops for fungal protection. The strength of this study is the possibility of using completely plant-derived, biodegradable/compostable additive materials for controlled agrochemical delivery formulations, which will contribute to reducing the frequency of fungicide applications and the potential accumulation of formulation components in soil and water.

Background: To explore further potential natural product-based antifungal agents, a series of novel nopol-based carboxamide and hydrazide derivatives containing a natural pinene structure were designed, synthesized, and evaluated for their inhibitory activities against seven phytopathogenic fungi and oomycetes., Results: The bioassay results indicated that some compounds exhibited good inhibitory activities against Gibberella zeae, Sclerotinia sclerotiorum, and Phytophthora capsici. Among them, compound 3h displayed excellent in vitro activities against G. zeae, with EC 50 values of 1.09 mg L -1 , which was comparable with the commercial fungicides bixafen and carbendazim (median effective concentration [EC 50 ] = 1.21 and 0.89 mg L -1 , respectively). Notably, in vivo bioassay results suggested that compound 3h also showed prominent protective and curative effects (95.6% and 94.2%) at 200 mg L -1 against G. zeae. The scanning electron microscopy study indicated that compound 3h could destroy the morphological integrity of G. zeae hyphae. The in vitro enzyme inhibitory bioassay revealed that compound 3h exhibited potent inhibitory activity against laccase with median inhibitory concentration (IC 50 ) values of 4.93 μm, superior to positive control cysteine (IC 50  = 35.50 μm), and its binding modes with laccase were elucidated by molecular docking study. In addition, the fluorescent imaging of the dansylamide-labeled derivatives 8 on wheat leaf epidermal cells and the hyphae of G. zeae revealed that this class of hydrazide derivatives could readily permeate into wheat leaves and reached the laccase target in fungal cells., Conclusion: Some nopol-based hydrazide derivatives exhibited excellent anti-G. zeae activity and laccase inhibitory activity, which merits further development as a new fungicide candidate for controlling Fusarium head blight. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

In our previous work, two dopamine derivatives with benzothiazole fragment were isolated and identified from Polyrhachis dives (P. dives). Based on their characteristic structure, we used them as lead compound to carry out structural optimization and subsequent fungicidal evaluation. Here 20 dopamine derivatives with benzothiazole fragment were designed and synthesized by a facile method, and their structures were characterized by 1 H-NMR, 13 CNMR and HMRS. In bioassays, most of the title compounds possess potential fungicidal activities against Altenaia alternala (A. alternala) and Botrytis cinerea (B. cinerea). Especially, (E)-N-(2-(benzo[d]thiazol-6-yl)ethyl)-3-(p-tolyl)acrylamide and (E)-N-(2-(benzo[d]thiazol-6-yl)ethyl)-3-(4-(trifluoromethyl)phenyl)acrylamide displayed 29.3 mg/L and 10.7 mg/L EC 50 value against A. alternala, respectively, which possessed equivalent fungicidal activities level to hymexazol., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Two series of dehydroabietyl-1,2,4-triazole-4-Schiff-based derivatives were synthesized from rosin to control plant fungal diseases. In vitro evaluation and screening of the antifungal activity were performed using Valsa mali , Colletotrichum orbiculare , Fusarium graminearum , Sclerotinia sclerotiorum , and Gaeumannomyces graminis . Compound 3f showed excellent fungicidal activity against V. mali (EC 50 = 0.537 μg/mL), which was significantly more effective than the positive control fluconazole (EC 50 = 4.707 μg/mL). Compound 3f also had a considerable protective effect against V. mali (61.57%-92.16%), which was slightly lower than that of fluconazole (85.17-100%) at 25-100 μg/mL. Through physiological and biochemical analyses, the preliminary mode of action of compound 3f against V. mali was explored. Ultrastructural observation of mycelia showed that compound 3f hindered the growth of the mycelium and destroyed the ultrastructure of V. mali seriously. Conductivity analysis and laser scanning confocal microscope staining showed that compound 3f changed cell-membrane permeability and caused accumulation of reactive oxygen species. The enzyme activity results showed that compound 3f significantly inhibited the activity of CYP51 (59.70%), SOD (76.9%), and CAT (67.86%). Molecular docking identified strong interaction energy between compound 3f and crystal structures of CYP51 (-11.18 kcal/mol), SOD (-9.25 kcal/mol), and CAT (-8.79 kcal/mol). These results provide guidance for the discovery of natural product-based antifungal pesticide candidates.

Photodegradation behavior of a new fungicide isopyrazam in water under simulated sunlight and ultraviolet (UV) irradiation was studied. The photolysis half-life ( t 1/2 ) of isopyrazam in purified water was 195 h under simulated sunlight, which was decreased to 46-88 h, 28-51 h, and 13-18 h in the presence of NO 3 - , Fe 3+ , and riboflavin, respectively. UV irradiation accelerated the photolysis of isopyrazam with a half-life of 30 min and revealed varied degradation rates in acidic (0.011 min -1 ), neutral (0.024 min -1 ), and alkaline solutions (0.022 min -1 ). Nine transformation products under simulated sunlight and UV were found, and photolytic pathways were proposed to include cleavage of C-N bonds, hydroxylation, nitration, demethylation, dehydrofluorination, and photoisomerization. The acute toxicity of defluorinated isopyrazam (TP 4) and the chronic toxicity of isomerized isopyrazam (TP 9) to aquatic organisms were approximately twice that of isopyrazam. These findings provide insights into environmental risk assessment and management of water pollution.

Aiming to develop novel antifungal agents with a distinctive molecular scaffold targeting succinate dehydrogenase (SDH), 24 N '-phenyl-1 H -pyrazole-4-sulfonohydrazide derivatives were first devised, synthesized, and verified by 1 H NMR, 13 C 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 EC 50 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 IC 50 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-1 H -pyrazole pyrazole-4-sulfonohydrazide derivatives are worthy of being further investigated as the promising replacements of traditional carboxamide derivatives targeting SDH of fungi.

A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis of the structure of commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping and evaluated for their antifungal activities against five fungi. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activity against Rhizoctonia solani and some compounds exerted remarkable antifungal activities against Sclerotinia sclerotiorum , Botrytis cinerea , Fusarium graminearum , and Alternaria alternate . Particularly, compounds 7d and 12b displayed outstanding antifungal activity against R. solani , with an EC 50 value of 0.046 μg/mL, far superior to that of boscalid (EC 50 = 0.741 μg/mL) and fluxapyroxad (EC 50 = 0.103 μg/mL). Meanwhile, compound 12b also presented a broader fungicidal spectrum than other compounds. Moreover, in vivo anti- R. solani results showed that compounds 7d and 12b could significantly inhibit the growth of R. solani in rice leaves with excellent protective and curative efficacies. In addition, the results of the succinate dehydrogenase (SDH) enzymatic inhibition assay showed that compound 7d generated significant SDH inhibition, with an IC 50 value of 3.293 μM, which was about 2 times better than that of boscalid (IC 50 = 7.507 μM) and fluxapyroxad (IC 50 = 5.991 μM). Furthermore, scanning electron microscopy (SEM) analysis indicated that compounds 7d and 12b significantly destroyed the typical structure and morphology of R. solani hyphae. The molecular docking study revealed that compounds 7d and 12b could embed into the binding pocket of SDH and form hydrogen bond interactions with TRP173 and TRY58 at the activity site of SDH, which was in line with fluxapyroxad, indicating that they had a similar mechanism of action. These results demonstrated that compounds 7d and 12b could be promising candidates of SDHI fungicides, which deserved further investigation.

Penthiopyrad is a widely used succinic dehydrogenase inhibitor fungicide with two enantiomers, while the data on its enantioselective behaviors in crops are limited. The enantioselective dissipation may directly or indirectly expose people to the preferentially residual enantiomer, which may affect the dietary risks of chiral penthiopyrad. In this study, the enantioselective behaviors of chiral penthiopyrad in five kinds of crops and whole-age dietary risk assessments were conducted. The dissipation half-lives of penthiopyrad enantiomers were in the range of 0.48-13.7 days. S -(+)-Penthiopyrad was preferentially dissipated in soybean plants, soybean, peanut kernel, peanut shell, celery, tomato, and soil, which was opposite in cabbage. The opposite enantioselective residue might expose people to different enantiomer, which bring more complex risks. On the 35th day (the harvest time), the residue concentrations of penthiopyrad were all lower than MRLs except celery. For acute dietary intake risks, the children aged 2-7 suffered the highest risks, especially for cabbage (RQ a , 138%) and celery (RQ a , 140%), which were unacceptable. For other people, the acute dietary intake risks of rac -penthiopyrad in cabbage and celery were also very high and in the range of 88.6-94.8%, which should raise concern. The chronic dietary intake risks of rac -penthiopyrad in the all crops for groups of Chinese population with different ages and genders were acceptable (HQ, 0.0006-29.1%), and the risks were the highest in celery, especially for children aged 2-7. This study could provide data support for the environmental behaviors and risk assessments of penthiopyrad at the enantiomeric level.

Benzovindiflupyr has gained increasing attention as a new chiral succinate dehydrogenase inhibitor fungicide; however, its determination, bioactivity, and mechanism at the enantiomeric level are very limited. In the present study, optical rotation determination and X-ray single-crystal diffraction results identified that the absolute configurations were (+)-(1 R ,4 S )-benzovindiflupyr and (-)-(1 S ,4 R )-benzovindiflupyr. A quantitative determination method for enantiomers was established using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for pesticide detection. The stereoselective bioactivity assay indicated that (-)-(1 S ,4 R )-benzovindiflupyr exhibited greater potency than (+)-(1 R ,4 S )-benzovindiflupyr against seven phytopathogenic fungi. Molecular docking analysis showed that (-)-(1 S ,4 R )-benzovindiflupyr possessed a stronger binding affinity to succinate dehydrogenase than (+)-(1 R ,4 S )-benzovindiflupyr. The binding modes between enantiomers and the mutant with H272(B) predicted that the phytopathogenic fungi with H272(B) of succinate dehydrogenase mutation would not be resistant to benzovindiflupyr enantiomers. This study provides a basis for residue evaluation, risk assessment, and the safe application of benzovindiflupyr at the enantiomer level.

Hydrazides are present in many bioactive molecules and exhibit a variety of biological activities, such as insecticidal, herbicidal, antifungal, antitumor, and antiviral effects. In this Review, we review the application of hydrazide and its derived structures in the agricultural fungicidal field, including monohydrazides, diacylhydrazines, hydrazide-hydrazones, and sulfonyl hydrazides. In addition, the antifungal mechanism of action of the hydrazide derivatives was analyzed and summarized, mainly involving succinate dehydrogenase inhibitors, laccase inhibitors, and targeting plasma membranes. Finally, based on the structural analysis of the novel fungicidal lead compounds, the structure-activity relationship of the hydrazide derivatives was constructed and the development trend of hydrazide structures in fungicidal applications was prospected. It is hoped that this Review can provide some significant guidance for the development of new hydrazide fungicides in the future.

Pyridachlometyl is a unique pyridazine fungicide with a novel mode of action. Herein, we describe the pathway for the invention of pyridachlometyl. First, we identified a diphenyl-imidazo[1,2-a]pyrimidine as our proprietary lead with potent fungicidal activity. Then, aiming to simplify the chemical structure, we applied judicious estimations to explore monocyclic heterocycles as pharmacophores. This enabled the identification of a novel class of tetrasubstituted pyridazine compounds with potent fungicidal activity, likely retaining the same mode of action as the aforementioned compounds. The findings indicated bioisosteric similarity between diphenyl-imidazo[1,2-a]pyrimidine and pyridazine. Further structure-activity and mammalian safety investigations of pyridazine compounds resulted in the discovery of pyridachlometyl as a candidate for commercial development., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This study was funded by Sumitomo Chemical Co. Ltd., and all authors are employees of Sumitomo Chemical Co. Ltd. The patent-claiming substances, including pyridachlometyl, have been applied under PCT application WO2005/121104 and have been issued in certain countries., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Prothioconazole (PTC), as a popular triazole fungicide, with its main metabolite prothioconazole desthio (PTC-d), have attracted widespread concern due to their widely use and toxicological effects on non-target organisms. However, toxic effects of study analyzed PTC and PTC-d on the hepatic metabolism of mammalian still remains unclear. In this study, we conducted the study of the C57BL/6 mice which oral exposure to 30 mg/kg PTC and PTC-d via metabolomic analysis. In the liver, the metabolomics profile unveiled that exposure to 30 mg/kg PTC and PTC-d led to significantly altered 13 and 28 metabolites respectively, with 6 metabolites in common including significant decreased d-Fructose, Glutathione, showing the change of carbohydrate, lipid and amino acid metabolism. Via the further exploration of genes related to hepatic glycolipid metabolism and the biomarkers of oxidative stress, we found that liver was potentially damaged after exposure to 5 and 30 mg/kg PTC and PTC-d. Particularly, it was proved that PTC-d caused more adverse effect than its parent compound PTC on hepatotoxicity, and high concentration PTC or PTC-d exposure is more harmful than low concentration exposure., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We assessed the mechanism of human androgen receptor-mediated endocrine-disrupting effect by a triazole fungicide, metconazole in this study. The internationally validated stably transfected transactivation (STTA) in vitro assay, which was established for determination of a human androgen receptor (AR) agonist/antagonist by using 22Rv1/MMTV&#95;GR-KO cell line, alongside an in vitro reporter-gene assay to confirm AR homodimerization was used. The STTA in vitro assay results showed that metconazole is a true AR antagonist. Furthermore, the results from the in vitro reporter-gene assay and western blotting showed that metconazole blocks the nuclear transfer of cytoplasmic AR proteins by suppressing the homodimerization of AR. These results suggest that metconazole can be considered to have an AR-mediated endocrine-disrupting effect. Additionally, the evidence from this study might help identify the endocrine-disrupting mechanism of triazole fungicides containing a phenyl ring., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: To obtain new environmentally friendly fungicides, we used the natural product pimprinine as the lead compound, and designed and synthesized two series of ring-opening derivatives of pimprinine containing amide/thioamide. We then studied their antifungal activity against six common plant pathogenic fungi in vitro., Results: Most of the target compounds have good antifungal activity against six important plant pathogenic fungi in vitro. At a concentration of 50 μg ml -1 , compound 3o showed prominent antifungal effects on Alternaria solani and Rhioctornia solani, with inhibition rates of 91.8% and 97.4%, and a 50% effective concentration (EC 50 ) of 6.2255 and 0.6969 μg ml -1 respectively. The EC 50 of compound 3o against Alternaria solani was significantly lower than that of boscalid (13.0380 μg ml -1 ) and flutriafol (11.9057 μg ml -1 ). In addition, compound 3o had good antifungal activity against Sclerotinia sclerotiorum, cucumber powdery mildew, cucumber Botrytis cinerea and Phytophthora capsici in vivo; the antifungal activity of compound 3o against cucumber Botrytis cinerea is 91.7%. At the same time, docking results for highly active compound 3o with the presumed target succinate dehydrogenase and the molecular docking prediction scores of all compounds further indicate its possible antifungal activity mechanism., Conclusion: The designed and optimized derivative 3o of ring-opening pimprinine has good antifungal activity and can be used as a new antifungal drug for further research. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Background: In order to promote the green development of agriculture, it is important to study the enantioselective effect of chiral pesticides. The bioactivity of the chiral fungicide penthiopyrad (PEN) racemate and enantiomers against phytopathogens, toxicity to non-target organisms, effect on tomato fruit growth and maturation, and environmental fate in tomato cultivation were evaluated at an enantioselective level in this study., Results: The results indicated that at the same efficacy, the optically pure S-(+)-PEN could lower the dosage of racemate by 20-96%. The S-enantiomer had low toxicity to earthworms. Besides, the S-(+)-PEN did not cause significant abiotic stress to the tomato and increased fruit fresh weight and size via modulating the contents of plant hormones. However, the content of hydrogen peroxide (H 2 O 2 ), superoxide (O 2 - ) and malondialdehyde in the R-enantiomer treatment group was significantly higher than the control group. The effect of the racemate on tomato fruit was between the enantiomers. Furthermore, compared to R-(-)-PEN and racemate, the S-enantiomer degraded more quickly in tomato fruit, leaves, and soil, reducing the danger of human exposure., Conclusion: The S-enantiomer is highly effective and less toxic. The development of enantiomer pure S-(+)-PEN products might be an efficient and low-risk strategy. The results lay the foundation for comprehensive evaluation and proper application of PEN. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Fungal and viral diseases account for 70-80% of agricultural production losses caused by microbial diseases. Synthetic fungicides and antiviral agents have been used to treat plant diseases caused by plant pathogenic fungi and viruses, but their use has been criticized due to their adverse side effects. As alternative strategies, natural fungicides and antiviral agents have attracted many researchers' interest in recent years. Herein, we designed and synthesized a series of novel polycarpine simplified analogues. Antiviral activity research against tobacco mosaic virus (TMV) revealed that most of the designed compounds have good antiviral activities. The virucidal activities of 4, 6d, 6f, 6h, and 8c are higher than that of polycarpine and similar to that of ningnanmycin. The structure simplified compound 8c was selected for further antiviral mechanism research which showed that compound 8c could inhibit the formation of 20S protein discs by acting on TMV coat protein. These compounds also displayed broad-spectrum fungicidal activities against 7 kinds of plant fungi. This work lays the foundation for the application of polycarpine simplified analogues in crop protection., 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 © 2023 Elsevier Inc. All rights reserved.)

Boscalid is a carboxamide fungicide widely used for crop protection, however owing to its high persistence, it is detected in high concentrations in various environments. Since the fate of such xenobiotics is strongly influenced by its interaction with soil components a better understanding of its adsorption onto soils of varying properties could allow the adjustment of its application in a given agro-ecological region to limit the consequent environmental burden. The present investigation was carried out to examine the kinetics of boscalid adsorption onto ten Indian soils of varying physico-chemical properties. Kinetic data of boscalid for all soils under investigation fitted well to both pseudo-first-order and pseudo-second-order kinetic models. However, based on the standard error of estimate (S.E. est. ) values pseudo-first-order model was better for all soil samples, except one soil which had the lowest readily oxidizable organic carbon. Adsorption of boscalid by soils appeared to be controlled by the diffusion-chemisorption process while for soils especially rich in readily oxidizable organic carbon or clay + silt content the intra-particle diffusion process seemed to be more important. Stepwise regression of kinetic parameters on soil properties revealed that the inclusion of a set of some soil properties could help better prediction of adsorbed amounts of boscalid and kinetic constants. These findings may help assess the fate and possible transport of boscalid fungicide in different soils., 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 © 2023 Elsevier Ltd. All rights reserved.)