Discovery and Mechanism of a Nematicide Candidate (W3): A Novel Amide Compound Containing a Cyclopropyl Moiety.

To find novel nematicides, we screened the nematicidal activity of compounds in our laboratory compound library. Interestingly, the compound N-((1R,2R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)-2-(trifluoromethyl)benzamide (W3) showed a broad spectrum and excellent nematicidal activity. The LC50 values of compound W3 against second-stage juveniles of Bursaphelenchus xylophilus (B. xylophilus), Aphelenchoides besseyi, and Ditylenchus destructor are 1.30, 1.63, and 0.72 mg/L, respectively. Nematicidal activities of compound W3 against second-stage juveniles of Meloidogyne incognita were 87.66% at 100 mg/L. Meanwhile, compound W3 can not only observably inhibit the feeding, reproduction, and egg hatching of B. xylophilus but can also effectively promote the oxidative stress adverse reactions of nematodes and cause intestinal damage. Compound W3 can promote the production of MDA and inhibit the activities of defense enzymes SOD and GST in B. xylophilus. Compound W3 can affect the transcription of genes involved in regulating the tricarboxylic acid cycle in nematodes, resulting in weakened nematode respiration and reduced nematode activity and even death. In addition, compound W3 had good inhibitory activity against five pathogenic fungi. Among them, the EC50 of compound W3 against Fusarium graminearum was 8.4 mg/L. In the future, we will devote ourselves to the toxicological and structural optimization research of the candidate nematicide W3.

Design, Synthesis, Nematicidal, and Fungicidal Activities of Novel Azo and Azoxy Compounds.

Bursaphelenchus xylophilus (B. xylophilus) and Meloidogyne are parasitic nematodes that have caused severe ecological and economic damage in pinewood and crops, respectively. Jietacins (jietacin A and B) were found to have excellent biological activity against B. xylophilus. Based on our tremendous demand for chemicals against B. xylophilus, a novel scaffold based on the azo and azoxy groups was designed, and a series of compounds were synthesized. In the bioassay, Ia, IIa, IIc, IId, and IVa exhibited higher activity against B. xylophilus in vitro than avermectin (LC50 = 2.43 µg·mL-1) with LC50 values of 1.37, 1.12, 0.889, 1.56, and 1.10 µg·mL-1, respectively. Meanwhile, Ib, Ic, IIc, and IVa showed good inhibition effects against Meloidogyne in vivo at the concentrations of 80 and 40 µg·mL-1 with inhibition rates of 89.0% and 81.6%, 95.6% and 75.7%, 96.3% and 41.2%, and 86.8% and 78.7%, respectively. In fungicidal activity in vitro, IIb and IVa exhibited excellent effect against Botryosphaeria dothidea with the inhibition of 82.59% and 85.32% at the concentration of 10 µg·mL-1, while the inhibition of Ia was 83.16% against Rhizoctonia solani at the concentration of 12.5 µg·mL-1. Referring to the biological activity against B. xylophilus, a 3D-QASR model was built in which the electron-donating group and small group at the 4-phenylhydrazine were favorable for the activity. In general, the novel azoxy compounds, especially IIc possess great potential for application in the prevention of B. xylophilus.

Rational Design of a Potential New Nematicide Targeting Chitin Deacetylase.

In a previously published study, the authors devised a molecular topology QSAR (quantitative structure-activity relationship) approach to detect novel fungicides acting as inhibitors of chitin deacetylase (CDA). Several of the chosen compounds exhibited noteworthy activity. Due to the close relationship between chitin-related proteins present in fungi and other chitin-containing plant-parasitic species, the authors decided to test these molecules against nematodes, based on their negative impact on agriculture. From an overall of 20 fungal CDA inhibitors, six showed to be active against Caenorhabditis elegans. These experimental results made it possible to develop two new molecular topology-based QSAR algorithms for the rational design of potential nematicides with CDA inhibitor activity for crop protection. Linear discriminant analysis was employed to create the two algorithms, one for identifying the chemo-mathematical pattern of commercial nematicides and the other for identifying nematicides with activity on CDA. After creating and validating the QSAR models, the authors screened several natural and synthetic compound databases, searching for alternatives to current nematicides. Finally one compound, the N2-(dimethylsulfamoyl)-N-{2-[(2-methyl-2-propanyl)sulfanyl]ethyl}-N2-phenylglycinamide or nematode chitin deacetylase inhibitor, was selected as the best candidate and was further investigated both in silico, through molecular docking and molecular dynamic simulations, and in vitro, through specific experimental assays. The molecule shows favorable binding behavior on the catalytic pocket of C. elegans CDA and the experimental assays confirm potential nematicide activity.

Discovery of Trifluorobutene Amide Derivatives as Potential Nematicides: Design, Synthesis, Nematicidal Activity Evaluation, SAR, and Mode of Action Study.

Plant-parasitic nematodes are one of the major threats to crop protection. However, only limited nematicides are currently available and are confronted with a growing resistance problem, which necessitates the development of novel nematicides. In this study, a series of trifluorobutene amide derivatives was synthesized through the strategy of amide bond reversal, and their nematicidal activity against Meloidogyne incognita was evaluated. The bioassay showed that compounds C2, C10, and C18 and some analogues thereof exhibited good nematicidal activity. Among them, the derivatives of compound C2 containing a benzene ring [C26 (R = 2-CH3) and C33 (R = 2-Cl)] exhibited excellent bioactivity against M. incognita in vitro. The LC50/72h values reached 14.13 and 14.71 mg·L-1, respectively. Moreover, analogues of compounds C10 and C18 containing a thiophene ring [C43 (R = 5-CH3), C44 (R = 4-CH3), and C50 (R = 5-Cl)] exhibited significant bioactivity against M. incognita in vivo with inhibition rates of 68.8, 65.5, and 69.8% at 2.5 mg·L-1 in a matrix, respectively. Meanwhile, C44 and C50 also showed excellent control effects against M. incognita in both cups and microplots. The structure-activity relationship (SAR) of synthesized compounds was discussed in detail. Comparative molecular field analysis (CoMFA) was also conducted to develop the SAR profile. The preliminary mode of action investigation showed that compound C33 exhibited strong inhibition on egg hatching, motility, feeding behavior, and growth of Caenorhabditis elegans. At the same time, the impact of active compounds on biochemical indicators related to oxidative stress showed that compound C33 influenced the production of ROS (reactive oxygen species), and the accumulation of lipofuscin and lipids on C. elegans.

Effective combination of arugula vermicompost, chitin and inhibitory bacteria for suppression of the root-knot nematode Meloidogyne javanica and explanation of their beneficial properties based on microbial analysis.

Root-knot nematodes (Meloidogyne spp.) are dangerous parasites of many crops worldwide. The threat of chemical nematicides has led to increasing interest in studying the inhibitory effects of organic amendments and bacteria on plant-parasitic nematodes, but their combination has been less studied. One laboratory and four glasshouse experiments were conducted to study the effect on M. javanica of animal manure, common vermicompost, shrimp shells, chitosan, compost and vermicompost from castor bean, chinaberry and arugula, and the combination of arugula vermicompost with some bacteria, isolated from vermicompost or earthworms. The extract of arugula compost and vermicompost, common vermicompost and composts from castor bean and chinaberry reduced nematode egg hatch by 12-32% and caused 13-40% mortality of second-stage juveniles in vitro. Soil amendments with the combination vermicompost of arugula + Pseudomonas. resinovorans + Sphingobacterium daejeonense + chitosan significantly increased the yield of infected tomato plants and reduced nematode reproduction factor by 63.1-76.6%. Comparison of chemical properties showed that arugula vermicompost had lower pH, EC, and C/N ratio than arugula compost. Metagenomics analysis showed that Bacillus, Geodermatophilus, Thermomonas, Lewinella, Pseudolabrys and Erythrobacter were the major bacterial genera in the vermicompost of arugula. Metagenomics analysis confirmed the presence of chitinolytic, detoxifying and PGPR bacteria in the vermicompost of arugula. The combination of arugula vermicompost + chitosan + P. resinovorans + S. daejeonense could be an environmentally friendly approach to control M. javanica.

Effect of 4-Ethylbenzaldehyde from the Volatilome of Annona muricata on Meloidogyne incognita.

The demand for new soil fumigants has increased as a result of more restrictive legislation regarding the use of pesticides. In the present study, the potent nematicidal activity of volatile organic compounds released by the Annona muricata leaf macerate was demonstrated. In addition, we searched in the A. muricata volatilome for a molecule with potential to be developed as a new fumigant nematicide. In the greenhouse, even the lowest concentration of soursop leaf macerate tested (1.0%) as a biofumigant caused a significant (P < 0.05) reduction in Meloidogyne incognita infectivity and reproduction when compared with the nontreated control (0%). Forty-one compounds were identified through gas chromatography-mass spectrometry analysis, of which three (sabinene, caryophyllene oxide, and 4-ethylbenzaldehyde) were selected for studies against the nematode. Among these compounds, in in vitro trails, only 4-ethylbenzaldehyde showed nematicidal activity at 250 µg ml-1. The effective doses of 4-ethylbenzaldehyde predicted to kill 50 and 95% of the M. incognita second-stage juvenile population after 48 h of exposure were 35 and 88 µg ml-1, respectively. In in vitro tests, 4-ethylbenzaldehyde at 150 µg ml-1 reduced M. incognita egg hatching to values similar (P > 0.05) to those of the commercial nematicide fluensulfone at a concentration of 200 µg ml-1. In plant experiments, as a soil fumigant, 4-ethylbenzaldehyde at a dose of 1 ml/liter of substrate had an effect similar (P > 0.05) to that of the commercial fumigant Dazomet (250 µg ml-1). Therefore, 4-ethylbenzaldehyde shows potential for development as a new nematicide.

Nematicidal activity of o-hydroxybenzaldehyde from common buckwheat methanol extract on Meloidogyne incognita.

The nematicidal activity of buckwheat (Fagopyrum esculentum Moench) on the root-knot nematode Meloidogyne incognita was tested. Dried plant methanol extract presented higher nematicidal activity than fresh plant extracts with an EC50 = 62.6 ± 26.0 and 40.8 ± 26.1 µg/ml after 48 and 72 hours of immersion, respectively. GC-MS analysis showed the presence of 17 aldehydes, with salicylaldehyde (o-hydroxybenzaldehyde) being the most abundant at 16%. Nematicidal activity of the latter refers to salicylaldehyde and other aldehydes with chemical similarities was then assessed. The most active aldehyde was o-hydroxybenzaldehyde followed by m-hydroxybenzaldehyde, p-hydroxybenzaldehyde and benzeneacetaldehyde with an EC50 of about 11.0 ± 1.0, 31.0 ± 22.0, 75.0 ± 23.0 and 168.1 ± 52.3 µg/ml after 1 day of immersion, respectively. Position 2 of the hydroxyl group in the benzene ring seems to be very important for the nematicidal activity, followed by positions 3 and 4. As a complementary experiment, synergistic activity was observed when we added o-hydroxybenzaldehyde to m-hydroxybenzaldehyde and to p-hydroxybenzaldehyde with an EC50 after 24 hours of immersion of 8.0 ± 2.5 and 6.1 ± 2.3 µg/ml, respectively. Antioxidant activity assessment showed that this latter is inversely proportional to nematicidal activity. Our results showed that F. esculentum and its major compound salicylaldehyde could be integrated into the pest management system.

Synthesis, Nematicidal Evaluation, and the Structure-Activity Relationship Study of Aurone Derivatives.

Plant-parasitic nematodes (PPNs) are one of the major threats to modern agriculture. Chemical nematicides are still required for the management of PPNs. Based on our previous work, the structure of aurone analogues was obtained using a hybrid 3D similarity calculation method (SHAFTS, SHApe-FeaTure Similarity). Thirty-seven compounds were synthesized. The nematicidal activity of target compounds against Meloidogyne incognita (root-knot nematode, M. incognita) was evaluated, and the structure-activity relationship of synthesized compounds was analyzed. The results showed that compound 6 and some of its derivatives exhibited impressive nematicidal activity. Among these compounds, compound 32 bearing 6-F showed the best in vitro and in vivo nematicidal activity. Its lethal concentration 50% after exposure to 72 h (LC50/72 h) value was 1.75 mg/L, and the inhibition rate reached 97.93% in the sand at 40 mg/L. At the same time, compound 32 also exhibited excellent inhibition on egg hatching and moderate inhibition on the motility of Caenorhabditis elegans (C. elegans).

Isolation, Identification and Molecular Mechanism Analysis of the Nematicidal Compound Spectinabilin from Newly Isolated Streptomyces sp. DT10.

Plant parasitic nematodes (PPNs) are highly destructive and difficult to control, while conventional chemical nematicides are highly toxic and cause serious environmental pollution. Additionally, resistance to existing pesticides is becoming increasingly common. Biological control is the most promising method for the controlling of PPNs. Therefore, the screening of nematicidal microbial resources and the identification of natural products are of great significance and urgency for the environmentally friendly control of PPNs. In this study, the DT10 strain was isolated from wild moss samples and identified as Streptomyces sp. by morphological and molecular analysis. Using Caenorhabditis elegans as a model, the extract of DT10 was screened for nematicidal activity, which elicited 100% lethality. The active compound was isolated from the extracts of strain DT10 using silica gel column chromatography and semipreparative high-performance liquid chromatography (HPLC). The compound was identified as spectinabilin (chemical formula C28H31O6N) using liquid chromatography mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). Spectinabilin exhibited a good nematicidal activity on C. elegans L1 worms, with a half-maximal inhibitory concentration (IC50) of 2.948 µg/mL at 24 h. The locomotive ability of C. elegans L4 worms was significantly reduced when treated with 40 µg/mL spectinabilin. Further analysis of spectinabilin against known nematicidal drug target genes in C. elegans showed that it acts via target(s) different from those of some currently used nematicidal drugs such as avermectin and phosphine thiazole. This is the first report on the nematicidal activity of spectinabilin on C. elegans and the southern root-knot nematode Meloidogyne incognita. These findings may pave the way for further research and application of spectinabilin as a potential biological nematicide.

Nematicidal Coumarins from Cnidium monnieri Fruits and Angelica dahurica Roots and Their Physiological Effect on Pine Wood Nematode (Bursaphelenchus xylophilus).

Pine wood nematode (PWN), Bursaphelenchus xylophilus, is a major pathogen of pine wilt disease (PWD), which is a devastating disease affecting pine trees. Eco-friendly plant-derived nematicides against PWN have been considered as promising alternatives to control PWD. In this study, the ethyl acetate extracts of Cnidium monnieri fruits and Angelica dahurica roots were confirmed to have significant nematicidal activity against PWN. Through bioassay-guided fractionations, eight nematicidal coumarins against PWN were separately isolated from the ethyl acetate extracts of C. monnieri fruits and A. dahurica roots, and they were identified to be osthol (Compound 1), xanthotoxin (Compound 2), cindimine (Compound 3), isopimpinellin (Compound 4), marmesin (Compound 5), isoimperatorin (Compound 6), imperatorin (Compound 7), and bergapten (Compound 8) by mass and nuclear magnetic resonance (NMR) spectral data analysis. Coumarins 1-8 were all determined to have inhibitory effects on the egg hatching, feeding ability, and reproduction of PWN. Moreover, all eight nematicidal coumarins could inhibit the acetylcholinesterase (AChE) and Ca2+ ATPase of PWN. Cindimine 3 from C. monnieri fruits showed the strongest nematicidal activity against PWN, with an LC50 value of 64 µM at 72 h, and the highest inhibitory effect on PWN vitality. In addition, bioassays on PWN pathogenicity demonstrated that the eight nematicidal coumarins could effectively relieve the wilt symptoms of black pine seedlings infected by PWN. The research identified several potent botanical nematicidal coumarins for use against PWN, which could contribute to the development of greener nematicides for PWD control.

Selective control of parasitic nematodes using bioactivated nematicides.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1-4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4-12. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Volatile Organic Compounds of Bacillus velezensis GJ-7 against Meloidogyne hapla through Multiple Prevention and Control Modes.

The Bacillus velezensis GJ-7 strain isolated from the rhizosphere soil of Panax notoginseng showed high nematicidal activity and therefore has been considered a biological control agent that could act against the root-knot nematode Meloidogyne hapla. However, little was known about whether the GJ-7 strain could produce volatile organic compounds (VOCs) that were effective in biocontrol against M. hapla. In this study, we evaluated the nematicidal activity of VOCs produced by the fermentation of GJ-7 in three-compartment Petri dishes. The results revealed that the mortality rates of M. hapla J2s were 85% at 24 h and 97.1% at 48 h after treatment with the VOCs produced during GJ-7 fermentation. Subsequently, the VOCs produced by the GJ-7 strain were identified through solid-phase micro-extraction gas chromatography mass spectrometry (SPME-GC/MS). Six characteristic VOCs from the GJ-7 strain fermentation broth were identified, including 3-methyl-1-butanol, 3-methyl-2-pentanone, 5-methyl-2-hexanone, 2-heptanone, 2,5-dimethylpyrazine, and 6-methyl-2-heptanone. The in vitro experimental results from 24-well culture plates showed that the six volatiles had direct-contact nematicidal activity against M. hapla J2s and inhibition activity against egg hatching. In addition, 3-methyl-1-butanol and 2-heptanone showed significant fumigation effects on M. hapla J2s and eggs. Furthermore, all six of the VOCs repelled M. hapla J2 juveniles in 2% water agar Petri plates. The above data suggested that the VOCs of B. velezensis GJ-7 acted against M. hapla through multiple prevention and control modes (including direct-contact nematicidal activity, fumigant activity, and repellent activity), and therefore could be considered as potential biocontrol agents against root-knot nematodes.

Activity of chitin/chitosan/chitosan oligosaccharide against plant pathogenic nematodes and potential modes of application in agriculture: A review.

Chemical nematicide is the most common method of controlling plant-parasitic nematodes (PPN). Given the negative impact of chemical nematicides on the environment and ecosystem, it is necessary to seek their alternatives and novel modes of application. Chitin oligo/polysaccharide (COPS), including chitosan and chitosan oligosaccharide, has unique biological properties. By producing ammonia, encouraging the growth of antagonistic bacteria, and enhancing crop tolerance, COPSs help suppress PPN growth during soil remediation. COPS is also an effective sustained-release carrier that can be used to overcome the shortcomings of nematicidal substances. This review summarizes the advancements of COPS research in nematode control from three perspectives of action mechanism as well as in slow-release carrier-loaded nematicides. Further, it discusses potential agricultural applications for nematode disease management.

Structure-Based Virtual Screening of Natural Products and Optimization for the Design and Synthesis of Novel CeCht1 Inhibitors as Nematicide Candidates.

Nematode chitinases are critical components of the nematode life cycle, and CeCht1 is a potential target for developing novel nematicides. Herein, lunidonine, a natural quinoline alkaloid, was first discovered to have inhibitory activity against CeCht1, which was acquired from a library of over 16,000 natural products using a structure-based virtual screening methodology. A pocket-based lead optimization strategy was employed based on the predicted binding mode of lunidonine. Subsequently, a series of benzo[d][1,3]dioxole-5-carboxylate derivatives were designed and synthesized, and their inhibitory activities against CeCht1 as well as in vitro nematicidal activities against Caenorhabditis elegans were assessed. The analysis of structure-activity relationship and inhibitory mechanisms provided insights into their interactions with the CeCht1 active site, which could facilitate future research in improving the potency of the inhibitory activity. Especially, compound a12 interacted well with CeCht1 and exhibited excellent in vitro nematicidal activity against C. elegans with a LC50 value of 41.54 mg/L, suggesting that it could be a promising candidate for a novel chemical nematicide targeting CeCht1. The known binding modes and structural features of these inhibitors will contribute to the design of stronger CeCht1-based nematicides to control nematodes in agriculture.

In silico analysis of koranimine, a cyclic imine compound from Peribacillus frigoritolerans reveals potential nematicidal activity.

Pine wilt disease (PWD) is a destructive vector-borne forest disease caused by the nematode Bursaphelenchus xylophilus. To date, several options are available for the management of pine wilt disease; however constant development and search for natural products with potential nematicidal activity are imperative to diversify management options and to cope with the possible future emergence of resistance in parasitic nematodes. Here, a combined metabolomics and genomics approach was employed to investigate the chemical repertoire and biosynthetic potential of the bacterial endophyte Peribacillus frigoritolerans BE93, previously characterized to exhibit nematicidal activity against B. xylophilus. Feature-based molecular networking revealed the presence of diverse secondary metabolites. A cyclic imine heptapeptide, koranimine, was found to be among the most abundant secondary metabolites produced. Genome mining displayed the presence of several putative biosynthetic gene clusters (BGCs), including a dedicated non-ribosomal peptide synthase (NRPS) BGC for koranimine. Given the non-ribosomal peptide nature of koranimine, in silico molecular docking analysis was conducted to investigate its potential nematicidal activity against the target receptor ivermectin-sensitive invertebrate α glutamate-gated chloride channel (GluCl). Results revealed the binding of koranimine at the allosteric site of the channel-the ivermectin binding site. Moreover, the ligand-receptor interactions observed were mostly shared between koranimine and ivermectin when bound to the α GluCl receptor thus, suggesting a possibly shared mechanism of potential nematicidal activity. This study highlights the efficiency of combined metabolomics and genomics approach in the identification of candidate compounds.

Synthesis of Hinokitiol Sulfonate Derivatives and Their Anti-Oomycete and Nematicidal Activities.

In order to explore novel natural product-based anti-oomycete and nematicidal agents, sixteen unreported 2-sulfonyloxyhinokitiol derivatives were prepared using the principle of active splicing, and structurally confirmed by proton nuclear magnetic resonance (1 H-NMR), carbon-13 nuclear magnetic resonance (13 C-NMR), high-resolution mass spectrometry (HRMS), and melting point. Moreover, we evaluated the title compounds as anti-oomycete and nematicidal agents against two serious agricultural pests of Phytophthora capsici and Meloidogyne incongnita. Among the sixteen hinokitiol esters tested: (1) Compounds 3a and 3m exhibited the most potent anti-oomycete activity compared to zoxamide against P. capsici, and the median effective concentration (EC50 ) values of 3a, 3m, and zoxamide were 18.64, 21.11, and 23.15 mg/L, respectively; Further studies showed that the existence of seven membered ring and carbonyl group was the necessary condition for the high anti-oomycete activity of hinokitiol. (2) Compounds 3n and 3p exhibited more promising nematicidal activity than hinokitiol, and the median lethal concentration (LC50 ) values of 3n, 3p and 1 against M. incongnita were 0.2111, 0.2079, and 0.3933 mg/L, respectively. This result will pave the way for further modification of hinokitiol to develop potential new fungicides and nematicides.

(R)-Carvone is a potential soil fumigant against Meloidogyne incognita whose likely enzymatic target in the nematode is acetylcholinesterase.

To contribute to the development of new fumigant nematicides for the control of the plant-parasitic nematode Meloidogyne incognita, this study started with 31 volatile organic compounds reported as toxic to nematodes. At 500 µg/mL, α-ionone, (S)-carvone, (R)-carvone, 2-methylpropyl acetate, undecan-2-one, decan-2-one, and dodecan-2-one caused mortalities to M. incognita second-stage juveniles (J2) that were similar to those obtained with the commercial nematicides carbofuran (170 µg/mL) and fluensulfone (42.2 µg/mL). (R)-carvone, with a lethal concentration to 50% J2 (LC50) equal to 524 µg/mL, was selected for subsequent studies. When J2 were exposed to the (R)-carvone solution, the infectivity and reproduction on tomato were reduced. In the M. incognita egg hatching assay, (R)-carvone behaved like a true ovicide. When employed as a fumigant, (R)-carvone (3.9 g/L) was as efficient as the soil fumigant dazomet (0.245 g/L) in eliminating eggs of the nematode in a substrate to be used for tomato planting. According to in silico studies employing pharmacophoric searches and molecular docking, acetylcholinesterases are the target of (R)-carvone in the nematode.

Bioisosterism and Scaffold Hopping in Modern Nematicide Research.

The application of agrochemicals is critical to global food safety. Nowadays, environmentally friendly green agrochemicals are the trend in field crop protection. The research and development of nematicides absorbed more attention as a typical representation of agrochemicals. This review describes the origin of recently commercialized nematicides, the application of bioisosterism and scaffold hopping in the discovery and optimization of agrochemicals, especially nematicides, and novel bioisosteric design strategies for the identification of fluensulfone analogues. Pesticide repurposing, high-throughput screening, computer-aided drug design, and incorporation of known pharmacophoric fragments have been the most successful approach for the discovery of new nematicides. As outlined, the strategies of bioisosteric replacements and scaffold hopping have been very successful approaches in the search for new nematicides for sustainable crop protection. In the exploration of novel fluensulfone analogues with nematicidal activity, bioisosteric replacement of sulfone by amide, chain extension by insertion of a methylene group, and reversal of the amide group have proven to be successful approaches and yielded new and highly active fluensulfone analogues. These attempts might result in compounds with an optimal balance of steric, hydrophobic, electronic, and hydrogen-bonding properties and contribute to deal with the complex problem during the research and development of new nematicides. Further ideas are also put forward to provide new approaches for the molecular design of nematicides.

Nematicidal activity of furanoeremophilenes against Meloidogyne incognita and Nacobbus aberrans.

BACKGROUND: While searching for novel small molecules for new organic pesticide agents against plant-parasitic nematodes, we found that the hexane extract from the roots of Senecio sinuatos and its main secondary metabolite, 3ß-angeloyloxy-6ß-hydroxyfuranoeremophil-1(10)-ene (1), possess nematicidal activity against the second stage juvenile (J2) of Meloidogyne incognita and Nacobbus aberrans. Both species reduce yield of various vegetable crops. These results encouraged us to synthesize esters 3-9 formed by diol 2, obtained by alkaline hydrolysis of 1 and acetic anhydride, benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid, respectively. The nematicidal activity of these esters was evaluated and compared with that of the free benzoic acids. RESULTS: Natural product 1 and derivatives 2-9 were obtained and characterized by their physical and spectroscopic properties, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments; X-ray diffraction analysis established their absolute configuration. The nematicidal activity of compounds 1-9 was assessed in vitro against M. incognita and N. aberrans J2 and was compared to activity shown by benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid. The esters suppressed nematodes more than free benzoic acid. Nacobbus aberrans J2 were suppressed, with compounds 5, 6, and 8 being the most active. CONCLUSION: Esters formed by 3ß,6ß-dihydroxyfuranoeremophil-1(10)-ene and ortho- or para-substituted benzoic acids containing electron acceptor groups had nematicidal activity against N. aberrans. These compound can potentially serve as a model for the development of new organic nematicidal agents. © 2022 Society of Chemical Industry.

Bioassay-Guided Isolation of Nematicidal Artemisinic Acid and Dihydroartemisinic Acid from Artemisia annua L. and Evaluation of Their Activity against Meloidogyne incognita.

The extract of Artemisia annua L. has been shown to possess the nematicidal activity but the potent constituents were unclear. Herein, two nematicidal sesquiterpenoid acids artemisinic acid (ArA) and dihydroartemisinic acid (DHArA) were isolated from the methanol extract of the aerial parts of A. annua L. by the bioassay-guided isolation method using Meloidogyne incognita second stage juveniles (J2s) as the screening target. The in vitro activity, control efficacy in the pot experiment, and toxic effects of these two natural compounds against M. incognita were evaluated. The in vitro results showed that the EC50/48h values of ArA and DHArA were 0.37 mM and 0.76 mM against J2s, respectively. In the pot experiment, ArA and DHArA at the dose of 5 mg (a.i.)/pot could achieve the same level of control efficacy compared with avermectins at 2 mg (a.i.)/pot. Microscopic observations indicated the obvious toxic symptoms of J2s after ArA- and DHArA-treatment, including the shrinking body, imperfect body wall, and undiscerning organs. The physiological and biochemical studies, together with the toxic symptoms, revealed that ArA and DHArA had great impacts on the membrane system of J2s. Additionally, ArA occurring the α, ß-unsaturated carbonyl was demonstrated to be reactive with glutathione (GSH) and cause the decrease of GSH content in J2s. Taken together, the present study suggests that ArA and DHArA or ArA- and DHArA-based extracts of A. annua L. have a substantial potential to be used as botanical agents for integrated disease management programs against root-knot nematodes in crop protection.