Effects of natural Ionones and derived novel analogues with simplified structures on behavioral responses of whiteflies.

BACKGROUND: Whiteflies are major pests in agriculture, causing damage to crops and transmitting plant viruses. Using Volatile Organic Compounds (VOCs) as semiochemicals offers a sustainable approach for combating whiteflies. One such group of compounds, represented by ß-ionone, has been found to possess repellent/attractant properties. To further explore the behavioral effects of these compounds on whiteflies, we selected five natural ionone compounds and synthesized six novel analogues to examine the impact of structural variations on whitefly behavior. RESULTS: Our results demonstrated that ß-ionone and its analogues have a significant impact on the behavior of whiteflies. Among them, 0.01% pseudo ionone solution exhibited an attractant effect on whiteflies. Notably, the application of 1% ß-ionone and 0.1% ß-ionol solution demonstrated a notable repellent effect and oviposition deterrent effect on whitefly. We also found that the novel ionone analogue (±)1A exhibited a strong repellent effect. Both ß-ionol and compound (±)1A possess high logP values and low saturation vapor pressures, which contribute to enhanced lipophilicity, making them more likely to penetrate insect antennae and prolong their presence in the air. CONCLUSION: The newly discovered ionone analogue (±)1A and ß-ionol exhibit improved repellent effects, while pseudo ionone shows an attractant effect. These three compounds hold promising potential for development as novel biological control agents. Our work highlights the efficacy of VOCs as a protection method against whiteflies. These findings indicate that our new technology for a 'push-pull' control method of B. tabaci can offer a novel tool for integrated pest management (IPM). © 2024 Society of Chemical Industry.

Discovery and properties of novel analogues of the aphid pheromones nepetalactone and nepetalactol.

BACKGROUND: Pheromones have unique advantages for pest control. Current aphid pheromone research focuses on alarm and sex pheromones. However, practical applications are limited so far, as (E)-ß-farnesene has only been investigated to a small extent as an alarm pheromone and only male aphids are targeted by sex pheromones. Previous literature reports electrophysiological responses and repellent behavior of asexual aphids to nepetalactone (1B), therefore our objective was to modify nepetalactone's structure to identify key fragments responsible for repellent effects, as guidance for subsequent modifications and further investigation. RESULTS: In this study, seven derivatives were designed and synthesized based on nepetalactol (1A) and nepetalactone (1B) as lead compounds. Free-choice tests, conducted using cowpea aphids (Aphis craccivora), revealed that the lactone moiety was crucial for the repellent activity, and the removal of the carbonyl group eliminated the repelling effect. Compound (±)1I, an analogue of nepetalactone (1B), demonstrated a significantly higher repellent value than nepetalactone (1B) at three different concentrations, and even at 0.1 mg/mL it maintained a considerable repellent effect (26.5%). Electrostatic potential and density functional theory calculations supported the importance of the carbonyl group for the repellent effects. CONCLUSION: The newly discovered para-pheromone (±)1I shows improved repellent effects and potential for development as a novel biological control agent. Based on our innovative findings, analogues with improved efficacy and properties can be designed and prepared. Our research contributes to understanding the effects of structural modifications on pheromone activity and properties, which is crucial for exploring novel pheromone-based products for crop protection. © 2024 Society of Chemical Industry.

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.

Synthesis and Biological Activity of Silicon-Containing Ethylsulfonylpyridine Insecticides.

Ethylsulfonylpyridines are a novel chemical class of insecticides with excellent broad-spectrum activity and an unprecedented mode of action. With the objective of discovering novel ethylsulfonylpyridines with a broader spectrum, wider range of uses, and/or improved properties, we have started a research program aimed at introducing silicon motifs and studying their biological effects. We designed a series of Oxazosulfyl analogues where the hydrogen atom at the 5-position of the pyridyl moiety is replaced by a trialkylsilyl group and prepared these compounds applying denovo synthetic methodology. Our novel ethylsulfonylpyridines exhibit excellent insecticidal activities. The best compound, A18, resulting from our research exhibited an LC50 value of 0.30 mg/L against Plutella xylostella and reached the activity level of the commercial standard Oxazosulfyl. Our findings confirmed our working hypothesis that at the 5-position of the pyridyl moiety larger groups with different hydrophobic, electronic, and steric properties are tolerated.

Novel Acaricidal Silico-Containing Pyrazolyl Acrylonitrile Derivatives Identified through Rational Carbon-Silicon Bioisosteric Replacement Strategy.

The identification of novel pyrazolyl acrylonitrile acaricides with improved properties is of great value for the control of phytophagous mites. A series of innovative silicon-containing pyrazolyl acrylonitriles were rationally designed by applying a bioisosteric carbon-silicon replacement strategy and prepared based on novel synthetic methodology. As a result of our research, we discovered compound A25 which possesses outstanding acaricidal activity. With an LC50 value of 0.062 mg/L, compound A25 was found to be 2.3-fold and 1.9-fold more potent than the commercial acaricides cyenopyrafen and cyetpyrafen, respectively. Enzymatic inhibitory assay indicated that the active principle M1 of compound A25 possesses an IC50 value of 2.32 µM against Tetranychus cinnabarinus SDH, which was about twofold superior compared to the active metabolites of cyenopyrafen (IC50 = 4.72 µM). Molecular docking study showed that the active metabolites 2 and 3 and their corresponding silicon counterparts form H-bonds and cation-π interaction with the residues of Trp165, Tyr433, and Arg279.

Design, Synthesis, and Properties of Silicon-Containing meta-Diamide Insecticides.

Silicon-containing compounds are sporadically used in crop protection and drug discovery and have demonstrated to increase the biological efficacy as well as to reduce toxicity, improve physicochemical properties, and favorably impact the environmental profile. As part of our research, we have investigated the application of bioisosteric silicon replacements in meta-diamide insecticides and studied the biological activity and molecular properties of the corresponding novel compounds. At all meaningful structural elements of the meta-diamides, silicon-containing substituents were introduced and synthetic methodology was developed for their syntheses. As the most promising compound, silicon-containing meta-diamide II-18 emerged, which exhibits a very low LC50 value of 2.00 mg/L against Mythimna separata and compares well to the reference compounds 28 (LC50 = 0.17 mg/L) and II-20 (LC50 = 0.27 mg/L). Our research on silicon-containing crop protection compounds once again confirmed that the biological activity can be beneficially affected by the insertion of silicone substituents and that the introduction of well-chosen silicone motifs is an excellent strategy for agrochemical research.

Rational Exploration of Novel SDHI Fungicide through an Amide-ß-ketonitrile Bioisosteric Replacement Strategy.

The identification of succinate dehydrogenase inhibitor (SDHI) fungicides bearing a novel scaffold is of great importance to control pathogenic fungi. Difluoromethyl-pyrazole ß-ketonitrile derivatives were rationally designed through an innovative amide-ß-ketonitrile bioisosteric replacement strategy and evaluated for their antifungal activities. In preliminary fungicidal screening, our new ß-ketonitrile compounds showed outstanding in vitro activity. Compounds A7 and A14 exhibited EC50 values of 0.116 and 0.165 µg/mL against Sclerotinia sclerotiorum, respectively, and A14 also displayed an EC50 of 0.0774 µg/mL against Rhizoctonia solani. Furthermore, A14 exhibited moderate in vivo protective activity against rice sheath blight on rice plants. Results from SDH enzymatic assays demonstrated that A14 possesses significant inhibitory effect toward porcine heart SDH, with an IC50 value of 0.183 µM, which was 20-fold more potent than that of fluxapyroxad (IC50 = 3.76 µM). A docking study indicated that H-bonds, cation-π interactions, and edge-to-face π-π interactions play key roles in the binding of A14 with R. solani SDH. The CoMSIA model guided the approach to further structural optimizations and indicated that hydrophobic and steric substituents on the benzene ring have decisive effects on the fungicidal activity against R. solani. The present work describes for the first time the successful bioisosteric replacement of the common SDHI amide moiety by a ß-ketonitrile group and highlights the potential of ß-ketonitriles as an innovative novel SDHI subclass.

Silicon-Containing Complex II Acaricides─Design, Synthesis, and Pharmacological Optimization.

Bioisosteric replacement has been proven to be a powerful strategy in life science research. In this review, general aspects of carbon-silicon bioisosteric substitution and its applications in pharmaceutical and crop protection research are described. Carbon and their silicon analogues possess similar intrinsic properties. Replacing carbon with silicon in pharmaceuticals and pesticides has shown to result in positive effects on efficacy and selectivity, physicochemical properties, and bioavailability and also to eliminate or improve human or environmental safety properties as well as to provide novelty and new intellectual property in many cases. Furthermore, the application of carbon-silicon substitution in the search for new complex II acaricides is highlighted. This research led to the discovery of sila-cyflumetofen 23a and other silicon-containing analogues of cyflumetofen that match or exceed the acaricidal activity of cyflumetofen. The molecular design strategy, synthetic aspects, biological activity, computational modeling work, and structure-activity relationships will be discussed.

Bioisosteric-Replacement-Driven Lead Optimization of Tyclopyrazoflor.

A heterocyclic replacement strategy has been applied attempting to further optimize the biological properties of the new insecticide tyclopyrazoflor, a pyridinyl-pyrazole compound with excellent activity against sap-feeding insects recently discovered by Corteva. Our research program on this novel chemical class of insecticide was targeted to evaluate the importance of both the pyridyl and pyrazole moieties on the biological activity, properties, and structure-activity. Synthetic methodologies have been developed delivering our designed target compounds in moderate to good yields. In our attempt to rationalize the biological activity differences of tyclopyrazoflor analogues, a potential surface analysis based on a density functional theory (DFT) calculation and DFT-derived Multiwfn and VMD program model was performed. Furthermore, the SwissBioisostere online database was applied as a great source for inspiration for bioisosteric replacements.

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.

Scaffold-Hopping Approach To Identify New Chemotypes of Dimpropyridaz.

Dimpropyridaz is a pyrazole carboxamide insecticide with a novel mode of action, currently under worldwide development by BASF, providing excellent activity against sucking pests. A series of dimpropyridaz analogues were designed to investigate the impact of bioisosteric heterocyclic replacements on the biological activity and molecular properties. Focus was given to prepare analogues where the 4-pyridazinyl moiety was replaced by 5-pyrimidinyl, 2-pyrimidinyl, 3-pyridazinyl, and 2-pyrazinyl groups. Five different synthetic routes were developed for the preparation of these analogues, delivering the target compounds in moderate to good yields. We explained some aspects of the observed structure-activity relationship by a density functional theory (DFT) calculation and DFT-derived Multiwfn and VMD program models. These findings provide first insights into the important role of the 4-pyridazinyl heterocyclic moiety in the pyrazole carboxamide insecticide chemical class and the mechanism of action of dimpropyridaz.

Design, synthesis and nematicidal activitives of trifluorobutene amide derivatives against Meloidogyne incognita.

Plant parasitic nematodes have always been a pressing problem in the field of plant protection. Well-established chemical nematicides, especially organophosphorus and carbamates are the most used products for nematode control worldwide. Due to long-term overuse, they have developed serious resistance and new innovative solutions are urgently required. In this study, thirty-one novel trifluorobutene amide derivatives were designed and synthesized, and their nematicidal activities were determined. Three different synthetic methods have been developed for the final amidation reaction enabling the successfully syntheses of the target compounds independently from the nucleophilicities of the substrate amino group. Most target compounds showed good nematicidal activity in our in vitro test. Among all the compounds, compounds A8 and A23 exhibited excellent nematicidal activity against Meloidogyne incognita, their LC50 values are 2.02 mg L-1 and 0.76 mg L-1, respectively. In particular, compound A23 has found to be almost as active as the commercial nematicide fluensulfone. Furthermore, most compounds gave full control (100% inhibition) of M. incognita at 40 mg L-1 in the in vivo tests in sandy soil, the best compounds were further investigated for in vivo activity in matrix soil. Among the compound tested, compound A8 showed excellent in vivo nematicidal activity. At a concentration of 5 mg L-1 still 56% inhibition was observed. The results of our study indicate that compound A8 possesses excellent in vitro and in vivo nematicidal activity, and can be considered as promising lead molecule for further modification.

Design, Synthesis, and Synergistic Activity of Eight-Membered Oxabridge Neonicotinoid Analogues.

Insecticide synergists are sought-after due to their potential in improving the pesticide control efficacy with a reduced dose of an active ingredient. We previously reported that a cis-configuration neonicotinoid (IPPA08) exhibited specific synergistic activity toward neonicotinoid insecticides. In this study, we synthesized a series of structural analogues of IPPA08 by converting the pyridyl moiety of IPPA08 into phenyl groups, via facile double-Mannich condensation reactions between nitromethylene compounds and glutaraldehyde. All of the oxabridged neonicotinoid compounds were found to increase the toxicity of imidacloprid against Aphis craccivora. Notably, compound 25 at 0.75 mg/L lowered the LC50 value of imidacloprid against A. craccivora by 6.54-fold, while a 3.50-fold reduction of the LC50 value was observed for IPPA08. The results of bee toxicity test showed that compound 25 display selectivity in its effects on imidacloprid toxicity against the honey bee (Apis mellifera L.). In summary, replacing the pyridyl ring with a phenyl ring was a viable approach to obtain a novel synergist with oxabridged moiety for neonicotinoid insecticides.

Design, synthesis and acaricidal activities of Cyflumetofen analogues based on carbon-silicon isosteric replacement.

The application of a carbon-silicon bioisosteric replacement strategy to find new acaricides with improved properties led to the discovery of Sila-Cyflumetofen 6B, a novel and highly potent acaricide. The essential t-butyl group in the beta-ketonitrile acaricide Cyflumetofen 6A could be swapped with the bioisosteric trimethyl-silyl group with retention of high level acaricidal activity and favourable pharmacological properties. Sila-Cyflumetofen 6B was found to possess similar preferred energy-minimized conformation and electrostatic potential surface compare to Cyflumetofen 6A. Herein we also report the development and application of the first homology model of the spider mite mitochondrial electron transport complex II (succinate ubiquinone oxidoreductase; SQR) and demonstrated that the active metabolite AB-1 of Cyflumetofen 6A and its sila-analogue Sila-AB-1 bind to the Qp site in same binding pose and that both compounds form two H-bonds and a cation-π interaction with Trp 165, Tyr 433 and Arg 279, respectively. Furthermore, we also developed a new mode of action test for spider mite Complex II using cytochrome c as electron acceptor and blocking its re-oxidation by addition of KCN resulting in a sensitive and convenient colorimetric assay. This new method avoids the use of non-specific artificial electron acceptors and allows to measure SQR inhibition in crude extracts of Tetranychus urtice. In this assay Sila-AB-1, the intrinsically active metabolite of Sila-Cyflumetofen, 6A exhibited even a somewhat lower IC50 value than the metabolite of Cyflumetofen AB-1. Synthetic methodologies are described for the preparation of Sila-Cyflumetofen 6B and its active metabolite Sila-AB-1 which enable an efficient synthesis of these compounds in only 5 and 4 steps, respectively, from cheap commercial starting materials. Although the value of carbon-silicon bioisosteric replacements has already be demonstrated in the past it is to the best of our knowledge the first report of a successful application in crop protection research in the last two decades.

Spiro N-methoxy piperidine ring containing aryldiones for the control of sucking insects and mites: discovery of spiropidion.

BACKGROUND: Crop protection solutions for the control of key economic sucking pests derive essentially from neuronal and muscular acting chemistries, wherein neonicotinoid uses largely dominated for the last two decades. Anticipating likely resistance development of some of those arthropod species to this particular class, we intensified research activities on a non-neuronal site of action targeting insect growth and development some 10 years ago. RESULTS: Our innovation path featured reactivation of a scarcely used and simple building block from the 1960s, namely N-methoxy-4-piperidone 3. Its judicious incorporation into the 2-aryl-1,3-dione scaffold of IRAC group 23 inhibitors of fatty acid biosynthesis resulted in novel tetramic acid derivatives acting on acetyl-coenzyme A carboxylase (ACCase). The optimization campaign focused on modulation of the aryl substitution pattern and understanding substituent options at the lactam nitrogen position of those spiroheterocyclic pyrrolidine-dione derivatives towards an effective control of sucking insects and mites. This work gratifyingly culminated in the discovery of spiro N-methoxy piperidine containing proinsecticide spiropidion 1. Following in planta release, its insecticidally active dione metabolite 2 is translaminar and two-way systemic (both xylem and phloem mobile) for a full plant protection against arthropod pests. CONCLUSION: Owing to such unique plant systemic properties, growing shoots and roots actually not directly exposed to spiropidion-based chemistry after foliar application nevertheless benefit from its long-lasting efficacy. Spiropidion is for use in field crops, speciality crops and vegetables controlling a broad range of sucking pests. In light of other performance and safety profiles of spiropidion, an IPM fit may be expected. © 2020 Society of Chemical Industry.

The invertebrate pharmacology of insecticides acting at nicotinic acetylcholine receptors.

The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel composed of 5 protein subunits arranged around a central cation selective pore. Several classes of natural and synthetic insecticides mediate their effect through interacting at nAChRs. This review examines the basic pharmacology of the neonicotinoids and related chemistry, with an emphasis on sap-feeding insects from the order Hemiptera, the principle pest target for such insecticides. Although the receptor subunit stoichiometry for endogenous invertebrate nAChRs is unknown, there is clear evidence for the existence of distinct neonicotinoid binding sites in native insect preparations, which reflects the predicted wide repertoire of nAChRs and differing pharmacology within this insecticide class. The spinosyns are principally used to control chewing pests such as Lepidoptera, whilst nereistoxin analogues are used on pests of rice and vegetables through contact and systemic action, the pharmacology of both these insecticides is unique and different to that of the neonicotinoids.

Identification and Optimization of New Leads for Malaria Vector Control.

A significant proportion of the world's population remains at risk from malaria, and whilst great progress has been made in reducing the number of malaria cases globally through the use of vector control insecticides, these gains are under threat from the emergence of insecticide resistance. The spread of resistance in the vector populations, principally to pyrethroids, is driving the need for the development of new tools for malaria vector control. In order to identify new leads 30,000 compounds from the Syngenta corporate chemical collection were tested in a newly developed screening platform. More than 3000 compounds (10%) showed activity at ≤200 mg active ingredient (AI) litre-1 against Anopheles stephensi. Further evaluation resulted in the identification of 12 viable leads for the control of adult mosquitoes, most originating from current or former insecticide projects. Surprisingly, one of these leads emerged from a former PPO herbicide project and one from a former complex III fungicide project. This indicates that representatives of certain herbicide and fungicide projects and modes of action can also represent a valuable source of leads for malaria vector control. Optimization of the diphenyl ether lead 1 resulted in the identification of the cyano-pyridyl compound 31. This compound 31 exhibits good activity against mosquito species including rdl resistant Anopheles. It is only slightly weaker than permethrin and does not show relevant levels of cross-resistance to the organochlorine insecticide dieldrin.