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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 objective of this study was to evaluate the physicochemical compatibility of mixtures of synthetic and botanical limonoid-based insecticides, as well as the toxicity of these associations, in the management of Spodoptera frugiperda (J.E. Smith) under laboratory and field conditions. For this, the associations of 4 commercial botanical insecticides based on neem registered in Brazil (Azamax, Agroneem, Azact CE, and Fitoneem) were tested with synthetic insecticides from the group of growth regulators (IGRs [triflumuron, lufenuron, methoxyfenozide and tebufenozide]). When mixed, all combinations caused a significant reduction in the pH of the mixture and a significant increase in electrical conductivity. However, all tested combinations showed similar stability behavior to the negative control (distilled water), which demonstrated their physicochemical compatibility. Furthermore, in laboratory and field bioassays, mixtures of IRGs with limonoid-based formulations provided satisfactory effects in the management of S. frugiperda. However, binary mixtures of insecticide Intrepid 240 SC with Azamax or Azact CE (at LC25 previously estimated) showed the highest toxicities on S. frugiperda larvae in laboratory bioassays and damage reduction caused by S. frugiperda in a 2-yr field experiments. Therefore, mixtures of IGRs with limonoid-based botanical insecticides are promising alternatives for the management of S. frugiperda and important component of integrated pest management and insect resistance management programs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Herein, we developed a novel magnetic solid phase extraction method based on attapulgite-modified magnetic metal-organic frameworks (ATP@Fe 3 O 4 @ZIF-8), and this method could be used for the determination of benzoylureas when it was coupled with high-performance liquid chromatography. The established method was validated in terms of linearity (2.5-500 μg L -1 , with correlation coefficient (R 2 ) > 0.9994), accuracy (with satisfactory recovery of 88.29-95.99%) and precision (with relative standard deviation (RSD) of less than 8%). In addition, the enrichment factors (EF) ranged from 63.6 to 72.2. Limit of detection (LOD) and limit of quantitation (LOQ) were 0.7-3.2 μg L -1 and 2.3-10.7 μg L -1 , respectively. Moreover, there was hardly any noticeable loss of the extraction efficiency when this extraction method undergoes five cycles. Finally, this method was successfully used for the determination of six benzoylureas in different tea infusions and the determined relative recoveries ranged from 78.8 to 114.3%., 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 © 2020 Elsevier Ltd. All rights reserved.)

Animals with exoskeleton need to molt to grow and develop. Molting is well described in some arthropods especially insects. Chitin is a polymer of N-acetylglucosamine, and one of the major components of the exoskeleton of arthropods. Chitin is synthesized and degraded by a series of enzymes during the molting cycle. However, the presence and function of these enzymes are largely unknown in copepods such as the ectoparasite salmon louse (Lepeophtheirus salmonis) a major pest in salmonid aquaculture. Here we describe six genes found in the L. salmonis genome (LsCHS1, LsCHS2, LsGFAT, LsGNA1, LsAGM, and LsUAP) with high homology to enzymes in the chitin synthesis pathway. The transcription profiles of these enzymes together with three chitinases enzymes (LsChi1, LsChi2, and LsChi4), which have been characterized before, were examined during the synthesis of a new exoskeleton and revealed a dynamical expression concurrent with the morphological changes during the molt cycle. Further understanding of chitin metabolism and its regulation may prove useful tool to develop new pesticides., (Copyright © 2018. Published by Elsevier Inc.)

Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine hydrolase, whose main function is to modulate neurotransmission at cholinergic synapses. It is, therefore, the primary target of some pesticides and heavy metals. Its inhibition in aquatic organisms has been used as an indicator of the presence of these pollutants in water bodies. The present study aimed to characterize physicochemical and kinetic parameters of brain AChE in the benthic fish Hoplosternum littorale and to analyze the in vitro effects of pesticides (dichlorvos, diazinon, chlorpyrifos, parathion-methyl, temephos, carbaryl, carbofuran, aldicarb, diflubenzuron, novaluron and pyriproxyfen) and metal ions (As 3+ , Cd 2+ , Cu 2+ , Fe 2+ , Mn 2+ , Mg 2+ , K + , Pb 2+ , Hg 2+ , Zn 2+ ) investigating the potential of this enzyme as environmental biomarker based on current regulations. Specific substrates and inhibitors have indicated AChE to be the predominant cholinesterase (ChE) in the brain of H. littorale. Peak activity was observed at pH 8.0 and 30 °C. The enzymatic activity is otherwise moderately thermostable (≈ 50% activity at 45 °C). The enzyme can reduce the activation energy of acetylthiocholine hydrolysis reaction to 8.34 kcal mol -1 while reaching a rate enhancement of 10 6 . Among the pesticides under study, dichlorvos presented an IC 50 value below the maximum concentrations allowed by legislation. This study presents the first report on the inhibition of brain AChE activity from Siluriformes by the pesticides novaluron and pyriproxyfen. Mercury ion also exerted a strong inhibitory effect on its enzymatic activity. The H. littorale enzyme thus has the potential to function as an in vitro biomarker for the presence of the pesticide dichlorvos as well as mercury in areas of mining and industrial discharge., (Copyright © 2018. Published by Elsevier B.V.)

Drug resistance in the salmon louse Lepeophtheirus salmonis is a global issue for Atlantic salmon aquaculture. Multiple resistance has been described across most available compound classes with the exception of the benzoylureas. To target this gap in effective management of L. salmonis and other species of sea lice (e.g. Caligus spp.), Elanco Animal Health is developing an in-feed treatment containing lufenuron (a benzoylurea) to be administered prior to seawater transfer of salmon smolts and to provide long-term protection of salmon against sea lice infestations. Benzoylureas disrupt chitin synthesis, formation, and deposition during all moulting events. However, the mechanism(s) of action are not yet fully understood and most research completed to date has focused on insects. We exposed the first parasitic stage of L. salmonis to 700 ppb lufenuron for three hours and observed over 90% reduction in survival to the chalimus II life stage on the host, as compared to vehicle controls. This agrees with a follow up in vivo administration study on the host, which showed >95% reduction by the chalimus I stage. Transcriptomic responses of salmon lice exposed to lufenuron included genes related to moulting, epithelial differentiation, solute transport, and general developmental processes. Global metabolite profiles also suggest that membrane stability and fluidity is impacted in treated lice. These molecular signals are likely the underpinnings of an abnormal moulting process and cuticle formation observed ultrastructurally using transmission electron microscopy. Treated nauplii-staged lice exhibited multiple abnormalities in the integument, suggesting that the coordinated assembly of the epi- and procuticle is impaired. In all cases, treatment with lufenuron had rapid impacts on L. salmonis development. We describe multiple experiments to characterize the efficacy of lufenuron on eggs, larvae, and parasitic stages of L. salmonis, and provide the most comprehensive assessment of the physiological responses of a marine arthropod to a benzoylurea chemical., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Rice sheath blight is a globally important rice disease. Unfortunately, this critical disease has not been effectively controlled, and the intensive and continuous use of the same fungicide might increase the risk of resistance development in the pathogen. To discover new active agents against rice sheath blight, in this study, three series of β-carboline urea, benzoylurea and benzoylthiourea derivatives were designed, synthesized and evaluated for in vitro and in vivo fungicidal activity against Rhizoctonia solani., Results: All these compounds (EC 50 : 0.131-1.227 mmol L -1 ) exhibited better fungicidal activity than harmine itself (EC 50 : 2.453 mmol L -1 ). Significantly, compound 17c (EC 50 : 0.131 mmol L -1 ) displayed the best efficacy in vitro and superior fungicidal activity compared with validamycin A (EC 50 : 0.397 mmol L -1 ). Moreover, the in vivo bioassay also indicated that compound 17c could be effective for the control of rice sheath blight., Conclusion: Based on the bioassay result and quantitative structure-activity relationship (QSAR) information, structure modification in β-carboline warrants further investigation and its benzoylurea derivative 17c, which showed the best fungicidal activities, could emerge as a potential fungicide against rice sheath blight. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

Enzyme biomarkers from several aquatic organisms have been used for assessing the exposure to contaminants at sublethal levels. Amongst them, the cholinesterases are commonly extracted from several organisms to evaluate/measure organophosphate and carbamate neurotoxic effects. Acetylcholinesterase (AChE; EC 3.1.1.7) is an enzyme of the group of serine esterases that acts on the hydrolysis of the neurotransmitter acetylcholine allowing the intermittence of the nerve impulses responsible for the neuronal communication. This enzyme is the main target for the action of some pesticides and the inhibition of its activity in bivalve mollusks may be used as biomarker due to their filter-feeding habit. In this context, the present study aimed to characterize physicochemical and kinetic parameters of the AChE extracted from gills and viscera of the oyster Crassostrea rhizophorae and investigate the in vitro effect of pesticides (dichlorvos, diazinon, chlorpyrifos, methyl-parathion, temephos, carbaryl, carbofuran, aldicarb, diflubenzuron and novaluron) in search for assessing its potential as biomarker. Specific substrates and inhibitors evidenced the predominance of AChE in both tissues. The optimum pH found for gills and viscera AChE were 8.0 and 8.5, respectively. The maximum peak of activity occurred at 70 °C for gill AChE and 75 °C for viscera AChE. The enzymes of both tissues presented remarkable thermostability. The Michaelis-Menten constant for both enzymes were 1.32 ± 0.20 mM for gills and 0.43 ± 0.12 mM for viscera. The V max values for gills and viscera were 53.57 ± 1.72 and 27.71 ± 1.15 mU/mg, respectively. The enzymes were able to reduce the activation energy to 9.75 kcal mol -1 (gills) and 11.87 kcal mol -1 (viscera) obtaining rate enhancements of 3.57 × 10 5 and 1.01 × 10 4 , respectively, in relation to non-catalyzed reactions. Among the pesticides under study, the carbamates carbaryl and carbofuran exerted the strongest inhibitory effects on the enzyme activity achieving important degrees of inhibition at concentrations below national and international current regulations. The first observation of the effects of benzoylurea pesticides (diflubenzuron and novaluron) on AChE from mollusks is reported here. The gills AChE of C. rhizophorae showed potential to be specific biomarker for the carbamate carbaryl while the viscera AChE showed it for carbofuran. According to their features, these enzymes may be proposed as promising tools for estuarine monitoring as well as biocomponent of biosensor devices., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We examined the susceptibility of field strains (BO-1, BO-2, TO-1, and YH-1) and one laboratory strain (H-1) of the western flower thrip, Frankliniella occidentalis , to benzoylureas. LC 50 values of novaluron were determined as 0.64 ppm against laboratory strain and 2.1-130 ppm against field strains. In the presence of piperonyl butoxide, a cytochrome P450 inhibitor, the insecticidal activity of novaluron tended to be enhanced. To examine whether point mutations in chitin synthase 1 ( CHS1 ) discovered in an etoxazole-resistant strain of Tetranychus urticae and a benzoylurea-resistant strain of Plutella xylostella exist in F. occidentalis , the nucleotide sequence of CHS1 was analyzed. We found a nonsynonymous substitution that corresponded to the location of the mutations found in T. urticae and P. xylostella in the field strains of F. occidentalis but not in the laboratory strain, indicating that this point mutation might be associated with the benzoylurea resistance exhibited by the field strains.

The insecticide Match® (lufenuron), one of the main insect growth regulators used in pest control, has been presented as a viable alternative against the boll weevil, Anthonomus grandis (Coleoptera: Curculionidae), by inhibiting chitin synthesis. Thus, this study aimed to examine whether Match® interferes in the synthesis of the peritrophic matrix, leading to changes in the midgut epithelium, resulting in nutritional deficiency and reflecting, thereby, in the gametogenesis process of A. grandis. Floral cotton buds were immersed in the insecticide solution (800μL of Match®+200mL of distilled water) and offered to the adult insects. The midguts of the insects were evaluated after 24 and 120h after feeding. The gonads were evaluated after 120h. The results showed that Match®, in both evaluation periods, induced histopathological alterations such as disorganization, vacuolization and desquamation of the midgut epithelium; histochemical modifications in the distribution patterns of carbohydrates, although without quantitative changes; and a strong decrease in protein levels. No apoptosis were observed, however, there was an increase in the number of regenerative cell nests. In the testicles, a reduction in the amount of spermatozoids and reduced carbohydrate levels were observed, but no difference in protein levels. The ovarioles presented structural disorganization of follicular cells, yolk reduction and decrease in protein levels, however, no change in carbohydrates levels was noted. Therefore, it is concluded that Match® performs histopathologic and histochemical alterations in the midgut epithelium and the gonads of A. grandis adults, reflecting in the gametogenesis process, presenting itself as a promising tool in the management of this pest on cotton crops., (Copyright © 2016 Elsevier Inc. All rights reserved.)

According to Article 12 of Regulation (EC) No 396/2005, EFSA has reviewed the maximum residue levels (MRLs) currently established at the European level for the pesticide active substance lufenuron. To assess the occurrence of lufenuron residues in plants, processed commodities, rotational crops and livestock, EFSA considered the conclusions derived in the framework of Directive 91/414/EEC, the MRLs established by the Codex Alimentarius Commission as well as the authorisations reported by the Member States (including the supporting residues data) and import tolerances. Based on the assessment of the available data, MRL proposals were derived and a consumer risk assessment was carried out. Although no apparent risk to consumers was identified, some information required by the regulatory framework was missing. Hence, the consumer risk assessment is considered indicative only and some MRL proposals derived by EFSA still require further consideration by risk managers., (© 2017 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.)

Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

Abstract  Chitin is the most abundant natural aminopolysaccharide and serves as a structural component of extracellular matrices. It is found in fungal septa, spores, and cell walls, and in arthropod cuticles and peritrophic matrices, squid pens, mollusk shells, nematode egg shells, and some protozoan cyst walls. As prokaryotes, plants and vertebrates including humans do not produce chitin, its synthesis is considered as an attractive target site for fungicides, insecticides, and acaricides. Although no chitin synthesis inhibitor has been developed into a therapeutic drug to treat fungal infections in humans, a larger number of compounds have been successfully launched worldwide to combat arthropod pests in agriculture and forestry. This review summarizes the latest advances on the mode of action of chitin synthesis inhibitors with a special focus on those molecules that act on a postcatalytic step of chitin synthesis., (© 2012 Institute of Zoology, Chinese Academy of Sciences.)