Application of Asymmetric Catalysis in Chiral Pesticide Active Molecule Synthesis.

The different configurations of chiral pesticides generally have significant influence on their biological activities. Chiral agrochemicals with high optical purities have become a prominent topic in the research field of new pesticides due to their advantages including lower toxicity, higher efficiency, and reduced residue levels. However, most commercially available pesticides that possess chiral elements are still used in their racemic forms. To date, asymmetric catalysis has emerged as a versatile tool for the enantioselective synthesis of various chiral agrochemicals and novel chiral pesticide active molecules. This perspective provides a comprehensive overview of the applications of diverse asymmetric catalytic approaches in the facile preparation of numerous novel pesticide active molecules, and our own outlook on the future development of this highly active research direction is also presented at the end of this review.

Design, Synthesis and Bioactivity of Novel Pyrimidine Sulfonate Esters Containing Thioether Moiety.

Pesticides play an important role in crop disease and pest control. However, their irrational use leads to the emergence of drug resistance. Therefore, it is necessary to search for new pesticide-lead compounds with new structures. We designed and synthesized 33 novel pyrimidine derivatives containing sulfonate groups and evaluated their antibacterial and insecticidal activities. Results: Most of the synthesized compounds showed good antibacterial activity against Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac), Pseudomonas syringae pv. actinidiae (Psa) and Ralstonia solanacearum (Rs), and certain insecticidal activity. A5, A31 and A33 showed strong antibacterial activity against Xoo, with EC50 values of 4.24, 6.77 and 9.35 µg/mL, respectively. Compounds A1, A3, A5 and A33 showed remarkable activity against Xac (EC50 was 79.02, 82.28, 70.80 and 44.11 µg/mL, respectively). In addition, A5 could significantly improve the defense enzyme (superoxide dismutase, peroxidase, phenylalanine ammonia-lyase and catalase) activity of plants against pathogens and thus improve the disease resistance of plants. Moreover, a few compounds also showed good insecticidal activity against Plutella xylostella and Myzus persicae. The results of this study provide insight into the development of new broad-spectrum pesticides.

Synthesis and evaluation of novel 1-(((6-substitutedbenzo[d]thiazol-2-yl)amino)(heteroaryl)methyl)naphthalen-2-ol as pesticidal agents.

To discover new agrochemicals with prominent pesticidal properties, a series of novel ß-naphthol derivatives containing benzothiazolylamino and various heteroaryl groups (8a-q) were efficiently synthesised via Betti reaction. The bioassay results showed that most of the synthesised compounds exhibited favourable insecticidal potentials, particularly towards oriental armyworm (50-100% at 200 mg·L-1) and diamondback moth (50-95% at 10 mg·L-1). Compounds 8 b, 8f, 8 g, 8j, 8k, 8n, and 8o possessed LC50 values of 0.0988-5.8864 mg·L-1 against diamondback moth. Compounds 8i, 8 l, and 8 m also displayed lethality rates of 30-90% against spider mite at the concentration of 100 mg·L-1. Overall, some compounds could be considered as new insecticidal/acaricidal leading structures for further investigation. The calcium imaging experiments revealed that 8 h, 8i, and viii could activate the release of calcium ions in insect (M. separata) central neurons at a higher concentration (50 mg·L-1). The SAR analysis provided valuable information for further structural modifications.

Construction of spiro-1,2,4-oxadiazoline-fused matrine-type alkaloids as pesticidal agents.

In order to increase the agricultural properties of matrine, a series of novel matrine-type alkaloidscontaining spiro-1,2,4-oxadiazoline fragment at the C-15 position were prepared. Eight target molecules were elucidated by X-ray single-crystal diffraction. The antifeedant activities of Ig and IIIh against Mythimna separata Walker were>1.7 folds of the precursor matrine. The acaricidal activities of Ij, IIe, IIg, IIi and IIIa against Tetranychus cinnabarinus Boisduval were 2.6-3.7 folds of matrine. Especially IIg (R1 = R2 = 4-Cl) and IIi (R1 = 4-Cl; R2 = 4-Br) exhibited the pronounced antifeedant and acaricidal activities. SARs showed that their pesticidal activities were related to the substitutents and their positions on the phenyl rings at the C-3 and N-4 positions of 1,2,4-oxadiazoline skeleton.

Discovery of a Novel Fusarium Graminearum Mitogen-Activated Protein Kinase (FgGpmk1) Inhibitor for the Treatment of Fusarium Head Blight.

Mitogen-activated protein kinase FgGpmk1 plays vital roles in the development and virulence of Fusarium graminearum (F. graminearum), the causative agent of Fusarium head blight (FHB). However, to date, the druggability of FgGpmk1 still needs verification, and small molecules targeting FgGpmk1 have never been reported. Here, we reported the discovery of a novel inhibitor 94 targeting FgGpmk1. First, a novel hit (compound 21) with an EC50 value of 13.01 µg·mL-1 against conidial germination of F. graminearum was identified through virtual screening. Then, guided by molecular modeling, compound 94 with an EC50 value of 3.46 µg·mL-1 was discovered, and it can inhibit the phosphorylation level of FgGpmk1 and influence the nuclear localization of its downstream FgSte12. Moreover, 94 can inhibit deoxynivalenol biosynthesis without any damage to the host. This study reported a group of FgGpmk1 inhibitors with a novel scaffold, which paves the way for the development of potent fungicides to FHB management.

Bio-Based Formulations for Sustainable Applications in Agri-Food-Pharma.

Currently, there is a strong enduring interest towards obtaining high-value, sustainable bio-based bioactive compounds from natural resources, as there is great demand for these compounds in various market sectors such as agriculture, food, pharma, cosmeceuticals, and others [...].

Development of leaf-adhesive pesticide nanocapsules with pH-responsive release to enhance retention time on crop leaves and improve utilization efficiency.

Pesticides play a very important role in pest control and plant protection. However, they can be limited by a tendency to cause ecological system damage due to significant losses into the environment. To increase pesticide utilization efficiency, we developed highly leaf-adhesive avermectin nanocapsules (Av-pH-cat@CS) with pH-responsive controlled release properties. The Av-pH-cat@CS nanocapsules displayed good thermal stability and photostability in response to UV light irradiation. The Av-pH-cat@CS nanocapsules could be disrupted at low pH and they exhibited excellent controlled release in response to pH, which improved the release of avermectins. In addition, the Av-pH-cat@CS nanocapsules were highly adhesive to crop leaves as a result of strong hydrogen bonding, which prolonged the retention time on crop leaves. The Av-pH-cat@CS nanocapsules with pH-responsive release and strong leaf adhesion improved the control efficacy and enhanced the utilization efficiency. Our findings offer a promising approach to prolonging pesticide duration on crop leaves and improving the utilization efficiency.

Smart Synthesis of Trimethyl Ethoxysilane (TMS) Functionalized Core-Shell Magnetic Nanosorbents Fe3O4@SiO2: Process Optimization and Application for Extraction of Pesticides.

In the current study, a smart approach for synthesizing trimethyl ethoxysilane-decorated magnetic-core silica-nanoparticles (TMS-mcSNPs) and its effectiveness as nanosorbents have been exploited. While the magnetite core was synthesized using the modified Mössbauer method, Stöber method was employed to coat the magnetic particles. The objective of this work is to maximize the magnetic properties and to minimize both particle size (PS) and particle size distribution (PSD). Using a full factorial design (2k-FFD), the influences of four factors on the coating process was assessed by optimizing the three responses (magnetic properties, PS, and PSD). These four factors were: (1) concentration of tetraethyl-orthosilicate (TEOS); (2) concentration of ammonia; (3) dose of magnetite (Fe3O4); and (4) addition mode. Magnetic properties were calculated as the attraction weight. Scanning electron microscopy (SEM) was used to determine PS, and standard deviation (±SD) was calculated to determine the PSD. Composite desirability function (D) was used to consolidate the multiple responses into a single performance characteristic. Pareto chart of standardized effects together with analysis of variance (ANOVA) at 95.0 confidence interval (CI) were used to determine statistically significant variable(s). Trimethyl ethoxysilane-functionalized mcSNPs were further applied as nanosorbents for magnetic solid phase extraction (TMS-MSPE) of organophosphorus and carbamate pesticides.

A sodium alginate-based nano-pesticide delivery system for enhanced in vitro photostability and insecticidal efficacy of phloxine B.

To improve in vitro photostability and enhance insecticidal activity, a novel esterase/glutathione (GSH) responsive photoactivated nano-pesticide delivery system was synthesized by conjugation of photoactivated pesticide phloxine B(PB) to sodium alginate (SA) via esterase/GSH sensitive phenolic ester bond followed by ultrasonic dispersion. The system was stable in PBS (pH 7.4) and could protect effectively the conjugated PB from in vitro photodegradation because of aggregation-caused quenching effect, whose maximum photodegradation rate did not exceed 10 % after 270 min illumination. However, upon exposure to esterase-6 or GSH stimulus, high photoactivity was observed due to the destruction of the system and accompanied by PB release. The combined stimulation could trigger more PB release than any single stimulus and thus resulting in a higher photoactivity. Compared with free PB, The system showed a higher phototoxicity on Sf9 insect cells and the in vitro light exposure had little influence on the phototoxicity.

Synthesis and Pesticidal Activities of New Quinoxalines.

Natural products are a source of many novel compounds with biological activity for the discovery of new pesticides and pharmaceuticals. Quinoxaline is a fused N-heterocycle in many natural products and synthetic compounds, and seven novel quinoxaline derivatives were designed and synthesized via three steps. Pesticidal activities of title quinoxaline derivatives were bioassayed. Most of these compounds had herbicidal, fungicidal, and insecticidal activities. The compounds 2-(6-methoxy-2-oxo-3-phenylquinoxalin-1(2H)-yl)acetonitrile (3f) and 1-allyl-6-methoxy-3-phenylquinoxalin-2(1H)-one (3g) were the most active herbicides and fungicides. Mode-of-action studies indicated that 3f is a protoprophyrinogen oxidase-inhibiting herbicide. Compound 3f also possessed broad-spectrum fungicidal activity against the plant pathogen Colletotrichum species. Some of these compounds also had insecticidal activity. Molecular docking and DFT analysis can potentially be used to design more active compounds.

Novel 1,3,4-oxadiazole thioether derivatives containing flexible-chain moiety: Design, synthesis, nematocidal activities, and pesticide-likeness analysis.

Seventy-two novel 1,3,4-oxadiazole thioether derivatives containing different flexible-chain moieties were designed and synthesized. The nematicidal activities of all the title compounds were evaluated, and some compounds showed excellent nematicidal activities against citrus nematodes. The compounds 15, 16, 18, 27, 41, 42, 44, 53, and 71 had the mortality to citrus nematodes of 92.5, 93.7, 90.3, 91.5, 92.6, 92.8, 93.5, 91.3, and 91.0% at the concentration of 100 mg/L, which were better than the control agent of avermectin (85.9%). After the test concentration was reduced to 50 mg/L, the nematicidal activities of the compounds 16, 42, 44, 53, and 71 were still superior to avermectin (65.1%), with the mortality of 72.3, 71.3, 70.6, 71.1, and 73.9%, respectively. The LC50 values of the compounds 16, 42, 44, 53, and 71 were 16.3, 18.8, 20.8, 17.5, and 14.7 mg/L, which were better than the commercial positive control agent of avermectin (24.8 mg/L). Meanwhile, the qualitative and quantitative analysis of the pesticide-likeness shows that compound 71 exhibits the potential insecticide-likeness. This work indicates that novel 1,3,4-oxadiazole thioether derivatives containing flexible-chains deserve further research as potential nematicides to protect citrus crops in the future.

Visible-Light-Mediated Dearomatisation of Indoles and Pyrroles to Pharmaceuticals and Pesticides.

Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.

Semisynthesis of Matrinic Acid/Alcohol/Ester Derivatives, Their Pesticidal Activities, and Investigation of Mechanisms of Action against Tetranychus cinnabarinus.

To discover new natural-product-based potential pesticides, 85 matrinic acid/alcohol/ester derivatives were synthesized by structural modifications of a quinolizidine alkaloid matrine. N-(4-Methyl)benzylmatrinyl n-decylate (76) and N-(2-chloro)benzylmatrinyl n-undecylate (86) exhibited greater than seven-fold more pronounced acaricidal activity than matrine against Tetranychus cinnabarinus; N-(2-chloro)benzylmatrinyl benzoate (80) showed the most promising insecticidal activity against Mythimna separata. The carboxyl group of matrinic acids and introduction of n-decyl/ n-undecylcarbonyl into matrinic alcohols were important for the acaricidal activity; introduction of alkyloxy into the carboxyl of matrinic acids and introduction of the electron-withdrawing groups on the N-benzyl of matrinic esters were necessary for the insecticidal activity. Through RT-PCR and qRT-PCR analysis, it was shown that the lactam ring of matrine was vital for action on VGSC; opening the lactam ring of matrine and the alkylcarbonyl of side-chain were two important factors for acting with α1, α2, and α4 nAChR subunits; α1, α2, α4, and ß3 subunits may be the target of action of compound 86 against T. cinnabarinus.

Synthesis of Piperine Analogs Containing Isoxazoline/Pyrazoline Scaffold and Their Pesticidal Bioactivities.

In continuation of our program to discover new potential pesticidal agents, thirty-one piperine analogs containing isoxazoline/pyrazoline scaffold were prepared, and confirmed by infrared spectra, proton/carbon-13 nuclear magnetic resonance spectra, and high-resolution mass spectra. The structures of compounds VIIb and VIIIc were further determined by 1H-1H COSY spectra. Especially the configuration of compound VIIIc was unambiguously confirmed by single-crystal X-ray diffraction. Their pesticidal activities were evaluated against three serious and typically crop-threatening agricultural pests, Tetranychus cinnabarinus Boisduval (spider mite), Mythimna separata Walker (Oriental armyworm), and Plutella xylostella Linnaeus (diamondback moth). Compounds VIIIb and VIIIc exhibited greater than 40-fold more potent acaricidal activity than the lead compound piperine against T. cinnabarinus. Notably, compounds VIa-c exhibited more pronounced oral toxicity against P. xylostella than toosendanin; compounds VIb and VIc displayed more promising growth inhibitory activity against M. separata than toosendanin. It demonstrated that the methylenedioxy and isoxazoline scaffolds were important for the oral toxicity and growth inhibitory activity against P. xylostella and M. separata, respectively; the ethylenedioxy and isoxazoline scaffolds were vital for the acaricidal activity against T. cinnabarinus. Moreover, compounds VIb, VIIf, and VIIIc showed very low toxicity against NRK-52E cells.

Investigation of Novel Pesticides with Insecticidal and Antifungal Activities: Design, Synthesis and SAR Studies of Benzoylpyrimidinylurea Derivatives.

In order to find pesticides with insecticidal and antifungal activities, a series of novel benzoyl pyrimidinylurea derivatives were designed and synthesized. All target compounds were identified by ¹H-NMR spectroscopy and HRMS. Insecticidal and antifungal activity of these compounds were evaluated and the structure-activity relationships (SAR) were clearly and comprehensively illustrated. Compound 7, with low toxicity to zebrafish (LC50 = 378.387 µg mL-1) showed 100% inhibition against mosquito (Culex pipiens pallens) at 0.25 µg mL-1. Both compounds 19 and 25 exhibited broad-spectrum fungicidal activity (>50% inhibitory activities against 13 phytopathogenic fungi), which were better than those of the commercial pesticide pyrimethanil (>50% inhibitory activities against eight phytopathogenic fungi). Furthermore, compounds 19 and 25 exhibited protective activity against Sclerotinia sclerotiorum on leaves of Brassica oleracea L. during in vivo experiments.

Design, Synthesis, and Biological Activity of ß-Carboline Analogues Containing Hydantoin, Thiohydantoin, and Urea Moieties.

A series of novel ß-carboline derivatives was designed by combining the anti-tobacco mosaic virus (TMV) lead compound tetrahydro-ß-carboline ester with the hydantoin, thiohydantoin, and urea motifs. These derivatives were synthesized from tetrahydro-ß-carboline ester via a structural diversity-oriented synthesis in one step, and their biological activities were evaluated. Most of the derivatives exhibited anti-TMV activity higher than that of commercial plant virucide ribavirin, such as compounds 2, 4, 5, 7, 9, 15, 16, 19, and 21. Compared with the lead compounds, some of these derivatives showed good insecticidal activity against Plutella xylostella and Culex pipiens pallens. At the same time, these derivatives also showed broad-spectrum fungicidal activity. The systematic study provides strong evidence that the hydantoin, thiohydantoin, and urea motifs of these molecules can improve and modulate the activities of the analogues of natural products.

Design of a New Glutamine-Fipronil Conjugate with α-Amino Acid Function and Its Uptake by A. thaliana Lysine Histidine Transporter 1 ( AtLHT1).

Creating novel pesticides with phloem mobility is essential for controlling insects in vascular tissue and root, and conjugating existing pesticides with amino acid is an effective approach. In order to obtain a highly phloem-mobile candidate for efficient pesticides, an electro-neutral l-glutamine-fipronil conjugate (l-GlnF) retaining α-amino acid function was designed and synthesized to fit the substrate specificity of an amino acid transporter. Cotyledon uptake and phloem loading tests with Ricinus communis have verified that l-GlnF was phloem mobile, and its phloem mobility was higher than that of its enantiomer d-GlnF and other previously reported amino acid-fipronil conjugates. Inhibition experiments then suggested that the uptake of l-GlnF was, at least partially, mediated by an active transport mechanism. This inference was further strengthened by assimilation experiments with Xenopus oocytes and genetically modified Arabidopsis thaliana, which showed a direct correlation between the uptake of l-GlnF and the expression of amino acid transporter AtLHT1. Thus, conjugation with l-Gln appears to be a potential strategy to ensure the uptake of pesticides via an endogenous amino acid transport system.

Natural Product-Based Pesticide Discovery: Design, Synthesis and Bioactivity Studies of N-Amino-Maleimide Derivatives.

Natural products are an important source of pesticide discovery. A series of N-amino-maleimide derivatives containing hydrazone group were designed and synthesized based on the structure of linderone and methyllinderone which were isolated from Lindera erythrocarpa Makino. According to the bioassay results, compounds 2 and 3 showed 60% inhibition against mosquito (Culex pipiens pallens) at 0.25 µg·mL−1. Furthermore, the results of antifungal tests indicated that most compounds exhibited much better antifungal activities against fourteen phytopathogenic fungi than linderone and methyllinderone and some compounds exhibited better antifungal activities than commercial fungicides (carbendazim and chlorothalonil) at 50 µg·mL−1. In particular, compound 12 exhibited broad-spectrum fungicidal activity (>50% inhibitory activities against 11 phytopathogenic fungi) and compounds 12 and 14 displayed 60.6% and 47.9% inhibitory activity against Rhizoctonia cerealis at 12.5 µg·mL−1 respectively. Furthermore, compound 17 was synthesized, which lacks N-substituent at maleimide and its poor antifungal activity against Sclerotinia sclerotiorum and Rhizoctonia cerealis at 50 µg·mL−1 showed that the backbone structure of N-amino-maleimide derivatives containing hydrazone group was important to the antifungal activity.

A bionanohybrid ZnAl-NADS ecological pesticide as a treatment for soft rot disease in potato (Solanum tuberosum L.).

Pectobacterium carotovorum (Pc) is a phytopathogenic strain that causes soft rot disease in potato (Solanum tuberosum L.), resulting in postharvest losses. Chemical control is effective for managing this disease, but overdoses cause adverse effects. Because farmers insist on using chemical agents for crop protection, it is necessary to develop more effective pesticides in which the active compound released can be regulated. In this context, we proposed the synthesis of ZnAl-NADS, in which nalidixic acid sodium salt (NADS) is linked to a ZnAl-NO3 layered double hydroxide (LDH) host as a nanocarrier. XRD, FT-IR, and SEM analyses confirmed the successful intercalation of NADS into the interplanar LDH space. The drug release profile indicated that the maximum release was completed in 70 or 170 min for free NADS (alone) or for NADS released from ZnAl-NADS, respectively. This slow release was attributed to strong electrostatic interactions between the drug and the anion exchanger. A modulated release is preferable to the action of the bulk NADS, showing increased effectiveness and minimizing the amount of the chemical available to pollute the soil and the water. The fitting data from modified Freundlich and parabolic diffusion models explain the release behavior of the NADS, suggesting that the drug released from ZnAl-NADS bionanohybrid was carried out from the interlamellar sites, according to the ion exchange diffusion process also involving intraparticle diffusion (coeffect). ZnAl-NADS was tested in vitro against Escherichia coli (Ec) and Pc and exhibited bacteriostatic and biocidal effects at 0.025 and 0.075 mg mL-1, respectively. ZnAl-NADS was also tested in vivo as an ecological pesticide for combating potato soft rot and was found to delay typical disease symptoms. In conclusion, ZnAl-NADS can potentially be used to control pests, infestation, and plant disease.

Genotoxic evaluation of newly synthesized iminothiazolidinones.

The current study was designed to assess the potential toxicological effects of newly synthesized iminothiazolidinones by employing Ames Salmonella, Escherichia coli WP2, Zea mays seed germination, and random amplified polymorphic DNA (RAPD) assay systems. The bacterial tester strains S. typhimurium TA1535, TA1537, TA1538, TA98, TA100, and E. coli WP2 uvrA were chosen to test the direct gene mutation inducing capabilities of the test materials in prokaryotic systems and Z. mays seeds for determination of potential toxicological effects in eukaryotic systems. OPA-3 and OPA-6 primers were used in the RAPD analysis to determine genotoxic activities on the eukaryotic genomes. According to the results, none of the test materials showed significant mutagenic activity on the bacterial tester strains at the chosen concentrations. Additionally, none of the tested compounds showed inhibition of the germination of Z. mays seeds. In contrast, the RAPD analysis results were inconsistent with the bacterial reversion assays and the seed germination assay results. All test materials significantly changed the RAPD profiles for OPA-3; however, only compound 5 showed a significant change for OPA-6 when compared with the control groups. In conclusion, the newly synthesized iminothiazolidinone derivatives (C1-C5) were determined as potentially genotoxic compounds and they should be checked with multiple toxicology test systems before further studies to determine their actual use.