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

Discovery of 3‑Formyl‑<i>N</i>‑(un)Substituted Benzylindole Pyrimidines as an Acaricidal Agent and Their Mechanism of Action

To discover the pronounced acaricide candidate, herein, a series of 3-formyl-N-(un)­substituted benzylindole pyrimidines were prepared by structural modification of indoles at the N-1 and C-3 positions via the successive Vilsmeier–Haack–Arnold (VHA), aldol condensation, and cyclization reactions. The steric structures of nine compounds were undoubtedly confirmed by X-ray single-crystallography. Against Tetranychus cinnabarinus Boisduval, compounds V-15, V-31, V-34, V-42, V-44, and V-60 exhibited promising acaricidal activity with LC50 values of 0.299–0.481 mg/mL. In particular, compound V-34 displayed 4.2 times the acaricidal activity of its precursor 6-methylindole. Scanning electron microscopy (SEM) imaging revealed that the construction of the cuticle layer of V-34-treated T. cinnabarinus was seriously destroyed. Furthermore, RNA-Seq analysis indicated that compound V-34 could regulate the homeostasis metabolism of T. cinnabarinus through arachidonic acid and linoleic acid metabolism and lysosome pathways. These results suggested that compound V-34 can be further studied as a lead acaricidal agent

Development of Botanical Pesticides: Exploration on the Phenotype of Vestigial Wings of Insect Pests Induced by Plant Natural Products or Their Derivatives by Blocking Tyrosine Phosphorylation of Insulin Receptor 1

Unlike faster-acting conventional insecticides, some botanical insecticides exhibit growth inhibitory activity against some insect pests. One of the distinguishing features of growth inhibitory activity appears to be in malformed moths with vestigial wings. However, the molecular mechanism underlying vestigial wings of insect pests induced by plant natural products or their derivatives is still elusive. In this work, based upon the phenotype of the vestigial wings of Mythimna separata Walker (as a model pest) induced by a podophyllotoxin derivative 2a (as a model compound), we found that compound 2a not only resulted in 22.1% of malformed moths with vestigial wings but also significantly decreased the fecundity of vestigial-winged female moths in the P generation; the trait of vestigial wings caused by 2a in the P generation can be inherited by the F1 generation; compound 2a may target insulin receptor 1 (InR1), suppress the InR1 mRNA level, and block InR1-pY1229 and InR1-pY1233/1234 phosphorylation levels in a tissue-specific manner “head/thorax/wing tissues”. Notably, compound 2a can also induce the vestigial wings of Spodoptera frugiperda (another seriously harmful migratory lepidoptera pest). It is noteworthy that this insect insulin receptor can be used as a new kind of target receptors for the design of novel green insecticides

High Value-Added Application of Natural Plant Products in Crop Protection: Honokiol Monoester/Diester Derivatives Containing the Novel Core Scaffold of Benzodihydrofuran and Their Agricultural Bioactivities and Control Effects

To discover new potential botanical insecticides from plant secondary metabolites, a series of new honokiol-type monoester/diester derivatives containing the core scaffold of benzodihydrofuran were synthesized by structural modification of honokiol. Against Mythimna separata Walker, 2-hydroxymethy-5-(2′-(para-chlorobenzoyloxy)-5′-(1″,2″-epoxypropanyl))­phenyl-2,3-dihydrobenzofuran (5) and 2-(2″-chloropyridin-5″-ylcarbonyloxy)­methylene-5-(2′-(2″-chloropyridin-5″-ylcarbonyloxy)-5′-(1″,2″-epoxypropanyl))­phenyl-2,3-dihydrobenzofuran (37) displayed >2.1-fold promising insecticidal activity of the precursor honokiol. Against Aphis citricola Van der Goot, 2-hydroxymethy-5-(2′-(tridecylcarbonyloxy)-5′-(1″,2″-epoxypropanyl))­phenyl-2,3-dihydrobenzofuran (21) (LD50: 0.049 μg/nymph) and 2-(para-fluorobenzylcarbonyloxy)­methylene-5-(2′-(para-fluorobenzylcarbonyloxy)-5′-(1″,2″-epoxypropanyl))­phenyl-2,3-dihydrobenzofuran (31) (LD50: 0.040 μg/nymph) showed 3.5- and 4.3-folds potent aphicidal activity of honokiol (LD50: 0.171 μg/nymph), respectively. Interestingly, 2-(tridecylcarbonyloxy)­methylene-5-(2′-(tridecylcarbonyloxy)-5′-(1″,2″-epoxypropanyl))­phenyl-2,3-dihydrobenzofuran (46) (LC50: 0.186 mg/mL) and 2-(dodecylcarbonyloxy)­methylene-5-(2′-(dodecylcarbonyloxy)-5′-(1″,2″-epoxypropanyl))­phenyl-2,3-dihydrobenzofuran (53) (LC50: 0.159 mg/mL: >6.4-fold of honokiol (LC50: 1.024 mg/mL)) exhibited promising acaricidal activity and control efficiency against Tetranychus cinnabarinus Boisduval. Structure–activity relationships indicated that a specific length of the aliphatic chain is necessary for the agricultural activities of honokiol monoester/diester derivatives, especially for the acaricidal activity of diester derivatives

High Value-Added Application of Natural Products in Crop Protection: Semisynthesis and Acaricidal Activity of Limonoid-Type Derivatives and Investigation of Their Biocompatible O/W Nanoemulsions as Agronanopesticide Candidates

The increasingly serious resistance of Tetranychus cinnabarinus Boisduval to a wide range of insecticides/acaricides poses a major challenge to their control. The citrus processing industry generates a huge quantity of various wastes that contain many limonoids. To effectively utilize these byproducts and discover more potent green acaricidal molecules as sustainable alternatives for traditional resistant pesticides, various limonoid-type derivatives (halogenated/seven-membered lactam derivatives of obacunone and halogenated/oxime esters/oxime ethers/seven-membered lactam derivatives of limonin) were synthesized based on a diversity-oriented synthetic strategy. The key steric configurations of 10 derivatives were further confirmed by X-ray crystallography. Compound 9m, which displayed greater than 9.7-fold potent acaricidal activity of limonin, was of preeminence. In addition, some interesting structure–activity relationships were observed. Moreover, a biocompatible O/W nanoemulsion delivery system was used to prepare the limonin-based agronanoacaricide, which exhibited pronounced control efficiency against T. cinnabarinus Boisduval in the greenhouse. This systematic investigation will provide valuable information and guidance for future value-added applications of novel eco-friendly natural product-based nanopesticides

Discovery of Pesticide Candidates from Natural Plant Products: Semisynthesis and Characterization of Andrographolide-Based Esters and Study of Their Pesticidal Properties and Toxicology

To explore the use of nonfood plant-derived secondary metabolites for plant protection, a series of ester derivatives for controlling the major migratory agricultural pests were obtained by structural modification of andrographolide, a labdane diterpenoid isolated from Andrographis paniculata. Compound Id showed good insecticidal activity against the fall armyworm Spodoptera frugiperda Smith. Compounds IIa (LC50: 0.382 mg/mL) and IIIc (LC50: 0.563 mg/mL), the acaricidal activities of which were, respectively, 13.1 and 8.9 times that of andrographolide (LC50: 4.996 mg/mL), exhibited strong acaricidal and control effects against Tetranychus cinnabarinus Boisduval. Against Aphis citricola Van der Goot, compounds IIIc and IVb displayed 3.9- and 3.7-fold pronounced aphicidal activity of andrographolide. Effects of compound Id on three protective enzymes (superoxide dismutase, peroxidase, and catalase) of S. frugiperda were also observed. The obvious differences of epidermal cuticle structures of mites treated with compound IIa were determined by scanning electron microscopy. Structure–activity relationships indicated that 14-ester derivatives of andrographolide showed potential insecticidal/acaricidal activities and can be further utilized as lead compounds

Optimization of Osthole in the Lactone Ring as an Agrochemical Candidate: Synthesis, Characterization, and Pesticidal Activities of Osthole Amide/Ester Derivatives and Their Effects on Morphological Changes of Mite Epidermis

Structural modification of natural products is one of the important ways in the discovery of novel pesticides. Based on a diversity-oriented synthesis strategy, herein, two series of amide/ester derivatives (52 compounds) were obtained by opening the lactone of osthole. Interestingly, the effect of different concentrations of aq. sodium hydroxide on the ratio of two isomers (cis- and trans-2) was investigated, and a magical phenomenon of ultraviolet (UV) light irradiation on intertransformation of two isomers (cis- and trans-2) was observed. Against Mythimna separata, when compared with the precursor osthole, compounds 4b, 4l, 5l, 5m, 7h, 7l, and 7m displayed more pronounced growth inhibitory activity with the final mortality rates of 62.0–68.9%. Compounds 4b, 4i, and 5m showed 5.7–6.6 times stronger acaricidal activity against Tetranychus cinnabarinus than osthole, and notably, control effects of compounds 4i and 5m were 2.4- and 2.7-fold that of osthole in the management of T. cinnabarinus in the greenhouse. Scanning electron microscopy (SEM) images of the epidermis of 5m-treated T. cinnabarinus indicated that compound 5m can destroy the mite cuticle layer. Compounds 4b and 5m can be used as leads to further explore more promising pesticidal agents

Ile-1781-Leu Target Mutation and Non-Target-Site Mechanism Confer Resistance to Acetyl-CoA Carboxylase-Inhibiting Herbicides in Digitaria ciliaris var. chrysoblephara

Digitaria ciliaris var. chrysoblephara is a xerophytic weed severely invading rice fields along with the application of rice mechanical direct seeding technology in China. This study identified one resistant population (M5) with an Ile-1781-Leu substitution in ACCase1 showing broad-spectrum resistance to three chemical classes of ACCase-inhibiting herbicides, including metamifop, cyhalofop-butyl, fenoxaprop-p-ethyl, haloxyfop-p-methyl, clethodim, sethoxydim, and pinoxaden. The other two populations, M2 and M4, without any resistance-responsible mutations, only exhibited resistance to aryloxyphenoxypropionate (APP) herbicides cyhalofop-butyl and fenoxaprop-p-ethyl. Pre-treatment with the cytochrome P450 monooxygenase (P450) inhibitor PBO significantly reduced the cyhalofop-butyl resistance by 43% in the M2 population. Pre-emergence weed control with soil-applied herbicides, such as pretilachlor, pendimethalin, and oxadiazon, can effectively inhibit the germination and growth of D. ciliaris var. chrysoblephara. The present study reported a xerophytic weed species invading rice fields featuring broad-spectrum resistance to ACCase-inhibiting herbicides as a result of Ile-1781-Leu mutation of ACCase. Both target- and P450-involved non-target-site mechanisms may be contributing to resistance in D. ciliaris var. chrysoblephara species