Construction and Single-Crystal Structures of N-Isoxazolin-5-ylcarbonylindole Derivatives, and Their Pesticidal Activities and Toxicology Study.

To explore natural product-based pesticide candidates, a series of indole derivatives containing the isoxazoline skeleton at the N-1 position were synthesized by 1,3-dipolar [2 + 3] cycloaddition reaction. Their structures were characterized by melting points (mp), infrared (IR) spectra, proton nuclear magnetic resonance spectra (1H NMR), carbon-13 nuclear magnetic resonance spectra (13C NMR), and high resolution mass spectrometry (HRMS). The single-crystal structures of five compounds were presented. Against Tetranychus cinnabarinus Boisduval, compound 3b showed greater than 3.8-fold acaricidal activity of indole and good control effects under glasshouse conditions. Against Aphis citricola Van der Goot, compounds 3b and 3q exhibited 48.3- and 36.8-fold aphicidal activity of indole and 6-methylindole, respectively. Particularly, compound 3b showed good bioactivities against T. cinnabarinus and A. citricola. Against Eriosoma lanigerum Hausmann, compound 3h and 3i showed 2.1 and 1.9 times higher aphicidal activity compared to indole. Furthermore, the construction of the epidermal cuticle layer of 3b-treated carmine spider mites was distinctly damaged, which ultimately led to their death.

Optimization of Osthole as a Pesticide Candidate: Synthesis, Crystal Structures, and Agrochemical Properties of Acrylate Derivatives of Isopropenyl 2,3-Dihydrobenzofurans.

For high-value-added application of osthole derivatives as a pesticide candidate in crop protection, by the use of osthole as a lead compound, a series of novel acrylate derivatives of isopropenyl 2,3-dihydrobenzofurans were prepared by the successive bromination, rearrangement, and esterization reactions. Three-dimensional structures of four compounds were determined by single-crystal X-ray diffraction. The possible mechanism for construction of this new isopropenyl 2,3-dihydrobenzofuran skeleton from the osthole was presented. Against Plutella xylostella Linnaeus, compound 32 (R = PhCH2CH2) displayed 3.5-fold potent insecticidal activity of osthole. Against Tetranychus cinnabarinus Boisduval, compound 40 (LC50: 0.165 mg/mL; R = (CH2)13CH3) showed 8.3-fold pronounced acaricidal activity of osthole (LC50: 1.367 mg/mL); notably, its control effect can be comparable to that of the commercial acaricide spirodiclofen. Additionally, the scanning electron microscopy imaging method demonstrated that compound 40 can destroy the stratum corneum of T. cinnabarinus. Compound 40 can be further explored as a lead acaricidal agent.

Discovery of 3-Formyl-N-(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.

Expedient discovery of novel oxime ester derivatives of piperine/piperine analogs as potent pesticide candidates and their mode of action against Tetranychus cinnabarinus Boisduval.

BACKGROUND: Nowadays, pest infestation and resistance have appeared as a consequence of repeated and extensive use of pesticides. Thus, development of new effective pesticide candidates in crop protection is highly desirable. Herein, a series of new piperine derivatives containing oxime ester scaffolds were regioselectively and stereoselectively prepared as pesticidal agents. RESULTS: Steric configurations of compounds 2, 5z and 13e were definitively determined by single-crystal X-ray diffraction. Against Tetranychus cinnabarinus, notably, compounds 5f [median lethal concentration (LC50 ) = 0.14 mg mL-1 ] and 5v (LC50 = 0.13 mg mL-1 ) showed >107-fold greater acaricidal activity than piperine (LC50 = 15.02 mg mL-1 ), which were comparable to the commercial acaricide spirodiclofen. Against Aphis citricola, compound 5d (LD50 = 19.12 ng aphid-1 ) exhibited 6.1-fold more potent aphicidal activity than piperine (LD50 = 116.06 ng aphid-1 ). Additionally, through scanning electron microscopy, the toxicology study suggested that the acaricidal activity of piperine derivatives may be related to damage of the cuticle layer crest of T. cinnabarinus. CONCLUSION: The structure-activity relationships suggested that 3,4-dioxymethylene of piperine was crucial for its acaricidal activity; and introduction of a certain length of aliphatic chain at the C-2 position was beneficial to the aphicidal and acaricidal activities. Compounds 5f and 5v are potential leads for further structural modification as acaricidal agents. © 2023 Society of Chemical Industry.

Exploration of Synergistic Pesticidal Activities, Control Effects and Toxicology Study of a Monoterpene Essential Oil with Two Natural Alkaloids.

With the increasing development of pest resistances, it is not easy to achieve satisfactory control effects by using only one agrochemical. Additionally, although the alkaloid matrine (MT) isolated from Sophora flavescens is now utilized as a botanical pesticide in China, in fact, its pesticidal activities are much lower in magnitude than those of commercially agrochemicals. To improve its pesticidal activities, here, the joint pesticidal effects of MT with another alkaloid oxymatrine (OMT) (isolated from S. flavescens) and the monoterpene essential oil 1,8-cineole (CN) (isolated from the eucalyptus leaves) were investigated in the laboratory and greenhouse conditions. Moreover, their toxicological properties were also studied. Against Plutella xylostella, when the mass ratio of MT and OMT was 8/2, good larvicidal activity was obtained; against Tetranychus urticae, when the mass ratio of MT and OMT was 3/7, good acaricidal activity was obtained. Especially when MT and OMT were combined with CN, the significant synergistic effects were observed: against P. xylostella, the co-toxicity coefficient (CTC) of MT/OMT (8/2)/CN was 213; against T. urticae, the CTC of MT/OMT (3/7)/CN was 252. Moreover, the activity changes over time of two detoxification enzymes, carboxylesterase (CarE) and glutathione S-transferase (GST) of P. xylostella treated with MT/OMT (8/2)/CN, were observed. In addition, by scanning electron microscope (SEM), the toxicological study suggested that the acaricidal activity of MT/OMT (3/7)/CN may be related to the damage of the cuticle layer crest of T. urticae.

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.

Natural products in crop protection: thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles as antifungal agents and their mechanism of action.

BACKGROUND: Phytopathogenic fungi can cause a direct loss in economic value of agriculture. Especially Valsa mali Miyabe et Yamada, a devastating phytopathogenic disease especially threatening global apple production, is very difficult to control and manage. To discover new potential antifungal agents, a series of thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles were prepared. Their antifungal activities were first tested against six typically phytopathogenic fungi including Curvularia lunata, Valsa mali, Alternaria alternate, Fusarium graminearum, Botrytis cinerea and Fusarium solani. Then their mechanism of action against V. mali was investigated. RESULTS: Derivatives displayed potent antifungal activity against V. mali. Notably, 3-acetyl-N-benzylindole thiosemicarbazone (IV-1: EC50 : 0.59 µg mL-1 ), whose activity was comparable to that of a commercial fungicide carbendazim (EC50 : 0.33 µg mL-1 ), showed greater than 98-fold antifungal activity of the precursor indole. Moreover, compound IV-1 displayed good protective and therapeutic effects on apple Valsa canker disease. By scanning electron microscope (SEM) and RNA-Seq analysis, it was demonstrated that compound IV-1 can destroy the hyphal structure and regulate the homeostasis of metabolism of V. mali via the ergosterol biosynthesis and autophagy pathways. CONCLUSION: 3-Acetyl-N-(un)substituted benzylindoles thiosemicarbazones (IV-1-IV-5) can be studied as leads for further structural modification as antifungal agents against V. mali. Particularly, these ergosterol biosynthesis and autophagy pathways can be used as target receptors for design of novel green pesticides for management of congeneric phytopathogenic fungi. © 2023 Society of Chemical Industry.

High Value-Added Application of Natural Plant Products in Crop Protection: Construction and Pesticidal Activities of Piperine-Type Ester Derivatives and Their Toxicology Study.

To discover new potential pesticide candidates, recently, structural modification of natural bioactive products has received much attention. In this work, a series of new piperine-type ester derivatives were regio- and stereoselectively synthesized based on a natural alkaloid piperine isolated from Piper nigrum. Their structures were characterized by IR, mp, 1H NMR (13C NMR), and high-resolution mass spectrometry (HRMS). Against Tetranychus cinnabarinus Boisduval (Acari: Tetranychidae), compounds 4e, 4f, 4u, and 4v displayed the most significant acaricidal activity with LC50 values of 0.155, 0.117, 0.177, and 0.164 mg/mL, respectively. Particularly, compound 4f showed >120-fold higher acaricidal activity than piperine (LC50: 14.198 mg/mL). Notably, the acaricidal activity of 4f was equivalent to that of the commercial acaricide spirodiclofen (LC50: 0.115 mg/mL). Additionally, against Eriosoma lanigerum Hausmann (Hemiptera: Aphididae), compounds 4w and 4b' showed 1.8-fold aphicidal activity of piperine. Furthermore, via the scanning electron microscope (SEM) imaging method, the obvious destruction of the construction of the cuticle layer of 4f-treated T. cinnabarinus was observed. Compound 4f could be further studied as a lead acaricidal agent.

Recent Advances on Biological Activities and Structural Modifications of Dehydroabietic Acid.

Dehydroabietic acid is a tricyclic diterpenoid resin acid isolated from rosin. Dehydroabietic acid and its derivatives showed lots of medical and agricultural bioactivities, such as anticancer, antibacterial, antiviral, antiulcer, insecticidal, and herbicidal activities. This review summarized the research advances on the structural modification and total synthesis of dehydroabietic acid and its derivatives from 2015 to 2021, and analyzed the biotransformation and structure-activity relationships in order to provide a reference for the development and utilization of dehydroabietic acid and its derivatives as drugs and pesticides.

Synthesis of Piperine-Based Ester Derivatives with Diverse Aromatic Rings and Their Agricultural Bioactivities against Tetranychus cinnabarinus Boisduval, Aphis citricola Van der Goot, and Eriosoma lanigerum Hausmann.

Exploration of plant secondary metabolites or by using them as leads for development of new pesticides has become one of the focal research topics nowadays. Herein, a series of new ester derivatives of piperine were prepared via the Vilsmeier−Haack−Arnold (VHA) reaction, and their structures were characterized by infrared spectroscopy (IR), melting point (mp), proton nuclear magnetic resonance spectroscopy (1H NMR), and carbon nuclear magnetic resonance spectroscopy (13C NMR). Notably, the steric configurations of compounds 6 and 7 were confirmed by single-crystal analysis. Against T. cinnabarinus, compounds 9 and 11 exhibited 47.6- and 45.4-fold more pronounced acaricidal activity than piperine. In particular, compounds 9 and 11 also showed 2.6-fold control efficiency on the fifth day of piperine. In addition, compound 6 (>10−fold higher than piperine) displayed the most potent aphicidal activity against A. citricola. Furthermore, some derivatives showed good aphicidal activities against E. lanigerum. Moreover, the effects of compounds on the cuticles of T. cinnabarinus were investigated by the scanning electron microscope (SEM) imaging method. This study will pave the way for future high value added application of piperine and its derivatives as botanical pesticides.