Design, synthesis, and biological activities of milbemycin analogues

Milbemycins have received considerable interest in agricultural chemistry due to a special action mode, extremely high activity against arachnoide pests, low toxicity to mammals, and environmentally benign characteristics. Two series of novel milbemycin analogues (4Ia-6IIc) containing alkyl and aryl groups at the 4'- and 13-positions were designed and synthesized by five schemes. These analogues were identified by (1)H NMR, (13)C NMR, and elemental analysis (or HRMS). Their insecticidal activities against carmine spider mite, oriental armyworm, and black bean aphid were evaluated. The results showed that all of the title compounds had low acaricidal activity against carmine spider mite. However, most of them exhibited good insecticidal activities against oriental armyworm and black bean aphid at a concentration of 200 mg L(-1). The most potent substituents of 2,2-dimethylbutanoyl (4Ib), phenylacetyl (4IIm), and (Z)-1-(methoxyimino)-1-phenylacetyl (4IIn) exhibited the highest larvicidal activities, and its insecticidal LC(50) values against oriental armyworm were 0.250, 0.204, and 0.350 mg L(-1), while its insecticidal LC(50) values against black bean aphid were 0.150, 0.070, and 0.120 mg L(-1), respectively. These substituents provided some hints for further investigation on structure modification.     

Synthesis, insecticidal, and acaricidal activities of novel 2-aryl-pyrrole derivatives containing ester groups

A series of novel 2-aryl-pyrrole derivatives containing ester groups were synthesized, and their structures were characterized by (1)H NMR spectroscopy and elemental analysis. The insecticidal activities against oriental armyworm, mosquito, diamondback moth, green rice leafhopper, and bean aphids and acaricidal activities against spider mite of these new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal and acaricidal activities. The insecticidal activities against oriental armyworm of compounds IVa, IVd, IVe, IVf, IVg, IVi, IVk, and IVp were equal to commercialized Chlorfenapyr, and the insecticidal activities of most of compounds IVb, IVc, IVd, IVf, IVg, IVj, IVk, IVl, IVs, IVt, IVu, IVw, IVx, IVz, and Chlorfenapyr against mosquito at 0.10 mg kg (-1) were 100%, and the acaricidal activities of compounds IVd, IVe, IVf, IVg, IVh, IVi, and IVk were equal or superior to Chlorfenapyr. Especially, the results indicated that the acaricidal activity of [4-bromo-2-(4-chlorophenyl)-3-cyano-5-(trifluoromethyl)pyrrol-1-yl]methyl 3-methylbutanoate ( IVg) against spider mite was 2.65-fold as high as that of Chlorfenapyr from the value of LC 50.     

N'-Nitro-2-hydrocarbylidenehydrazinecarboximidamides: design, synthesis, crystal structure, insecticidal activity, and structure-activity relationships

A novel series of acyclic imine-substituted nitenpyram analogues were designed and synthesized from nitroaminoguanidine, and their structures were confirmed using X-ray diffraction crystallography. Preliminary bioassays showed that the target molecules exhibited good activities against aphids in laboratory (Myzus persicae Sulzer) and field trials (M. persicae Sulzer and Brevicoryne brassicae Linnaeus). Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to develop a three-dimensional quantitative structure-activity relationship model that describes the insecticidal activity of 21 neonicotinoid derivatives. Simple synthesis, low cost, and good insecticidal activity have made this series of compounds become very promising candidates for future commercial pesticides.     

Synthesis and insecticidal activities of novel anthranilic diamides containing acylthiourea and acylurea

Two series of anthranilic diamides containing acylthiourea and acylurea linkers were designed and synthesized, with changed length and flexibility of the linkers to compare to known anthranilic diamide insecticides. In total, 26 novel compounds were synthesized, and all compounds were characterized by (1)H nuclear magnetic resonance and high-resolution mass spectrometry. Their insecticidal activities against oriental armyworm ( Mythimna separata ), mosquito larvae ( Culex pipiens pallens ), and diamondback moth ( Plutella xylostella ) were evaluated. The larvicidal activities against oriental armyworm indicated that the introduction of acylthiourea into some structures could retain their insecticidal activity; 8 of the 15 compounds (13a-13e, 14a-14e, and 15a-15e) exhibited 100% larvicidal activity at 10 mg/L. However, the introduction of acylurea decreased the insecticidal activity; only 3 of the 11 compounds (17a-17k) exhibited 100% larvicidal activity at 200 mg/L. The whole-cell patch-clamp technique indicated that compound 13b and chlorantraniliprole exhibited similar effects on the voltage-gated calcium channel. The calcium-imaging technique was also applied to investigate the effects of compounds 13b and 15a on the intracellular calcium ion concentration ([Ca(2+)](i)), which indicated that they released stored calcium ions from endoplasmic reticulum. Experimental results denoted that several new compounds are potential activators of the insect ryanodine receptor (RyR).     

Synthesis and insecticidal activity of novel carbamate derivatives as potential dual-binding site acetylcholinesterase inhibitors

In biological systems, bivalent ligands often possess increased functional affinity for their receptors compared with monovalent ligands. On the basis of the structure of acetylcholinesterase (AChE), a series of novel carbamate heterodimetic derivatives were designed and synthesized with the aim of increasing the potency toward AChE inhibition. The AChE inhibitory ability of all the novel compounds was tested using AChE obtained from the brain of the housefly. The bioassay results showed that compounds 6j, 6k, 6m, 6n, 6p, and 6q had increased inhibitory activities in comparison with parent phenyl N-methylcarbamate (MH) at the concentration of 100 mg/L. Among them, the most potent AChE inhibitor of these compounds was 6q (IC(50) = 12 μM), which showed 62-fold greater AChE inhibitory activity than that of MH and 12-fold greater activity than metolcarb (MT), which suggested that the 3-nitrophenoxy moiety of compound 6q was able to interact with the aromatic amino acid residues lining the gorge and the phenyl N-methylcarbamate moiety was able to interact with the catalytic sites of AChE, simultaneously. The insecticidal activities of compounds 6j, 6k, 6m, 6n, 6p, and 6q were further evaluated. Consistent with the result in vitro bioassay, those compounds demonstrated better activities against Lipaphis erysimi than parent compound MH at the concentration of 300 mg/L, and compound 6q showed the best insecticidal activity, causing 98% mortality after 24 h of treatment.     

Chemical synthesis, in vitro acetohydroxyacid synthase (AHAS) inhibition, herbicidal activity, and computational studies of isatin derivatives

Acetohydroxyacid synthase (AHAS) catalyzes the first common step in the biosynthesis of the branched-chain amino acids. As a result of its metabolic importance in plants, it is a target for many commercial herbicides. Virtual screening analysis inspired the evaluation of 19 commercially available isatin analogues and 13 newly synthesized isatin derivatives as novel AHAS inhibitors and for their herbicidal activity. The best compound demonstrated 95% inhibition of the activity of Arabidopsis thaliana AHAS at a concentration of 100 mg L(-1), whereas the herbicidal activities of three compounds reached 50% inhibition at a concentration of 10 mg L(-1) using the rape root growth test. CoMFA contour models were established to understand the structure-activity relationships for this class of AHAS inhibitor. The compounds were docked to the active site cavity of A. thaliana AHAS using FlexX, and the dominant binding mode was consistent with frontier molecular orbital from DFT calculations. This is the first comprehensive study of isatin derivatives as AHAS inhibitors and provides a valuable starting point for the design of new herbicides.     

Design, synthesis, and fungicidal activities of new strobilurin derivatives

Strobilurins are one of the most important classes of agricultural fungicides. To discover new strobilurin analogues with high activity against resistant pathogens, a series of new strobilurin derivatives bearing structurally diverse heterocycle side chains 3a-m and 4a-g were designed and synthesized via a microwave-assisted procedure. The advantages, such as good to excellent yields, shorter reaction times, mild reaction conditions, and simple purification procedures, distinguish the present synthetic protocol as a highly efficient method for the preparation of strobilurin thioether derivatives. Bioassays indicated that most of the compounds showed broad-spectrum fungicidal activity in vitro. Interestingly, as compared to the control of a commercial strobilurin fungicide, Kresoxim-methyl, compounds 3b, 3g, 4c, and 4d possessed remarkably higher in vitro fungicidal activity against six kinds of tested fungi. Exhilaratingly, compound 3g exhibited higher in vivo activity against Sphaerotheca fuliginea and Pseudoperoniospora cubensis than Kresoxim-methyl, and the in vivo fungicidal activities of compound 4d and Kresoxim-methyl against S. fuliginea and P. cubensis are at the same level. The present work demonstrated that strobilurin analogues containing benzothiazole side chains could be used as a lead structure for further developing novel fungicides.     

Synthesis and biological evaluation of new analogues of the active fungal metabolites N-(2-methyl-3-oxodecanoyl)-2-pyrroline and N-(2-methyl-3-oxodec-8-enoyl)-2-pyrroline (II)

New analogues of the bioactive enamides isolated from P. brevicompactum (2 and 3) have been synthesized to improve the biological activities. Two different structural modifications have been introduced: substitution of the aliphatic side chain present in the natural products (1-4) by other groups frequently found in other active compounds and use of other nitrogen-containing five-membered rings with different degrees of oxidation. In this way, the insecticidal and fungicidal activities have been improved. Thus, compound 9, which possess a 3-pyrroline ring, exhibited important insecticidal activity against third-instar nymphs of Oncopeltus fasciatus Dallas (100% mortality at 7.5 microg/cm(2)). Remarkable fungicidal activity was also found, and preliminary structure-activity relationships could be established.     

Synthesis and biological activities of novel pyrazole oxime derivatives containing a 2-chloro-5-thiazolyl moiety

A series of novel pyrazole oxime derivatives containing a 2-chloro-5-thiazolyl moiety were synthesized. Their structures were confirmed by (1)H NMR, (13)C NMR, and elemental analysis. The preliminary bioassays showed that all of the title compounds had low acaricidal activity against Tetranychus cinnabarinus . However, most of them exhibited excellent insecticidal activity against Aphis medicagini at the dosage of 0.5 mg/mL, and some compounds still showed good insecticidal activity against A. medicagini even at the dosage of 0.2 mg/mL. Meanwhile, some title compounds displayed fungicidal and plant growth regulatory activities.     

Synthesis and insecticidal activity of N-tert-butyl-N,N'-diacylhydrazines containing 1,2,3-thiadiazoles

N-tert-Butyl-N,N'-diacylhydrazines are nonsteroidal ecdysone agonists used as environmental benign pest regulators. In this paper, two series of new N-tert-butyl-N,N'-diacylhydrazine derivatives containing 1,2,3-thiadiazole were designed and synthesized. All structures of the synthesized compounds were confirmed by proton nuclear magnetic resonance ((1)H NMR), infrared spectroscopy (IR), and high-resolution mass spectrometry (HRMS). Bioasssay results indicated that most of the synthesized compounds possessed good insecticidal activities against Plutella xylostella L. and Culex pipiens pallens as compared with the positive control, tebufenozide. The results of this study indicated that 1,2,3-thiadiazoles, as an important active substructure, could improve or maintain the activity of the dicylhydrazines and favor novel pesticide development.     

Design, synthesis, and particular biological behaviors of chain-opening nitromethylene neonicotinoids with cis configuration

On the basis of the structure of heterocyclic-fused cis configuration derivatives and chain-opening neonicotinoids, two series of novel chain-opening tetrahydropyridine analogues were designed and synthesized. The preliminary bioassay tests were determined on cowpea aphid (Aphis craccivora) and armyworm (Pseudaletia separata Walker). The results showed that some of the target compounds exhibited repellent effects, whereas others showed good insecticidal activities.     

Evaluation of the antioxidant activity of capsiate analogues in polar, nonpolar, and micellar media

Synthesis of 10 capsiate analogues was conducted by lipase-mediated (Novozyme 435) esterification of vanillyl alcohol with different fatty acids. The antioxidant activity of the synthesized capsiates was evaluated using three in vitro assays: DPPH radical scavenging assay (polar medium), Rancimat assay (nonpolar medium), and autoxidation of linoleic acid (micellar medium). The objective of this study is to find the influence of structural characteristics of the alkyl chain of capsiate analogues on their antioxidant activity. In these assays, BHT and α-tocopherol were used as reference compounds. Both DPPH and Rancimat assays did not show any specific trend of antioxidant activity with the increase in lipophilicity and also with the type of fatty acids grafted to the phenolic moiety. In the Tween 20 micellar system for the inhibition of autoxidation of linoleic acid, vanillyl ester attached to a C18 alkyl chain (vanillyl stearate, oleate, and ricinoleate) exhibited maximum inhibition of autoxidation of linoleic acid.     

固液气分流式瘤胃模拟系统的设计与测试

针对现有批次培养和连续培养瘤胃模拟装置存在的不足,设计了一种在不影响系统气密性的情况下,由计算机自动控制的固液气分流式连续培养瘤胃模拟系统。并进行了为期10d的培养试验。试验表明:本系统的各发酵参数平行性好,4个发酵罐PH值从第5天开始稳定,变化趋势与牛瘤胃内pH值变化一致;各发酵单元从第3天开始,原虫数量稳定在(0.99±0.32)×104个/mL(p=0.6877),溢流液中氨态氮的浓度维持在(3.91±1.10)mg/100mL;试验全期干物质消失率为62%±2%,总排气次数为(2370±33)次,总挥发性脂肪酸为(41.77±3.78)mmol/L(p=0.488)。因此该固液气分流式连续培养瘤胃模拟系统综合了批次培养和连续培养瘤胃模拟装置的特点,并能有效的模拟瘤胃发酵状况。     

Design, synthesis, and biological activities of arylmethylamine substituted chlorotriazine and methylthiotriazine compounds

Heterocyclic rings were introduced into the core structure of s-triazine to design and synthesize a series of novel triazines containing arylmethylamino moieties. These compounds were characterized by using spectroscopic methods and elemental analysis. Their herbicidal, insecticidal, fungicidal, and antitumor activities were evaluated. Most of these compounds exhibited good herbicidal activity, especially against the dicotyledonous weeds, and compound F8 was almost at the same level as the control compound atrazine. Their structure-activity relationships were discussed. At the same time, some triazines had interesting fungicidal and insecticidal activities, of which F4 exhibited 100% efficacy against Puccinia triticina even at 20 ppm, and F5 showed Lepidopteran-specific activity in both leaf-piece and artificial diet assays. Moreover, these compounds showed antitumor activities against leukemia HL-60 cell line and lung adenocarcinoma A-549 cell line.     

Synthesis and insecticidal activities of novel N-sulfenyl-N'-tert-butyl-N,N'-diacylhydrazines. 1. N-alkoxysulfenate derivatives

A series of novel N-alkoxysulfenyl-N'-tert-butyl-N, N'-diacylhydrazines were designed and synthesized as insect growth regulators by the key intermediates N-chlorosulfenyl-N'-tert-butyl-N, N'-diacylhydrazines, which were prepared for the first time. Compared to N'-tert-butyl-N, N'-diacylhydrazines, these N-alkoxysulfenyl derivatives displayed better solubility and improved hydrophobicities. The insecticidal activities of the new compounds were evaluated. The results of bioassays showed that the title compounds possessed a combination of strong stomach as well as contact poison property higher than the corresponding parent compounds. In particular, N-methoxysufenyl-N'-tert-butyl-N-4-ethylbenzoyl-N'-3,5-dimethylbenzoylhydrazide (IIIf) as a field testing candidate has higher stomach toxicities against oriental armyworm and beet armyworm than the corresponding parent compound RH-5992. Furthermore, the compound IIIf exhibits higher contact activities against oriental armyworm, Asian corn borer, tobacco cutworm, and cotton bollworm than RH-5992. The sulfenyl substituent was essential for high larvacidal activity.     

Synthesis, crystal structure, and insecticidal activity of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole

Two series of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole were synthesized, and their structures were characterized by (1)H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities, and their insecticidal activities against oriental armyworm, mosquito, and spider mite are comparable to those of the commercialized Chlorfenapyr.     

Synthesis and insecticidal activity of some novel fraxinellone-based esters

In continuation of a program aimed at the discovery and development of natural products-based insecticidal agents, two series of novel fraxinellone-based esters were synthesized by modification at the C-4 or C-10 position of fraxinellone and evaluated for their insecticidal activity against the pre-third-instar larvae of Mythimna separata in vivo. An efficient method for the stereoselective synthesis of 4α-hydroxyfraxinellone from fraxinellonone was developed, and the steric configuration of 6h was unambiguously confirmed by X-ray crystallography. Among 37 compounds, some derivatives displayed potent insecticidal activity; especially compounds 6h, 6q, 6t, and 7q showed more promising insecticidal activity than toosendanin, a commercial botanical insecticide derived from Melia azedarach . This suggested that introduction of the fluorine atom on the phenyl ring could lead to a more potent compound than one possessing chlorine or bromine. Meanwhile, introduction of the heterocyclic fragments at the C-4 or C-10 position of fraxinellone was essential for their insecticidal activity. This will pave the way for further design, structural modification, and development of fraxinellone as an insecticidal agent.     

New analogues of (E)-β-farnesene with insecticidal activity and binding affinity to aphid odorant-binding proteins

(E)-β-farnesene is a strong and efficient alarm pheromone in most aphid species. However, applications in agriculture are prevented by its relatively high volatility, its susceptibility to oxidation and its complex and expensive synthesis. To develop novel compounds for aphid control, we have designed and synthesized analogues of (E)-β-farnesene, containing a pyrazole moiety present in several insecticides. Their structures have been confirmed by 1H NMR, elemental analysis, high-resolution mass spectroscopy and IR. Binding activities to three odorant-binding proteins (OBPs) of the pea aphid Acythosiphon pisum have been evaluated and correlated with their structures with reference to (E)-β-farnesene. Several derivatives were shown both to bind to A. pisum OBPs with a specificity similar to that of (E)-β-farnesene and to have aphicidal activity comparable to that of thiacloprid, a commercial insecticide. The compounds synthesized in this work represent new potential agents for aphid population control and provide guidelines to design analogues of (E)-β-farnesene endowed with both insecticidal and repellent activity for aphids.     

Insecticidal and fumigant activities of Cinnamomum cassia bark-derived materials against Mechoris ursulus (Coleoptera: attelabidae)

The insecticidal and fumigant activities of Cinnamomum cassia (Blume) bark-derived materials against the oak nut weevil (Mechoris ursulus Roelofs) were examined using filter paper diffusion and fumigation methods and compared to those of the commercially available Cinnamomum bark-derived compounds (eugenol, salicylaldehyde, trans-cinnamic acid, and cinnamyl alcohol). The biologically active constituent of the Cinnamomum bark was characterized as trans-cinnamaldehyde by spectroscopic analysis. In a test with the filter paper diffusion method, trans-cinnamaldehyde showed 100 and 83.3% mortality at rates of 2.5 and 1.0 mg/filter paper, respectively. At 2.5 mg/paper, strong insecticidal activity was produced from eugenol (90.0% mortality) and salicylaldehyde (88. 9%), whereas trans-cinnamic acid revealed moderate activity (73.3%). At 5 mg/paper, weak insecticidal activity (50.0%) was produced from cinnamyl alcohol. In a fumigation test, the Cinnamomum bark-derived compounds were much more effective against M. ursulus larvae in closed cups than in open ones. These results indicate that the insecticidal activity of test compounds was attributable to fumigant action, although there is also significant contact toxicity. As a naturally occurring insect-control agent, the Cinnamomum bark-derived materials described could be useful as a new preventive agent against damage caused by M. ursulus.