Synthesis and insecticidal activity studies of novel phenylpyrazole derivatives containing arylimine or carbimidate moiety.

Phenylpyrazole insecticides are successful for crop protection and public hygiene by blocking gamma-aminobutyric acid (GABA)-gated chloride channels and glutamate-gated chloride (GluCl) channels. A series of novel phenylpyrazoles containing arylimine or 1-methoxyaryl groups were designed and synthesized. The addition reaction of methanol to the imines 1-11 was investigated and the cayno addition products 13-15 were obtained. The compounds 1-15 were confirmed by 1H NMR and elemental analysis. The results of bioassay indicated that some compounds exhibited comparable bioactivity to fipronil against a broad spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens), diamondback moth (Plutella xylostella) and Oriental armyworm (Mythimna separata). Especially, the foliar contact activity against bean aphid of compound 7 at 10 µg mL-1 was 68%, the larvacidal activity against mosquito of compounds 5, 13 and 15 at 0.0025 µg mL-1 was 100%, the larvacidal activity against diamondback moth of compounds 9 and 11 at 0.05 µg mL-1 was 100%, the larvacidal activity against Oriental armyworm of compound 9 at 1 µg mL-1 was 100%. The 3-cayno moiety on pyrazole ring was essential for the high insecticidal activities against bean aphid, diamondback moth and Oriental armyworm, while the 3-carbimidate moiety on pyrazole ring was crucial to the excellent high insecticidal activities against mosquito.

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.

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.

Pyridine-phosphinimine ligand-accelerated Cu(I)-catalyzed azide-alkyne cycloaddition for preparation of 1-(pyridin-2-yl)-1,2,3-triazole derivatives.

A series of phosphinimine ligands were designed and used in the Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of tetrazolo[1,5-a]pyridines and alkynes for the first time. By optimizing the reaction conditions, an efficient catalytic system (CuCl/2-PyCH2N[double bond, length as m-dash]P(t)Bu3) was developed to give 1-(pyridin-2-yl)-1,2,3-triazole derivatives in moderate to excellent yields (46-98%).

Copper-catalyzed direct alkylation of 1,3-azoles with N-tosylhydrazones bearing a ferrocenyl group: a novel method for the synthesis of ferrocenyl-based ligands.

Copper-catalyzed cross-coupling of ferrocenyl ketone-derived N-tosylhydrazones with benzo[d]oxazole leads to the direct C-H bond functionalization by a secondary ferrocenyl alkyl group. This direct C-H bond alkylation of azoles with N-tosylhydrazones bearing a ferrocenyl group uses inexpensive CuBr as the catalyst without any ligand. The reaction is operationally simple and conducted under mild conditions, giving the corresponding ferrocenyl-based ligands in moderate to good yields. Furthermore, they were able to act as bidentate ligands, giving rise to the corresponding palladium chelated complex 6a-6c, which were obtained by reaction of 5a-5c with [PdCl2(MeCN)2].

Discovery of 2-Naphthol from the Leaves of Actephila merrilliana as a Natural Nematicide Candidate.

To identify natural nematicides that can replace chemical nematicides, 2-naphthol with high activity against Meloidogyne incognita was isolated from Actephila merrilliana. The nematicidal activity of 2-naphthol against M. incognita was 100% at 100 µg/mL with an EC50 value of 38.00 µg/mL. Moreover, 2-naphthol had a significant negative effect on egg incubation. 2-Naphthol effectively inhibited the invasion of M. incognita into crops in both a pot experiment and field trial. In addition, the structure-activity relationship indicated that the naphthalene ring and its ß-site hydroxyl group were the key pharmacophores for the nematicidal activity of 2-naphthol. Nematodes were stimulated by 2-naphthol to produce excessive reactive oxygen species, which may be the underlying mechanism of 2-naphthol nematicidal activity. A systemic evaluation of 2-naphthol in tomato plants demonstrated that 2-naphthol remained mainly fixed in the roots after being absorbed by the crop and was not transported to the stems or leaves. Thus, 2-naphthol can be developed as a natural nematicide candidate.

Imidacloprid-induced stress affects the growth of pepper plants by disrupting rhizosphere-plant microbial and metabolite composition.

Overusing imidacloprid (IMI) has been found to impede secondary metabolism and hinder plant growth. The impact of IMI stress on the interaction between metabolites, rhizosphere, and plant-microbe dispersion through various pathways in pepper plants has not been extensively studied. This study investigated the effects of IMI on plant signaling components, secondary metabolic pathways, and microbial communities in the rhizosphere and phyllosphere. Here, the distribution of IMI and its metabolites (6-chloronicotinic acid, IMI-desnitro, 5-hydroxy-IMI, IMI-urea, and IMI-olefin) was primarily observed in the pepper plant leaves. A rise in IMI concentration had a more significant inhibitive effect on the metabolism of pepper leaves than on pepper roots. The findings of non-target metabolomics indicated that IMI exposure primarily suppresses secondary metabolism in pepper plants, encompassing flavones, phenolic acids, and phytohormones. Notably, the IMI treatment disrupted the equilibrium between plants and microbes by decreasing the population of microorganisms such as Vicinamibacteria, Verrucomicrobiae, Gemmatimonadetes, and Gammaproteobacteria in the phyllosphere, as well as Vicinamibacteria, Gemmatimonadetes, Gammaproteobacteria, and Alphaproteobacteria in the rhizosphere of pepper plants. The study demonstrates that overexposure to IMI harms microbial composition and metabolite distribution in the rhizosphere soil and pepper seedlings, inhibiting plant growth.

Discovery of zeylenone from Uvaria grandiflora as a potential botanical fungicide.

BACKGROUND: Botanical pesticides play an important role in organic agricultural practices and are widely used in integrated pest management (IPM). Uvaria grandiflora was mainly reported as traditional medicines and possessed antibacterial, antioxidant, and antiprotozoal activities. Therefore, important biological activities of U. grandiflora may suggest that they have the potential to be used as botanical pesticides. RESULTS: The extract of U. grandiflora exhibited broad-spectrum inhibitory activity toward phytopathogenic fungi and oomycetes, particularly against Colletotrichum musae and Phytophthora capsici, and its secondary metabolite zeylenone also displayed strong antifungal and anti-oomycete activities against phytopathogens. Particularly, half maximal effective concentration (EC50 ) values of zeylenone against Phytophthora capsici and C. musae were 6.98 and 3.37 µg mL-1 , showing better inhibitory effects than those of commercial fungicides (azoxystrobin and osthole). Additionally, the pot experiments showed that the extract of U. grandiflora could effectively control Pseudoperonospora cubensis, Phytophthora infestans, Phytophthora capsici and Podosphaera xanthii. In the field experiment, 5% microemulsion of U. grandiflora extract exhibited 79.72% efficacy against cucumber powdery mildew at 87.5 g ha-1 on the 14th day after two sprayings, which was better than that of 21.5% trifloxystrobin and 21.5% fluopyram SC at 200.9 g ha-1 . Surprisingly, 5% microemulsion of U. grandiflora extract could promote cucumber growth significantly. Furthermore, the action mechanism analysis indicated that zeylenone may damage the cytoderm and affect energy metabolism of Phytophthora capsici. CONCLUSION: It is the first time that the extract of U. grandiflora and zeylenone have been discovered leading to broad application prospects in the development as botanical fungicides. © 2021 Society of Chemical Industry.

Photostable 1-Trifluoromethyl Cinnamyl Alcohol Derivatives Designed as Potential Fungicides and Bactericides.

In the current work, a series of 1-trifluoromethyl cinnamyl alcohol derivatives were designed and synthesized and their antifungal activities were evaluated. The bioassay result showed that most compounds exhibited excellent antifungal activity in vitro at 10 µg mL-1. Next, photostable and easily synthesized compound 2 with broad-spectrum antifungal activity in vitro was selected as a potential candidate to evaluate its antibacterial and antifungal activities. The EC50 values of compound 2 against eight fungal plant pathogens in vitro ranged from 3.806 to 17.981 µg mL-1; at the same time, compound 2 could effectively control Podosphaera xanthii, Odium heveae Steinm, Puccinia striiformis West, and Puccinia sorghi in pot experiments. In addition, compound 2 exhibited excellent antibacterial activities in vitro and in vivo against Xanthomonas oryzae pv. oryzae. Furthermore, the absorption and translocation of compound 2 in wheat plants were determined by the high-performance liquid chromatography method. The result showed that compound 2 could be translocated acropetally as well as basipetally in wheat plants. Finally, it was found that compound 2 had no cross-resistance with carbendazim, azoxystrobin, and boscalid.

Synthesis, larvicidal activity, and SAR studies of new benzoylphenylureas containing oxime ether and oxime ester group.

A series of new structural benzoylphenylureas (BPUs) containing oxime ether and oxime ester group were designed and synthesized. The larvicidal activities against Oriental armyworm and mosquito of these benzoylphenylureas were evaluated and the result of bioassay displayed specific structure-activity relationship (SAR). Most of the compounds exhibited excellent larvicidal activities against Oriental armyworm and mosquito. Interestingly, some compounds showed different structure-activity relationship towards diamondback moth, beet armyworm, and corn borer although three tested insects all belong to the same insect order.

Dehydrozingerone Inspired Discovery of Potential Broad-Spectrum Fungicidal Agents as Ergosterol Biosynthesis Inhibitors.

A series of dehydrozingerone derivatives were synthesized, and their fungicidal activities and action mechanism against Colletotrichum musae were evaluated. The bioassay result showed that most compounds exhibited excellent fungicidal activity in vitro at 50 µg mL-1. Compounds 13, 16, 18, 19, and 27 exhibited broad-spectrum fungicidal activity; especially, compounds 19 and 27 were found to have more potent fungicidal activity than azoxystrobin. The EC50 values of compounds 19 and 27 against Rhizoctonia solani were 0.943 and 0.161 µg mL-1 respectively. Moreover, compound 27 exhibited significant in vitro bactericidal activity against Xanthomonas oryzae pv. oryzae, with an EC50 value of 11.386 µg mL-1, and its curative effect (49.64%) and protection effect (51.74%) on rice bacterial blight disease was equivalent to that of zhongshengmycin (42.90%, 40.80% respectively). Compound 27 could also effectively control gray mold (87.10%, 200 µg mL-1) and rice sheath blight (100%, 200 µg mL-1; 82.89%, 100 µg mL-1) in vivo. Preliminary action mechanism study showed that compound 27 mainly acted on the cell membrane and significantly inhibited ergosterol biosynthesis in Colletotrichum musae.

Discovery of N-Aryl-pyridine-4-ones as Novel Potential Agrochemical Fungicides and Bactericides.

A series of N-aryl-pyridine-4-one derivatives were designed and synthesized using maltol and antidesmone as lead compounds, and then their fungicidal/bactericidal activities and possible mechanism of action against Colletotrichum musae were explored. Most of these compounds exhibited significant fungicidal activity in vitro. Especially, compound 23 has more than 90% inhibitory activity against nine plant pathogenic fungi at 50 µg mL-1, which is superior to azoxystrobin. Moreover, an in vivo bioassay also demonstrated that compound 23 exhibited high-efficiency broad-spectrum antifungal activity and can effectively control postharvest diseases of mango. In addition, it was found that compounds 22 and 23 can also effectively control rice bacterial leaf blight in pot experiments, which was even more effective than zhongshengmycin. Preliminary mechanism studies revealed that compound 23 may cause cell membrane and mitochondria destruction. These findings indicate that compound 23 can be used to develop potential agrochemical fungicides and bactericides.

Benzoylurea Chitin Synthesis Inhibitors.

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.

Design, synthesis, and insecticidal evaluation of new benzoylureas containing amide and sulfonate groups based on the sulfonylurea receptor protein binding site for diflubenzuron and glibenclamide.

On the basis of the sulfonylurea receptor (SUR) protein binding site for diflubenzuron and glibenclamide, 15 new benzoylphenylureas containing amide and sulfonate groups were designed and synthesized. Their structures were characterized by (1)H nuclear magnetic resonance (NMR) and elemental analysis [or high-resolution mass spectrometry (HRMS)]. The larvicidal activities of the new compounds against oriental armyworm and diamondback moth were evaluated. Compound II-3 showed nearly the same level of insecticidal activity against oriental armyworm as commercial insecticide flucycloxuron and, thus, emerged as a new lead compound for the development of new benzoylurea insecticides.

Studies on insecticidal activities and action mechanism of novel benzoylphenylurea candidate NK-17.

Insecticidal activity of NK-17 was evaluated both in laboratory and in field. It was found that the toxicity of NK-17 against S. exigua was 1.93 times and 2.69 times those of hexaflumuron and chlorfluazuron respectively, and the toxicity of NK-17 against P. xylostella was 1.36 times and 1.90 times those of hexaflumuron and chlorfluazuron respectively, and the toxicity of NK-17 against M. separate was 18.24 times those of hexaflumuron in laboratory, and 5% NK-17 EC at 60 g a.i ha(-1) can control S. exigua and P. xylostella with the best control efficiency of about 89% and over 88% respectively in Changsha and Tianjin in field. The insecticidal mechanism of NK-17 was explored for the first time by utilizing the fluorescence polarization method. NK-17 could bind to sulfonylurea receptor (SUR) of B. germanica with stronger affinity comparing to diflubenzuron and glibenclamide, which suggested that NK-17 may also act on the site of SUR to inhibit the chitin synthesis in insect body and the result can well explain that NK-17 exhibited stronger toxicity against B. germanica than diflubenzuron and glibenclamide in vivo.

Design and synthesis of benzoylphenylureas with fluorinated substituents on the aniline ring as insect growth regulators.

Enormous numbers of synthetic fluorine-containing compounds have been widely used in a variety of fields, especially in drug and pesticide design. To find novel insect growth regulators, a series of benzoylphenylureas with fluorinated substituents were designed and synthesized. The results of larvicidal activities of those novel fluoro-substituted benzoylphenylureas against oriental armyworm and mosquito revealed that most compounds exhibited excellent activities. It is worth mentioning that compounds 3 and 6 exhibited higher activities against oriental armyworm and mosquito than commercial Hexaflumuron. It can be further seen that the insecticidal activities would increase significantly by introducing fluorinated substituents into the structure of the designed benzoylphenylureas.

Design, synthesis, and insecticidal evaluation of new benzoylureas containing isoxazoline and isoxazole group.

Twenty-two new benzoylphenylureas containing isoxazoline and the isoxazole group were designed and synthesized, and their structures were characterized by (1)H NMR and elemental analysis (or HRMS). The larvicidal activities against Oriental armyworm, mosquito, and diamondback moth of the new compounds were evaluated. Compounds I-1 and III-1 showed nearly the same level of insecticidal activity against Oriental armyworm as commercial insecticide Flucycloxuron and surprisingly exhibited much higher larvicidal activities against diamondback moth than Flucycloxuron.

Design, synthesis, and bioactivity study of novel benzoylpyridazyl ureas.

A series of novel benzoylpyridazyl ureas were designed and synthesized from maleic anhydride and hydrazine monohydrate. These benzoylureas were identified by (1)H NMR spectroscopy and element analysis. The bioactivities of the new compounds were evaluated. These compounds exhibited larvicidal activities against oriental armyworm, and in particular, compound 13 displayed comparable activity to the commercial insecticide Hexaflumuron. Most of these compounds also had some larvicidal activities against mosquito. Interestingly, some compounds showed good plant growth regulatory activities.

Design, synthesis, and insecticidal activities of new N-benzoyl-N'-phenyl-N'-sulfenylureas.

A series of new N'-alkylaminothio, N'-arylaminothio (or dithio), and N',N'-thio (or dithio) derivatives of N-benzoyl-N'-phenylureas were designed and synthesized as insect-growth regulators with sulfur dichloride or disulfur dichloride as the original reactant. The new compounds were identified by (1)H nuclear magnetic resonancee (NMR) spectroscopy, elemental analysis [or high-resolution mass spectrometry (HRMS)], and single-crystal X-ray diffraction analysis. The X-ray results demonstrated that there exist N-S-N or N-S-S-N bonds in these new compounds. In comparison to the parent N-benzoyl-N'-phenylureas, these derivatives displayed better solubility. The insecticidal activities of the target compounds were evaluated. The results of bioassays showed that compounds 1-24 retained the larvicidal activities of the corresponding benzoylphenylureas (BPUs) and some compounds exhibited better larvicidal activities against oriental armyworm and mosquitoes than the parent BPUs. The larvicidal activities of the selected target compounds 1 and 24 against diamondback moth were better than that of the corresponding parent compounds E and triflumuron.

Design, synthesis, bioactivity, and structure-activity relationship (SAR) studies of novel benzoylphenylureas containing oxime ether group.

Novel benzoylphenylureas containing an oxime ether group were designed and synthesized by four schemes. These benzoylphenylureas were identified by (1)H NMR spectroscopy and element analysis (or HRMS). The bioactivities of the new compounds were evaluated. These benzoylphenylureas exhibited excellent larvicidal activities against oriental armyworm, some of which were much better in comparison with the commercial Flucycloxuron. In particular, the larvicidal activities against oriental armyworm of compounds 1 and 23 were 5-10 times better than that of Flucycloxuron. Most of these benzoylphenyureas exhibited excellent larvicidal activities against mosquito. At the same time, some of these compounds have good plant growth regulatory activities as well.