Strobilurin Derivatives Research Articles

Synthesis, crystal structure, biological evaluation, docking study and DFT calculation of novel strobilurins containing oxime ether phenyl ring or dihydrobenzofuran moiety

Two sets of strobilurin derivatives containing oxime ether phenyl ring or dihydrobenzofuran moiety were designed, synthesized and evaluated for their fungicidal and insecticidal activities. The structures of the target compounds were determined by 1H NMR, 13C NMR and elemental analysis, and the crystal structure of compound 3a was further determined by X-ray diffraction analysis. Some of the title compounds exhibited certain degree of fungicidal and insecticidal activities at the concentration of 500 mg/L. The control effects of compounds 1, 4a and 8 against Erysipe graminis and 1, 3a, 4a and 8 against Puccinia sorghi were all above 90%, which were close to the level of trifloxystrobin. The lethal rates of compounds 5a and 6a against Mythimna separata reached 100%, similar to that of positive control chlorantraniliprole, and the lethal rates of compounds 1, 2 and 8 against Aphis fabae were 100%, 100% and 98.6%, respectively, numerical equivalent to that of imidacloprid. Furthermore, molecular docking showed the potential mechanism for fungicidal activities of these compounds, and DFT calculation indicated that the frontier molecular orbitals and van der Waals surface electrostatic potentials could be related to insecticidal activity.

Inhibition of pyrimidine biosynthesis by strobilurin derivatives induces differentiation of acute myeloid leukemia cells

All-trans retinoic acid–based differentiation therapies have succeeded in the treatment of acute promyelocytic leukemia, which is a rare subtype of acute myeloid leukemia (AML). Their clinical efficacy is negligible, however, for other subtypes of AML. Here, we showed that strobilurin derivatives, a well-established class of inhibitors of mitochondrial electron transport chain (ETC) complex III, possessed differentiation-inducing activity in AML cells. Impairment of mitochondrial ETC activity was involved in the differentiation effects of strobilurin derivatives, where reactive oxygen species generation appeared unnecessary. Conversely, strobilurin derivative-mediated differentiation was triggered by pyrimidine deficiency, which resulted from the inhibition of the mitochondrial-coupled dihydroorotate dehydrogenase enzyme. Moreover, strobilurin derivative-mediated pyrimidine depletion led to the activation of the Akt/mTOR cascade, which was required for the differentiation. Our study provided evidence that strobilurin derivatives may represent a novel class of differentiation-inducing agents for the treatment of AML.

Design, Synthesis, and Evaluation of Fungicidal Activity of Novel Pyrazole‐Containing Strobilurin Derivatives†

Main observation and conclusionIn searching for novel fungicidal leads, a series of pyrazole‐containing strobilurins were rationally designed, synthesized and characterized. Bioassay indicated that compound I‐7 displayed excellent fungicidal activity against a broad spectrum of plant pathogens such as Gibberella zeae, Rhizoctonia cerealis, Sclerotinia sclerotiorum, Phytophthora infestans, Physalospora piricola and Pellicularia sasakii with EC50 of 0.16, 0.02, 0.72, 0.07, 0.77 and 0.65 μg/mL, respectively, which were 3—10 times more potent than the positive control azoxystrobin against the corresponding pathogens. Moreover, like azoxystrobin and kresoxim methyl, I‐7, displayed excellent protective activity against P. sorghi. Molecular docking validated that I‐7 and azoxystrobin would share a similar binding mode with cytochrome bc1 complex. This study demonstrates that I‐7 is a promising fungicidal candidate for further development.

Novel Strobilurin Derivatives Containing Carboxylate Unit as Potential Antifungal Agents

Background: Due to the extensive use of a single fungicide to control crop diseases, the increase of resistant individuals leads to control failures. The search for molecules with fungicidal activity is still ongoing. Strobilurin is one of the most popularly used fungicides in the agrochemical field. A large number of strobilurin derivatives with both high activity and low toxicity have been developed. Methods: In the present study, a series of novel ortho-substituted benzyl carboxylates were efficiently synthesized by the reaction of (E)-methyl 2-(2-(bromom-ethyl)phenyl)-2-methox-yiminoaceta with various carboxylic acids. Their structures were confirmed and characterized by 1H NMR, 13C NMR, and ESI-MS analysis. Their fungicidal activities against common phytopathogenic fungi from six major cash crops were screened based on the pesticides guidelines for the laboratory bioactivity tests. Results: The primary fungicidal activity test results indicate that all compounds showed a certain inhibitory effect on the growth of 13 plants pathogenic fungi at a concentration of 100 ppm, and Compd. 3 has the most obvious inhibitory effect on all fungi. Further fungicidal activity studies indicate that some of these novel strobilurin derivatives containing carboxylate unit exhibited potential in vitro fungicidal activities at the dosage of 6.25 mg/L-1. Conclusion: A series of the ortho-substituted benzyl carboxylates derivatives containing β- methoxyacrylate moiety were designed and synthesized by modifying the side chain of traditional strobilurin fungicide. Compd. 3, Compd. 2 and Compd. 16 were identified as the most promising candidates for further study.

Design, Synthesis and Fungicidal Activities of Novel 1,2,3‐Triazole Functionalized Strobilurins

AbstractA series of new strobilurin derivatives bearing different 1,2,3‐triazole side chains were designed and synthesized. The target compounds were characterized by HRMS, 1H NMR, 13C NMR spectra. Among them, the structure of compound 5q was confirmed by X‐ray single crystal diffraction. All of the target compounds were evaluated in vitro for their fungicidal activity against Gibberella zeae, Phytophythora capsici, Alternaria alternate, Botrytis cinerea and Sclerotonia sclerotiorum at a concentration of 25 mg/L. The bio‐assay results exhibited that some of them showed moderate to good fungicidal activity against Phytophythora capsici and Alternaria alternate. The inhibition rates of compound 5f and 5g were up to 73.6% against Phytophythora capsic, which were significantly higher than 42.5% for Difenoconazole. Preliminary structure‐activity relationships (SAR) were also discussed.

Design, Synthesis and Bioactivities of Novel Strobilurin Derivatives Containing 1,3,4-Oxadiazole Moity

Design, Synthesis and Bioactivities of Novel Strobilurin Derivatives Containing 1,3,4-Oxadiazole Moity

Synthesis and antifungal activities of novel strobilurin derivatives containing quinolin-2(1H)-one moiety

To discover novel lead compounds with better antifungal activities, a series of novel strobilurin derivatives containing quinolin-2(1H)-one moiety was designed and synthesized via intermediate derivatization method. Their structures were characterized by means of 1H nuclear magnetic resonance(1H NMR), 13C NMR and high resolution mass spectrometry(HRMS). The biological assay results indicate that most target compounds exhibit good to excellent fungicidal activities against 10 plant pathogens. Compounds 4d, 5b and 5c possess 94.1%, 83.8% and 80.9% in vitro inhibition respectively against Rhizotonia cereals at the concentration of 50 μg/mL, which are better than that of the control agents. Especially, the inhibition activities of compound 4d against all of the tested fungi approach or exceed those of the controls. The structure-activity relationship was also discussed.

Discovery of flufenoxystrobin: Novel fluorine-containing strobilurin fungicide and acaricide

Abstract To discover new strobilurin analogues with high activity, a series of new fluorine-containing strobilurin derivatives were synthesized utilizing intermediate derivatization methods (IDM). The compounds were identified by 1 H and 19 F nuclear magnetic resonance (NMR), IR and elemental analysis. Preliminary bioassays in greenhouse indicated that compounds 2a (SYP-3759, flufenoxystrobin) and 2c exhibited excellent fungicidal activities against Erysiphe graminis protecting wheat at 1.56 mg L −1 concentration and compounds 2a showed a moderately high acaricidal activity at 10 mg L −1 . Field trials showed the fungicidal activities of compounds 2a and 2c is almost equivalent to that of pyraclostrobin, higher than that of triadimefon and the acaricidal activity of compound 2a is almost equivalent to that of pyidaben, but lower than that of fluacrypyrim. The preliminary mammalian toxicology results showed compound 2a was a low-toxicity compound. In conclusion compound 2a is a promising candidate for further development; mammalian toxicology and ecotoxicology with compound 2a are in progress.

Design, synthesis, and biological activity of oxime ether strobilurin derivatives containing indole moiety as novel fungicide.

Twenty-one novel oxime ether strobilurins containing indole moiety, which employed an indole group to stabilize the E-styryl group in Enoxastrobin, were designed and synthesized. The biological assay indicated that most compounds exhibited potent fungicidal activities. The structure-activity relationship study demonstrated that the synthesized methyl 3-methoxypropenoate oxime ethers 7b-e exhibited remarkably high activities among all the synthesized oxime ether compounds 7. Moreover, the fungicidal activities of methyl α-(methoxyimino)benzeneacetate oxime ethers compounds 7f-i and N-methoxy-carbamic acid methyl esters compounds 7j-m showed significant differences compared to the corresponding products of ammonolysis.

Design, synthesis and structure-activity relationship of novel oxime ether strobilurin derivatives containing substituted benzofurans.

Strobilurins are one of the most important classes of agricultural fungicides. To discover new strobilurin analogues with broad spectrum and high activity, a series of novel oxime ether strobilurin derivatives containing substituted benzofurans in the side chain were synthesised and bioassayed. The synthesised compounds were characterised by (1) H NMR, (13) C NMR, MS and HRMS. Bioassays demonstrated that most target compounds possessed good or excellent fungicidal activities, especially against Erysiphe graminis and Pyricularia oryzae. Furthermore, methyl 3-methoxypropenoate oxime ethers exhibited remarkably higher activities against E. graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. Notably, (E,E)-methyl 3-methoxy-2-{2-[({[5-fluoro-1-(benzofuran-2-yl)ethylidene]amino}oxy)methyl]phenyl}propenoate (BSF2) and (E,E)-methyl 3-methoxy-2-{2-[({[5-chloro-1-(benzofuran-2-yl)ethylidene]amino}oxy)methyl]phenyl}propenoate (BSF3) were identified as the most promising candidates for further study. The present work demonstrates that oxime ether strobilurin derivatives containing benzofurans can be used as possible lead compounds for developing novel fungicides.

Synthesis and Fungicidal Activity of Strobilurin Analogues Containing 1,2,4‐Triazole Oxime Ether Moiety

Strobilurins are a class of important agricultural fungicides that are used widely in plant protection. To find new strobilurin analogues with high activity against resistant pathogens, a series of new strobilurin derivatives bearing 1,2,4‐triazole oxime ether side chain 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h were designed and synthesized. Their structures were confirmed by IR, 1H NMR, EIMS, and elemental analyses. Bioassays indicated that some of the compounds showed good fungicidal activities in the concentration of 50 mg/L. For example, compound 3f possessed 100%, 100%, and 95.5% inhibition against Fusarium omysporum, Physalospora piricola Nose, and Gibberella saubinetii at the concentration of 50 mg/L, respectively.

Management of powdery mildew (Podosphaera xanthii) on greenhouse cucumber in Ontario

Cucumber powdery mildew (Podosphaera xanthii) causes significant annual yield and quality losses in greenhouse production in Canada. Management of the disease was evaluated in various research trials conducted at Harrow, ON from 1999–2007 and at two commercial greenhouse operations in Leamington, ON in 2005–2006. Products evaluated included biological control agents, new classes of fungicides, and materials derived from natural products as well as several traditional fungicides with multi-site modes of action. Best control in the research greenhouse was obtained with applications of Nova, Quintec, strobilurin derivatives (Quadris, Flint, Sovran), Procure, Pristine, JMS Stylet-Oil®, V-10118, Prev-AM, copper soap, Actigard and sulphur. Disease control was also obtained with Milstop, two fermented milk by-products (Lactosan, Yo-K-San) + surfactant formulations (Agral 90), and Agral 90 only. Applications of K2HPO4 + Agral 90, CaCl2 + Agral 90, and Siliforce were significantly better than the water check while fumed silica was not effective. Among biological control products, Sporodex (Pseudozyma flocculosa) was effective in control of P. xanthii while Serenade (Bacillus subtilis) was not. Actinovate (Streptomyces lydicus) provided control also. Under commercial greenhouse conditions, Milstop, and Lactosan + Agral 90 when applied weekly suppressed powdery mildew development at least equal to that of Nova. Resistance in P. xanthii to high rates of Nova and Pristine was detected in 3 of 17 and 2 of 8 commercial greenhouse cucumber operations, respectively, near Leamington. None of the locations had resistance to both fungicides at commercial rates of application, although one site showed consistently greater resistance of P. xanthii to both fungicides.

Synthesis and bioactivity of novel strobilurin derivatives containing the pyrrolidine-2,4-dione moiety

Abstract ( E )-Methyl-2-(2-(bromomethyl)phenyl)-3-methoxyacrylate was reacted with substituted 1-acetylpyrrolidine-2,4-diones and 3-(1-(hydroxylamino)ethylidene)pyrrolidine-2,4-diones respectively to synthesize two series of β -methoxyacrylate derivatives containing the pyrrolidine-2,4-dione moiety. The structures of the targeted compounds were confirmed by IR, 1 H NMR, 13 C NMR, MS and elemental analysis. The fungicidal activity against Rhizoctonia solani , Botrytis cinerea and Fusarium graminearum was evaluated. The bioassay results demonstrated that these compounds showed visible fungicidal activity.

Synthesis of New Strobilurin Derivatives with Modified 1,3,5-Triazine Moiety

Synthesis of New Strobilurin Derivatives with Modified 1,3,5-Triazine Moiety

ChemInform Abstract: Synthesis and Antifungal Activities of New Type β‐Methoxyacrylate‐Based Strobilurin Analogues.

Strobilurins have become one of the most important classes of agricultural fungicides. To discover new strobilurin derivatives with high activity against resistant pathogens, a series of novel beta-methoxyacrylate analogues were designed and synthesized by integrating substituted pyrimidine with a strobilurin pharmacophore. The compounds were confirmed and characterized by infrared, 1H nuclear magnetic resonance, elemental analysis and mass spectroscopy. The bioassays indicated that most of the compounds 1 exhibited potent antifungal activity against Colletotrichum orbiculare, Botrytis cinerea Pers and Phytophthora capsici Leonian at the concentration of 50 mu g/mL. Exhilaratingly, compound 1a (R=methyl) showed better antifungal activity against all the tested fungi than the commercial strobilurin fungicide azoxystrobin.

Design, Synthesis, and Antifungal Activities of New β‐Methoxyacrylate Analogues

AbstractStrobilurins have become one of the most important classes of agricultural fungicides. To search for new strobilurin derivatives with high activity against resistant pathogens, a series of new β‐methoxyacrylate analogues containing substituted pyrimidine in the side chain with strobilurin pharmacophore were synthesized and their biological activities were tested. The compounds were confirmed and characterized by 1H‐NMR, elemental analysis and mass spectroscopy. The bioassays indicated that most of the compounds 1 exhibited potent antifungal activities against Colletotrichum orbiculare, Botrytis cinerea Pers and Phytophthora capsici Leonian at a concentration of 50 μg mL−1. Notably, compound 1b (R = 2,5‐dimethylphenyl) showed better antifungal activity against all the tested fungi than the commercial strobilurin fungicide azoxystrobin.

Design, Synthesis, and Bioevaluation of Novel Strobilurin Derivatives

AbstractStrobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally benign characteristics. Design and syntheses of strobilurin analogues therefore have attracted great attention in the field of agrochemistry. Previously, we successfully developed a new molecular design method of pharmacophore‐linked fragment virtual screening (PFVS) and discovered a lead compound (E)‐methyl‐2‐(2‐(((3‐(imino‐(phenyl)methyl)phenyl)thio)methyl)phenyl)‐3‐methoxyacrylate (1). To discover new strobilurin analogues with higher fungicidal activity, the structural modification of compound 1 was carried out guided by bioisosterism. A series of benzophenone derivatives 2a–2j were synthesized, among which compound 2j with a Ki value of 1.89 nmol/L was identified as the most promising inhibitor of porcine cytochrome bc1 complex, 157‐fold improved binding affinity compared to the commercially available bc1 inhibitor Azoxystrobin (AZ). In addition, most of the new compounds displayed excellent fungicidal activity against Sphaerotheca fuliginea at the concentration of 200 µmol/L. The present work indicates that strobilurin analogues containing benzophenone side chains may be the ideal leads for future fungicide discovery.

Design, Synthesis and Antifungal Activities of Novel Strobilurin Derivatives Containing Pyrimidine Moieties

Strobilurins are one of the most important classes of agricultural fungicides. To discover new strobilurin derivatives with high activity against resistant pathogens, a series of novel beta-methoxyacrylate analogues were designed and synthesized by integrating substituted pyrimidine with a strobilurin pharmacophore. The compounds were confirmed and characterized by infrared, H-1 nuclear magnetic resonance, elemental analysis and mass spectroscopy. The bioassays indicated that most of the compounds (1a-1h) exhibited potent antifungal activities against Colletotrichum orbiculare, Botrytis cinerea Pers and Phytophthora capsici Leonian at the concentration of 50 mu g/mL. Exhilaratingly, compound 1d (R=3-trifluoromethylphenyl) showed better antifungal activity against all the tested fungi than the commercial strobilurin fungicide azoxystrobin.

Synthesis and Antifungal Activities of New Type β‐Methoxyacrylate‐Based Strobilurin Analogues

AbstractStrobilurins have become one of the most important classes of agricultural fungicides. To discover new strobilurin derivatives with high activity against resistant pathogens, a series of novel β‐methoxyacrylate analogues were designed and synthesized by integrating substituted pyrimidine with a strobilurin pharmacophore. The compounds were confirmed and characterized by infrared, 1H nuclear magnetic resonance, elemental analysis and mass spectroscopy. The bioassays indicated that most of the compounds 1 exhibited potent antifungal activity against Colletotrichum orbiculare, Botrytis cinerea Pers and Phytophthora capsici Leonian at the concentration of 50 μg/mL. Exhilaratingly, compound 1a (R=methyl) showed better antifungal activity against all the tested fungi than the commercial strobilurin fungicide azoxystrobin.

Powdery mildew (Leveillula taurica) on greenhouse and field peppers in Ontario – host range, cultivar response and disease management strategies

Leveillula taurica was observed on field pepper at various sites in south-western Ontario in 2005–2007. The field isolates collected from these sites were similar to a greenhouse isolate based on morphological observations. Host range of greenhouse and field isolates was similar, with minor sporulation on potato, carrot and several weeds. The greenhouse pepper cultivar ‘Samanta’ was the most susceptible to L. taurica while ‘Triple 4’, ‘Duplo’ and ‘Bosanova’ were the least susceptible to infection. Best control of pepper powdery mildew in the greenhouse was obtained with applications of myclobutanil, triflumizole, pyraclostrobin + boscalid, quinoxyfen, strobilurin derivatives (azoxystrobin, trifloxystrobin, kresoxim-methyl), copper soap, JMS Stylet-Oil®, Valent-10118, acibenzolar-S-methyl and sulphur. Disease reduction was also obtained with applications of potassium bicarbonate, citrus oil + borax, Bacillus subtilis and a fermented milk byproduct + surfactant. K2HPO4 + surfactant was effective in reducing disease whereas CaCl2 + surfactant, fumed silica and Sporothrix flocculosa were not effective. In field plots, best disease control was achieved with applications of myclobutanil and the fermented milk byproduct + surfactant in 2006 whereas in 2007, citrus oil + borax and potassium bicarbonate were most effective. There were no significant differences in pepper yield among the treatments in field plots. In vitro survival studies showed that the fungus was able to survive in infected pepper leaves after exposure to temperatures of −10 °C for 2 months.