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Chiral fluoropyrrolidines were synthesized by Cu(i)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active fluorinated styrenes, with broad substrate scope and high yield, stereoselectivity and biological activity.

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.

In order to find new potential pesticide molecules with antifungal activities, we have designed and synthesized a series of amino acid-oriented poly-substituted tetramic acid derivatives, and evaluated their potential antifungal activities against six kinds of plant pathogenic fungus commonly found in agriculture systematically, including Phomopsis adianticola, Fusarium graminearum, Alternaria tenuis Nees, Magnaporthe oryzae, Gloeosporium theae-sinensis, Sclerotinia sclerotiorum. According to the preliminary bioassay studies, all tested molecules, especially compounds I-2, I-5, I-12, I-15, exhibited significant and broad-spectrum anti-fungal effect in vitro compared to the intermediates M-1, M-2, M-3 and hymexazol. What's more, the inhibition rate of compounds I-5, I-6, I-15 against Phomopsis adianticola reached 74.42%, 60.33%, 65.21%, as well as compounds I-3, I-5, I-15 against Sclerotinia sclerotiorum were 65.65%, 74.92%, 61.36%. Further investigation results indicated that compounds I-2, I-5, I-15 presented obviously inhibitory activities against Phomopsis adianticola compared with hymexazol, which might be considered as the basic active framework for further potential fungicides discovery.

Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, and the development of efficient methods for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, incorporating fluorine containing groups into small molecules often changes their activities to a great extent due to the special physicochemical properties of fluorine atoms. Herein, we report an efficient route to obtain enantioenriched 3,3-difluoro- and 3,3,4-trifluoropyrrolidinyl derivatives by Cu(i)-catalysed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluorostyrenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and with excellent stereoselectivities (up to20 : 1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant fungi showed that some products possess general and high biological activities; comparison with the low antifungal activities of corresponding nonfluorinated compounds revealed that the fluorine atoms at the pyrrolidinyl rings play a crucial role in the antifungal activity.

Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, thereupon, searching approaches for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, owing to the special physicochemical properties of fluorine atoms, the introduction of fluorine containing groups into small molecules often change their activities to a great extent. Herein, we reported an efficient route to chiral 3,3-difluoro- and 3,3,4-trifluoropyrrodinyl derivatives by Cu(I)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluoroalkenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and excellent stereoselectivities (up to > 20:1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant funguses showed that some products possess general and high biological activities (up to 93% inhibition rate), the comparison with the antifungal activities of corresponding non-fluorinated compounds (low to 13% inhibition rate) revealed that the fluorine atoms at pyrrolidinyl rings play a crucial role in the antifungal activity, which prove the special properties of fluorine atoms in organic molecules.

In this study, forty-four chiral triazole derivatives have been prepared via asymmetric synthesis, and which has been successfully characterized by typical spectroscopic techniques including 1H NMR, 13C NMR, EI-MS, elemental analysis and optical rotations. Their in vitro antiviral activities against EV71 and CVB3 were fully investigated in cell-based assays. It was observed that 13 synthetic triazole derivatives inhibited the CPE of EV71 on RD cells, with EC50S in the 5.3-15.9 μg/ml range and corresponding SIs of 4.0-27.6, while 17 triazole derivatives showed antiviral activities against CVB3, with EC50S in the 4.7-15.1 μg/ml range and the corresponding SIs of 3.7-14.5. In addition, in some cases, the respective enantiomers showed significantly selective inhibitory effect against EV71, most notably for the enantiomers 9(R) and 10(S), 42(R) and 43(S), which presented an obvious activity difference. The most potential molecules are the compounds 10 and 43 with S-configuration, and which exhibit good SI values compared with the control Ribavirin.

To study the novel functionalized heterocyclic molecules with highly potential biological activity, two series of heterocyclic lactam derivatives containing the piperonyl moiety were designed and synthesized. The newly obtained compounds have been identified on the basis of analytical spectral data, including 1H NMR, 13C NMR, and ESI-MS. The target compounds were evaluated for their potential antifungal activities in vitro against twelve species of the plant pathogen fungi (Sclerotinia sclerotiorum, Rhizoctonia solani, Rap Sclerotinia stemrot, Fusarium graminearum, Phomopsis adianticola, Pestallozzia theae, Pestalotiopsis guepinii, Alternaria tenuis Nees, Monilinia fructicola, Colletotrichum gloeosporioides, Phytophthora capsici, Magnaporthe oryzae). Preliminary bioassays suggested that all prepared compounds I1–14 displayed broad-spectrum and moderate antifungal activities compared with the positive control hymexazol, especially for Sclerotinia sclerotiorum, Rap Sclerotinia stemrot, and Monilinia fructicola. In particular, the inhibition rate of compound I9 exhibited good inhibition activity reached 95.16% against Sclerotinia sclerotiorum, and compounds I5, I12 against Phytophthora capsici were 93.44%, 91.25%. Further studies revealed that compounds I5 (IC50 = 19.13 µM) and I12 (IC50 = 9.12 µM) exhibited obviously antifungal activities against Phytophthora capsici, which were better than that of commercial agricultural fungicide hymexazol (IC50 = 325.45 µM). Therefore, these target compounds could be further studied and explored as a lead skeleton for discovery of novel antifungal agents.

A series of novel 3-aryl-4-hydroxy-2(5H) furanone-acrylate hybrids were designed and synthesized based on the natural butenolides and acrylates scaffolds. The structures of the prepared compounds were characterized by 1H-NMR, 13C-NMR and electrospray ionization mass spectrometry (ESI-MS), and the bioactivity of the target compounds against twelve phytopathogenic fungi was investigated. The preliminary in vitro antifungal activity screening showed that most of the target compounds had moderate inhibition on various pathogenic fungi at the concentration of 100 mg&middot, L&minus, 1, and presented broad-spectrum antifungal activities. Further studies also indicated that compounds 7e and 7k still showed some inhibitory activity against Pestallozzia theae, Sclerotinia sclerotiorum and Gibberella zeae on rape plants at lower concentrations, which could be optimized as a secondary lead for further research.

With the aim to develop highly potential active heterocyclic compounds, two series of multi-substituted pyrrolizinone and indolizinones derived from lactam were designed, synthesized and evaluated for their potential antifungal activities against six species of the plant pathogen fungi (Fusarium graminearum, Sclerotinia sclerotiorum, Phomopsis adianticola, Gloeosporium theae-sinensis, Alternaria tenuis Nees, Magnaporthe oryzae). The structure of all the newly molecules were confirmed by analytical spectroscopic data, including 1H NMR, 13C NMR and ESI-MS. According to the preliminary studies on bio-evaluation assay, some of the obtained compounds exhibited moderate and broad-spectrum activities against six fungi compared to the intermediates 6a, 6f and the hymexazol. Particularly, the inhibition rate of compounds 7l, 7m and 7t reached 69.25%, 74.76%, 65.38% against Phomopsis adianticola and Magnaporthe oryzae in vitro activity. Furthermore, compounds 7l and 7t displayed obviously inhibition activities against Phomopsis adianticola compared to the hymexazol. Consequently, compounds 7l and 7t with six-membered alkane ring could be used as new motifs for further investigation.

Essential oils (EOs) are plant-derived aroma compounds with a wide range of biological activity, but their actions are slow, and they are typically unstable to light or heat, difficult to extract and so on. To find highly potential fungicides derived from natural EOs, a series of essential oil-based β-methoxyacrylate derivatives have been designed and synthesized. The target compounds have been screened for their potential fungicidal activity against eleven species of plant pathogen fungi, including Alternaria alternata, Phomopsis adianticola, Pestalotiopsis theae, Sclerotinia sclerotiorum, etc. Compared with intermediates I, the parent essential oils and azoxystrobin, almost all of essential oil-based β-methoxyacrylate derivatives exhibited significantly better fungicidal activity. Further investigation revealed that some compounds showed remarkable inhibitory activities against Pestalotiopsis theae, Phomopsis adianticola, Sclerotinia sclerotiorum and Magnapothe grisea at different concentrations in contrast to the commercial product azoxystrobin. Compound II-8 exhibited particularly significant fungicidal activity.