Total Synthesis, structure revision and antifungal activity of palmarumycin B8 and B7.

Palmarymycins B8 (1), its regioisomer (2) and B7 (3) were synthesized via 10-, 9-, and 11-steps in 6.5 %, 2.3 % and 0.54 % overall yields from chroman-4-one (4), 4-hydroxyindanone (12), and 2,5-dimethoxybenzaldehyde (20) as the starting materials, using benzyl protection, enol trimethylsilyl ether by TMSOTf, Rubottom oxidation and deprotection with hydrogenation under Pd/C catalyst as the key steps, respectively. Their structures were characterized by 1H, 13C NMR, COSY, HSQC, HMBC and HR-ESI-MS spectral data. The structure of palmarumycin B8 was revised from 1 to 2 based on the total synthesis, 2D NMR analysis and DFT calculation. The antifungal assay results indicated that palmarumycin B8 (1) showed moderate inhibitory activity against Phytophthora capsica. Compounds 15 and 16 exhibited excellent in vitro antifungal activities against P. capsica with EC50 values of 2.17 and 8.50 µg/mL, respectively.

Synthesis and Antifungal Activity of New butenolide Containing Methoxyacrylate Scaffold.

In order to improve the antifungal activity of new butenolides containing oxime ether moiety, a series of new butenolide compounds containing methoxyacrylate scaffold were designed and synthesized, based on the previous reports. Their structures were characterized by 1H NMR, 13C NMR, HR-MS spectra, and X-ray diffraction analysis. The in vitro antifungal activities were evaluated by the mycelium growth rate method. The results showed that the inhibitory activities of these new compounds against Sclerotinia sclerotiorum were significantly improved, in comparison with that of the lead compound 3-8; the EC50 values of V-6 and VI-7 against S. sclerotiorum were 1.51 and 1.81 mg/L, nearly seven times that of 3-8 (EC50 10.62 mg/L). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observation indicated that compound VI-3 had a significant impact on the structure and function of the hyphal cell of S. sclerotiorum mycelium and the positive control trifloxystrobin. Molecular simulation docking results indicated that the introduction of methoxyacrylate scaffold is beneficial to improving the antifungal activity of these compounds against S. sclerotiorum, which can be used as the lead for further structure optimization.

Design, synthesis, antifungal activity and molecular docking of novel pyrazole-4-carboxamides containing tertiary alcohol and difluoromethyl moiety as potential succinate dehydrogenase inhibitors.

BACKGROUND: Resistance problems with the long-term and frequent use of existing fungicides, and the lack of structure diversity of traditional pyrazole-4-carboxamide succinate dehydrogenase inhibitors, it is highly required to design and develop new fungicides to address the resistance issue. RESULTS: Different from previous pyrazole-4-carboxamide succinate dehydrogenase inhibitors by breaking the norm of difluoromethyl at the C-3 position of pyrazole and introducing a tertiary alcohol group at the C-3 position, 27 novel pyrazole-4-carboxamide derivatives were designed, synthesized and characterized by proton (1 H) nuclear magnetic resonance (NMR), carbon-13 (13 C) NMR, fluorine-19 (19 F) NMR and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The crystal structures of compounds A14 and C5 were analyzed by single crystal X-ray diffraction. Their in vitro antifungal activities were evaluated against phytopathogen Fusarium graminearum, Botrytis cinerea, Phytophthora capsica, Sclerotinia sclerotiorum, Thanatephorus cucumeris. The results displayed that most of them exhibited significant antifungal activities against S. sclerotiorum at 50 mg/L, the half maximal effective concentration (EC50 ) data of A8 and A14 were 3.96 and 2.52 mg/L, respectively. Their in vivo antifungal activities were evaluated against Pseudoperonospora cubensis, Puccinia sorghi Schw, Colletotrichum gloeosporioides, F. graminearum, Erysiphe graminis, Thanatephorus cucumeris, the control efficacies of A6, B3, C3, and C6 against E. graminis reached 100% at a concentration of 400 mg/L. The molecular docking results showed that the binding mode of the target compounds containing tertiary alcohols were similar to that of fluxapyroxad in succinate dehydrogenase. In addition, tertiary alcohols were involved in the formation of hydrogen bonds. CONCLUSION: The excellent in vitro and in vivo inhibitory activities of novel pyrazole-4-carboxamide derivatives against succinate dehydrogenase were reported for the first time, and they could be used as the potential lead compounds. © 2023 Society of Chemical Industry.

Design, Synthesis, and Antifungal/Antioomycete Activity of Thiohydantoin Analogues Containing Spirocyclic Butenolide.

Novel fungicidal agents were designed based on the combination of two privileged scaffolds, thiohydantoin and spirocyclic butenolide, which are widely found in natural products. The synthesized compounds were characterized by 1H NMR, 13C NMR, and high-resolution electrospray ionisation mass spectrometry. The in vitro antioomycete activity evaluation showed that most of the compounds exhibited excellent inhibitory activities against different developmental stages in the life cycle of pathogenic oomycete Phytophthora capsici. Compound 5j could inhibit the mycelial growth, sporangium production, zoospore release, and cystospore germination significantly with EC50 values of 0.38, 0.25, 0.11, and 0.026 µg/mL, respectively. The in vivo antifungal/antioomycete bioassay results revealed that the series of compounds generally showed outstanding control efficacies against the pathogenic oomycete Pseudoperonospora cubensis, and compounds 5j, 5l, 7j, 7k, and 7l possessed broad-spectrum antifungal activities against the test phytopathogens. The in vivo protective and curative efficacies against P. capsici of the representative compound 5j were excellent, which were better than those of azoxystrobin. More prominently, 5j significantly promoted the biomass accumulation of the root system and reinforced the cell wall by callose deposition. The pronounced upregulation of immune response-related genes indicated that the active oomycete inhibitor 5j also functioned as a plant elicitor. Transmission electron microscopy observation and the enzyme activity test demonstrated that the mechanism of action of 5j was to bind to the pivotal protein, complex III on the respiratory chain, which resulted in a shortage of energy supply. Molecular docking results exhibited that compound 5j appropriately matched with the Qo pocket and had no interaction with the most commonly mutated site Gly-142, which may be of significant benefit in Qo fungicide resistance management. Compound 5j showed great advantages and potential in oomycete control, resistance management, and induction of disease resistance. A further investigation of 5j with a unique structure might have direct implications for the creation of novel oomycete inhibitors against plant-pathogenic oomycetes.

Research on Impulse Power Load Forecasting Based on Improved Recurrent Neural Networks.

Deep learning is good at extracting the required feature quantity from the massive input information through multiple hidden layers and completing the learning through training to achieve the task of load forecasting. The impulse power load data contain a lot of noise, burrs, and strong randomness. As an improved recurrent neural networks, the output of long short-term memory (LSTM) network is not only related to the current input, but also closely related to the historical information, which can effectively predict the impact power load. An impulse power load forecasting model based on improved recurrent neural networks is proposed. To solve the training difficulties caused by deep networks, database is divided into training data set and test data set. To accelerate running speed and improve accuracy and reliability, parameter setting in deep learning neural network is analyzed. The proposed load forecasting model is verified by simulation and compared with the existing methods. Taking the average relative error as the standard, the effectiveness of the proposed model for the forecasting of impulse power load connected to the bus is verified.

Total synthesis, structure revision and cytotoxic activity of Sch 53825 and its derivatives.

The first total synthesis of Sch 53825 (14) was achieved in 12 steps from 5-hydroxy-1-tetralone in 16% overall yield through N-benzyl cinchoninium chloride-catalyzed asymmetric epoxidation and a Mitsunobu reaction as the key steps. On this basis, the synthesis of palmarumycin B6 was improved using the same raw material with 6 steps and 32% overall yield. Also, three new analogues with two chlorine atoms were synthesized. Their structures were characterized by 1H, 13C NMR, HR-ESI-MS and X-ray diffraction data. The structure of natural Sch 53825 was revised as an epimer of compound 1 with the anti-hydroxy epoxide at C-4. Their cytotoxic activities against several tumor cell lines (HCT116, U251, BGC823, Huh-7 and PC9) showed that compound 11 exhibited excellent cytotoxicity against above mentioned cancer cell lines with IC50 < 0.5 µM.

Design, Synthesis, and Fungicidal Activity of Novel Plant Elicitors Based on a Diversity-Oriented Synthesis Strategy.

The novel plant elicitors, 3-benzyl-5-[1-(2-oxo-4-phenyl-1-oxaspiro[4.5]dec-3-en-3-yl)ethylidene]-2-aminoimidazolin-4-one derivatives, were designed based on the diversity-oriented synthesis strategy and synthesized in four steps via the Knoevenagel condensation reaction as the key step. They were characterized by 1H NMR, 13C NMR, HR-ESI-MS, and X-ray diffraction. The position of the C═N bond of Z- and E-configuration compounds was determined by X-ray diffraction. The in vivo fungicidal activity evaluation revealed that most of these compounds exhibited remarkable activities (100%) against Pseudoperonospora cubensis at 400 µg/mL, among which compound 8e still exhibited excellent protective activity with a 50% inhibition rate at 0.1 µg/mL. Because the in vitro effect on tested phytopathogens was poor, the mechanism to induce the immune responses and reinforce the resistance of cucumber against Botrytis cinerea was studied. The results indicated that the compound 8e-mediated defense response against B. cinerea was based on the accumulation of pathogenesis-related proteins and cell wall reinforcement by callose deposition. Quantitative analysis of salicylic acid (SA) and jasmonic acid (JA) and the increased expression of induced resistance-related genes and the defense-associated phenylalanine ammonia lyase revealed that the immune response triggered by compound 8e was highly associated with the SA signaling pathway. Significant upregulation of JA-related genes Cs-AOS2 indicated that the JA signaling pathway was also influenced. It was also shown that the plants treated with compound 8e promoted primary root elongation, which resulted in enhanced plant growth. Most importantly, these compounds have completely new structures compared with the traditional plant elicitors. Further research of 8e-mediated plant disease resistance might have a great influence on the development of plant elicitors.