Antifungal Activity and Putative Mechanism of HWY-289, a Semisynthetic Protoberberine Derivative, against Botrytis cinerea.

The emergence of resistant pathogens has increased the demand for alternative fungicides. The use of natural products as chemical scaffolds is a potential method for developing fungicides. HWY-289, a semisynthetic protoberberine derivative, demonstrated broad-spectrum and potent activities against phytopathogenic fungi, particularly Botrytis cinerea (with EC50 values of 1.34 µg/mL). SEM and TEM imaging indicated that HWY-289 altered the morphology of the mycelium and the internal structure of cells. Transcriptomics revealed that it could break down cellular walls through amino acid sugar and nucleotide sugar metabolism. In addition, it substantially decreased chitinase activity and chitin synthase gene (BcCHSV) expression by 53.03 and 82.18% at 1.5 µg/mL, respectively. Moreover, this impacted the permeability and integrity of cell membranes. Finally, HWY-289 also hindered energy metabolism, resulting in a significant reduction of ATP content, ATPase activities, and key enzyme activities in the TCA cycle. Therefore, HWY-289 may be a potential candidate for the development of plant fungicides.

Biologically active isoquinoline alkaloids covering 2019-2022.

Isoquinoline alkaloids are an important class of natural products that are abundant in the plant kingdom and exhibit a wide range of structural diversity and biological activities. With the deepening of research in recent years, more and more isoquinoline alkaloids have been isolated and identified and proved to contain a variety of biological activities and pharmacological effects. In this review, we introduce the research progress of isoquinoline alkaloids from 2019 to 2022, mainly in the part of biological activities, including antitumor, antimicrobial, antidiabetic, antiviral, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, analgesic, and other activities. This study provides a clear direction for the rational development and utilization of isoquinoline alkaloids, suggesting that these alkaloids have great potential in the field of drug research.

Piperine: Chemistry and Biology.

Piperine is a plant-derived promising piperamide candidate isolated from the black pepper (Piper nigrum L.). In the last few years, this natural botanical product and its derivatives have aroused much attention for their comprehensive biological activities, including not only medical but also agricultural bioactivities. In order to achieve sustainable development and improve survival conditions, looking for environmentally friendly pesticides with low toxicity and residue is an extremely urgent challenge. Fortunately, plant-derived pesticides are rising like a shining star, guiding us in the direction of development in pesticidal research. In the present review, the recent progress in the biological activities, mechanisms of action, and structural modifications of piperine and its derivatives from 2020 to 2023 are summarized. The structure-activity relationships were analyzed in order to pave the way for future development and utilization of piperine and its derivatives as potent drugs and pesticides for improving the local economic development.

Repurposing Salicylamides to Combat Phytopathogenic Bacteria and Induce Plant Defense Responses.

Based on the research strategy of "drug repurposing", a series of derivatives and marketed drugs that containing salicylic acid skeleton were tested for their antibacterial activities against phytopathogens. Salicylic acid can not only regulate some important growth metabolism of plants, but also induce plant disease resistance. The bioassay results showed that the salicylamides exhibited excellent antibacterial activity. Especially, oxyclozanide showed the best antibacterial effect against Xanthomonas oryzae, Xanthomonas axonopodis pv. citri and Pectobacterium atroseptica with MICs of 0.78, 3.12 and 12.5 µg.mL-1, respectively. In vivo experiments with rice bacterial leaf blight had further demonstrated that oxyclozanide exhibited stronger antibacterial activity than the commercial bactericide, thiodiazole copper. Oxyclozanide could induce plant defense responses through the determination of salicylic acid content and the activities of defense-related enzymes including CAT, POD, and SOD in rice. The preliminarily antibacterial mechanism study indicated that oxyclozanide exhibited the antibacterial activity by disrupting cell integrity and reducing bacterial pathogenicity. Additionally, oxyclozanide could induce plant defense responses through the determination of salicylic acid content.

Short pathways to highly active antimicrobial: structurally diverse polyamines derivatives from Amino-Aldehyde condensation strategy.

BACKGROUND: Chemical fungicides are the mainstay of plant disease control in agricultural production, but there are a very limited number of drugs that can effectively control plant diseases. Two series of secondary amine derivatives were synthesized using the diamine skeleton combined with saturated aromatic and aliphatic aldehydes, and their antibacterial and antifungal activities against plant pathogens were determined. In addition, the antimicrobial mechanism of the highly active compound A26 was preliminarily examined against Xanthomonas oryzae (Xoo). RESULTS: Compound A26 exhibited the highest antibacterial potency among all the target compounds, with MIC values of 3.12, 3.12 and 12.5 µg mL-1 against Xoo, Xanthomonas axonopodis pv. Citri and Pseudomonas sollamacearum, respectively. In addition, compound A26 had powerful curative and protective effects against Xoo at 200 µg mL-1 , and was better than the control agent Xinjunan. Preliminary mechanistic studies showed that compound A26 reduced the bacterial pathogenicity by targeting cell membranes and inhibiting the secretion of extracellular polysaccharides. Meanwhile, the toxicity of compound A26 to Human Embryonic Kidney 293 cells and Human Liver-7702 was similar to that of Xinjunan, and it had moderate toxicity according to the World Health Organization classification standard of oral exogenous toxicity, with an LD50 of 245.47 mg kg-1 . CONCLUSION: Secondary amines have efficient and broad-spectrum antibacterial activity against plant pathogenic bacteria and are expected to be a new class of candidate compounds for antibacterial drugs. © 2023 Society of Chemical Industry.

Efficacy of pterostilbene suppression on Aspergillus flavus growth, aflatoxin B1 biosynthesis and potential mechanisms.

Aspergillus flavus, a widespread saprotrophic filamentous fungus, could colonize agricultural crops with aflatoxin contamination, which endangers food security and the agricultural economy. A safe, effective and environmentally friendly fungicide is urgently needed. Pterostilbene, a natural phytoalexin originated from Pterocarpus indicus Willd., Vaccinium spp. and Vitis vinifera L., has been reported to possess excellent antimicrobial activity. More importantly, it is quite safe and healthy. In our screening tests of plant polyphenols for the inhibition of A. flavus, we found that pterostilbene evidently inhibited mycelial growth of Aspergillus flavus (EC50 = 15.94 µg/mL) and the inhibitory effect was better than that of natamycin (EC50 = 22.01 µg/mL), which is a natural product widely used in food preservation. Therefore, we provided insights into the efficacy of pterostilbene suppression on A. flavus growth, aflatoxin B1 biosynthesis and its potential mechanisms against A. flavus in the present study. Here, pterostilbene at concentrations of 250 and 500 µg/mL could effectively inhibit the infection of A. flavus on peanuts. And the biosynthesis of the secondary metabolite aflatoxin B1 was also inhibited. The antifungal effects of pterostilbene are exerted by inducing a large amount of intracellular reactive oxygen species production to bring the cells into a state of oxidative stress, damaging cellular biomolecules such as DNA, proteins and lipids and destroying the integrity of the cell membrane. Taken together, our study strongly supported the fact that pterostilbene could be considered a safe and effective antifungal agent against A. flavus infection.

Antimicrobial activity of natural and semi-synthetic carbazole alkaloids.

Since the first natural carbazole alkaloid, murrayanine, was isolated from Mwraya Spreng, carbazole alkaloid derivatives have been widely concerned for their anti-tumor, anti-viral and anti-bacterial activities. In recent decades, a growing body of data suggest that carbazole alkaloids and their derivatives have different biological activities. This is the first comprehensive description of the antifungal and antibacterial activities of carbazole alkaloids in the past decade (2012-2022), including natural and partially synthesized carbazole alkaloids in the past decade. Finally, the challenges and problems faced by this kind of alkaloids are summarized. This paper will be helpful for further exploration of this kind of alkaloids.

The role of flagellin F in Vibrio Parahaemolyticus-induced intestinal immunity and functional domain identification.

The marine pathogen Vibrio parahaemolyticus has caused huge economic losses to aquaculture. Flagellin is a key bacterial virulence factor that induces an inflammatory response via activation of Toll-like receptor 5 (TLR5) signaling. Herein, to explore the inflammatory activity of V. parahaemolyticus flagellins (flaA, flaB, flaC, flaD, flaE, and flaF), we investigated their ability to induce apoptosis in a fish cell line. All six flagellins induced severe apoptosis. Moreover, treatment with V. parahaemolyticus flagellins increased TLR5 and myeloid differentiation factor 88 (MyD88) expression and the production of TNF-α and IL-8 significantly. This indicated that flagellins might induce a TLR5-meditated immune response via an MyD88-dependent pathway. FlaF exhibited the strongest immunostimulatory effect; therefore, the interaction between TLR5 and flaF was screened using the yeast two-hybrid system. A significant interaction between the two proteins was observed, indicating that flaF binds directly to TLR5. Finally, the amino acids that participate in the TLR5-flaF interaction were identified using molecular simulation, which indicated three binding sites. These results deepen our understanding of the immunogenic properties of flagellins from V. parahaemolyticus, which could be used for vaccine development in the future.

Exploration of Synergistic Pesticidal Activities, Control Effects and Toxicology Study of a Monoterpene Essential Oil with Two Natural Alkaloids.

With the increasing development of pest resistances, it is not easy to achieve satisfactory control effects by using only one agrochemical. Additionally, although the alkaloid matrine (MT) isolated from Sophora flavescens is now utilized as a botanical pesticide in China, in fact, its pesticidal activities are much lower in magnitude than those of commercially agrochemicals. To improve its pesticidal activities, here, the joint pesticidal effects of MT with another alkaloid oxymatrine (OMT) (isolated from S. flavescens) and the monoterpene essential oil 1,8-cineole (CN) (isolated from the eucalyptus leaves) were investigated in the laboratory and greenhouse conditions. Moreover, their toxicological properties were also studied. Against Plutella xylostella, when the mass ratio of MT and OMT was 8/2, good larvicidal activity was obtained; against Tetranychus urticae, when the mass ratio of MT and OMT was 3/7, good acaricidal activity was obtained. Especially when MT and OMT were combined with CN, the significant synergistic effects were observed: against P. xylostella, the co-toxicity coefficient (CTC) of MT/OMT (8/2)/CN was 213; against T. urticae, the CTC of MT/OMT (3/7)/CN was 252. Moreover, the activity changes over time of two detoxification enzymes, carboxylesterase (CarE) and glutathione S-transferase (GST) of P. xylostella treated with MT/OMT (8/2)/CN, were observed. In addition, by scanning electron microscope (SEM), the toxicological study suggested that the acaricidal activity of MT/OMT (3/7)/CN may be related to the damage of the cuticle layer crest of T. urticae.

Natural products in crop protection: thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles as antifungal agents and their mechanism of action.

BACKGROUND: Phytopathogenic fungi can cause a direct loss in economic value of agriculture. Especially Valsa mali Miyabe et Yamada, a devastating phytopathogenic disease especially threatening global apple production, is very difficult to control and manage. To discover new potential antifungal agents, a series of thiosemicarbazone derivatives of 3-acetyl-N-benzylindoles were prepared. Their antifungal activities were first tested against six typically phytopathogenic fungi including Curvularia lunata, Valsa mali, Alternaria alternate, Fusarium graminearum, Botrytis cinerea and Fusarium solani. Then their mechanism of action against V. mali was investigated. RESULTS: Derivatives displayed potent antifungal activity against V. mali. Notably, 3-acetyl-N-benzylindole thiosemicarbazone (IV-1: EC50 : 0.59 µg mL-1 ), whose activity was comparable to that of a commercial fungicide carbendazim (EC50 : 0.33 µg mL-1 ), showed greater than 98-fold antifungal activity of the precursor indole. Moreover, compound IV-1 displayed good protective and therapeutic effects on apple Valsa canker disease. By scanning electron microscope (SEM) and RNA-Seq analysis, it was demonstrated that compound IV-1 can destroy the hyphal structure and regulate the homeostasis of metabolism of V. mali via the ergosterol biosynthesis and autophagy pathways. CONCLUSION: 3-Acetyl-N-(un)substituted benzylindoles thiosemicarbazones (IV-1-IV-5) can be studied as leads for further structural modification as antifungal agents against V. mali. Particularly, these ergosterol biosynthesis and autophagy pathways can be used as target receptors for design of novel green pesticides for management of congeneric phytopathogenic fungi. © 2023 Society of Chemical Industry.

Exploring boron applications in modern agriculture: Antifungal activities and mechanisms of phenylboronic acid derivatives.

BACKGROUND: The unreasonable use of chemical fungicides causes common adverse consequences that not only affect the environment, but also cause resistance and resurgence problems of plant pathogens, which are extremely harmful to human health, the economy, and the environment. Based on the rich biological activities of boron-based compounds, 82 phenylboronic acid derivatives were selected and their antifungal activities against six agricultural plant pathogens were determined. Combined with transcriptomics tools, the mechanism of action of compound A49 (2-chloro-5-trifluoromethoxybenzeneboronic acid) against Botrytis cinerea Pers (B. cinerea) was studied. RESULTS: The EC50 values of compounds A24, A25, A30, A31, A36, A41, A49 and B23 against all six fungi were under 10 µg/mL. Compound A49 displayed significant activity against B. cinerea (EC50 = 0.39 µg/mL), which was better than that of commercial fungicide boscalid (EC50 = 0.55 µg/mL). A49 not only inhibited the germination of B. cinerea spores, but also caused abnormal cell morphology, loss of cell membrane integrity, enhanced cell membrane permeability, and accumulation of intracellular reactive oxygen species. Further findings showed that A49 reduced cellular antioxidant activity, and peroxidase and catalase activities. Transcriptomic results indicated that A49 could degrade intracellular redox processes and alter the metabolism of some amino acids. Meanwhile, A49 showed obvious activity in vivo and low cytotoxicity to mammal cells. CONCLUSION: The boron-containing small molecule compounds had high efficiency and broad-spectrum antifungal activities against six plant pathogens, and are expected to be candidate compounds for a new class of antifungal drugs. © 2023 Society of Chemical Industry.

Role of oxygen vacancy in spinel (FeCoNiCrMn)3O4 high entropy oxides prepared via two different methods for the selective CH bond oxidation of p-chlorotoluene.

The selective CH bond oxidation of aromatic hydrocarbon is an interesting but challenging task, it is desirable to develop efficient heterogeneous non-noble metal catalyst for this reaction. Herein, two kinds of spinel (FeCoNiCrMn)3O4 high entropy oxides were fabricated via two different methods (i.e., c-FeCoNiCrMn, prepared by a co-precipitation method, and m-FeCoNiCrMn, prepared by physically mixing method). Different from traditional environmentally-unfriendly Co/Mn/Br system, the prepared catalysts were employed for the selective CH bond oxidation of p-chlorotoluene to p-chlorobenzaldehyde in a green approach. Compared to m-FeCoNiCrMn, c-FeCoNiCrMn have smaller particles size and larger specific surface area, which were related to the enhanced catalytic activity. More importantly, characterization results disclosed that abundant oxygen vacancies were formed over c-FeCoNiCrMn. Such a result facilitated the adsorption of p-chlorotoluene on the catalyst surface and promoted the formation of *ClPhCH2O intermediate as well as the desired p-chlorobenzaldehyde, as revealed by DFT (Density functional theory) calculations. Besides, scavenger tests and EPR (Electron paramagnetic resonance) results indicated that hydroxyl radical derived from H2O2 homolysis was the main active oxidative species for this reaction. This work revealed the role of oxygen vacancy in spinel high entropy oxide and also demonstrated its promising application for the selective CH bond oxidation in an environmentally-benign approach.

Anulamycins A-F, Cinnamoyl-Containing Peptides from a Lake Sediment Derived Streptomyces.

Bioinformatics analysis of a whole genome sequence coupled with HPLC-DAD analysis revealed that Streptomyces sp. Hu103 has the capacity to produce skyllamycin analogues. A subsequent chemical investigation of this strain yielded four new cinnamoyl-containing cyclopeptides, anulamycins A-D (1-4), two new cinnamoyl-containing linear peptides, anulamycins E and F (5 and 6), and two known cyclopeptides, skyllamycins A (7) and B (8). Their structures including absolute configurations were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data and the advanced Marfey's method. Compounds 1-4 exhibited antibacterial activity comparable to those of skyllamycins A and B.

Anti-phytopathogenic activity and the mechanisms of phthalides from Angelica sinensis (Oliv.) Diels.

BACKGROUND: The resistance of traditional chemical fungicides to plant pathogenic fungi and the threats to the safety of humans and the environment highlight an urgent need to find safe and efficient alternatives to chemical fungicides. Owing to the wide spectrum of antifungal activities, low persistence and nontoxicity to mammals and aquatic life, essential oils have considerable potential as low-risk pesticides. In this study, the essential oil and the main components of Angelica sinensis (Oliv.) Diels (Danggui) were extracted, analyzed by GC-MS, and evaluated for their antifungal activities against six plant pathogenic fungi. RESULTS: 3-butylidenephthalide (3-BPH) showed the best antifungal activity against Fusarium graminearum with an EC50 value of 14.35 µg mL-1 . The antifungal mechanistic studies revealed that 3-BPH induced the generation of endogenous ROS to cause lipid peroxidation of the cell membrane and inhibited the biosynthesis of ergosterol, thereby causing the cell membrane damaged to exert its fungicidal activity. Significantly, 3-BPH could reduce deoxynivalenol production compared to the control. CONCLUSION: This study demonstrated the potent fungicidal activity of natural phthalide compound 3-BPH and highlighted its potential as an alternative agent to control F. graminearum. © 2023 Society of Chemical Industry.

Climate Change Influences the Population Density and Suitable Area of Hippotiscus dorsalis (Hemiptera: Pentatomidae) in China.

Hippotiscus dorsalis is the main pest of Phyllostachys edulis in South China. The relationship between climate change and outbreak of H. dorsalis, and the current and future distribution of H. dorsalis are unknown. This study aimed to confirm the effect of climate on population density and the attacked bamboo rate of H. dorsalis, using field survey data from 2005 to 2013 in Huzhou, Zhejiang Province, and to reveal the potential distribution of H. dorsalis under current and future climate conditions using the MaxEnt model. The damage investigation and distribution forecast revealed the following: (1) The mean monthly temperature and maximum temperatures were main factors affecting the population density and the attacked bamboo rate in April in the Anji county of Zhejiang Province; they are all significantly and positively correlated. (2) High suitable area will significantly expand in Anhui and Jiangxi Provinces under the future climate circumstances, and the total suitable area will present a decrease because of the precipitation restriction. The significant expansion of high suitable area in the Anhui and Jiangxi Provinces under future climate circumstances means that the affected provinces will face even greater challenges. These findings provide a theoretical basis for the early forecasting and monitoring of pest outbreaks.

Structural Simplification of Cryptolepine to Obtain Novel Antifungal Quinoline Derivatives against Phytopathogenic Fungi.

A series of quinoline derivatives were designed and synthesized by the structural simplification of cryptolepine and evaluated for their fungicidal activity against six phytopathogenic fungi. Most of these compounds exhibited remarkable activities against Botrytis cinereain vitro. Among them, compounds A18 and L01 showed superior antifungal activity. Significantly, compared to cryptolepine, compound A18 exhibited broad-spectrum inhibitory activities against B. cinerea, Sclerotinia sclerotiorum, Rhizoctonia solani, Phytophthora capsica, Magnaporthe oryzae, and Fusarium graminearum with the respective EC50 values of 0.249, 1.569, 3.915, 0.505, 0.246, and 4.999 µg/mL. Compound L01 displayed the best antifungal activity against B. cinerea with an EC50 value of 0.156 µg/mL. Preliminary mechanistic studies showed that compound A18 could inhibit spore germination, affect the permeability of the cell membrane, increase the content of reactive oxygen species, and affect the morphology of hyphae and cells. Moreover, compound A18 showed excellent in vivo protective effect against B. cinerea, which was more potent than pyrimethanil and equitant to cryptolepine. These results evidenced that compound A18 displayed superior fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.

Confirmation of the absolute configuration of tenvermectin B by single-crystal X-ray diffraction analysis of its furan formate derivative.

Tenvermectins A and B are a kind of 16-membered macrocyclic lactone antibiotics with potent insecticidal property, which have been obtained from two genetically engineered strains Streptomyces avermitilis MHJ1011 and S. avermitilis AVE-H39. Aiming at confirming the absolute configuration of tenvermectin B by X-ray diffraction method, 4″, 5 -di-(2-furoyloxyl) tenvermectin B (1) was prepared and a suitable crystal of 1 was obtained from MeOH. The absolute configuration of 1 was unambiguously established by single-crystal X-ray diffraction analysis. The determination of the stereochemistry of tenvermectin B could promote its chemical and biological studies as agricultural and veterinary agents. In addition, compound 1 displayed weak acaricidal and nematocidal activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus respectively.

A novel spiro-heterocycle milbemycin metabolite from a genetically engineered strain of Streptomyces bingchenggensis.

Milbemycin R, a novel spiro-heterocycle milbemycin, was obtained from the metabolites produced by the mutant strain S. bingchenggensis BCJ60B11. Its structure was determined by spectroscopic and spectrometric analyses including 1 D, 2 D NMR, IR, HR-ESI-MS data. The acaricidal and nematicidal activities of milbemycin R against Tetranychus cinnabarinus and Bursaphelenchus xylophilus were tested. Milbemycin R possessed better acaricidal activity than milbemycins A3/A4.

A new ß-class milbemycin derivative from a mutant of genetically engineered strain Streptomyces avermitilis AVE-H39.

A new ß-class milbemycin, 13α-hydroxy milbemycin ß6 (1), was isolated from the fermentation broth of a mutant of genetically engineered strain Streptomyces avermitilis AVE-H39. Its structure and absolute configuration were elucidated by extensive spectroscopic methods and confirmed by single crystal X-ray diffraction.

Semisynthesis and Pesticidal Activities of Novel Cholesterol Ester Derivatives Containing Cinnamic Acid-like Fragments.

Due to the extensive use of agrochemicals resulting in the emergence of pesticide resistance and ecological environment problems, the research and development of new alternatives for crop protection is highly desirable. In order to discover potent natural product-based insecticide candidates, a series of new cholesterol ester derivatives containing cinnamic acid-like fragments at the C-7 position were synthesized. Some derivatives showed potent pesticidal activities. Against Mythimna separata Walker, compounds 2a, Id, Ig, and IIg showed 2.1-2.4-fold growth-inhibitory activity of the precursor cholesterol. Against Plutella xylostella Linnaeus, compounds Ig, IIf, and IIi exhibited 1.9-2.1-fold insecticidal activity of cholesterol. These results will pave the way for the future synthesis of cholesterol-based derivatives as agrochemicals.