RESUMEN
To explore active natural products against tobacco powdery mildew caused by Golovinomyces cichoracearum, an extract from the fermentation of endophytic Aspergillus fumigatus 0338 was investigated. The mechanisms of action for active compounds were also studied in detail. As a result, 14 indole alkaloid derivatives were isolated, with seven being newly discovered (1-7) and the remaining seven previously described (8-14). Notably, compounds 1-3 are rare linearly fused 6/6/5 tricyclic prenylated indole alkaloids, with asperversiamide J being the only known natural product of this kind. The isopentenyl substitutions at the 5-position in compounds 4 and 5 are also rare, with only compounds 1-(5-prenyl-1H-indol-3-yl)-propan-2-one (8) and 1-(6-methoxy-5-prenyl-1H-indol3-yl)-propan-2-one currently available. In addition, compounds 6 and 7 are new framework indole alkaloid derivatives bearing a 6-methyl-1,7-dihydro-2H-azepin-2-one ring. The purified compounds were evaluated for their activity against G. cichoracearum, and the results revealed that compounds 7 and 9 demonstrated obvious anti-G. cichoracearum activities with an inhibition rate of 82.6% and 85.2%, respectively, at a concentration of 250 µg/mL, these rates were better than that of the positive control agent, carbendazim (78.6%). The protective and curative effects of compounds 7 and 9 were also better than that of positive control, at the same concentration. Moreover, the mechanistic study showed that treatment with compound 9 significantly increased the structural tightness of tobacco leaves and directly affect the conidiospores of G. cichoracearum, thereby enhancing resistance. Compounds 7 and 9 could also induce systemic acquired resistance (SAR), directly regulating the expression of defense enzymes, defense genes, and plant semaphorins, which may further contribute to increased plant resistance. Based on the activity experiments and molecular dockings, the indole core structure may be the foundation of these compounds' anti-G. cichoracearum activity. Among them, the indole derivative parent structures of compounds 6, 7, and 9 exhibit strong effects. Moreover, the methoxy substitution in compound 7 can enhance their activity. By isolating and structurally identifying the above indole alkaloids, new candidates for anti-powdery mildew chemical screening were discovered, which could enhance the utilization of N. tabacum-derived fungi in pesticide development.
Asunto(s)
Alcaloides , Aspergillus fumigatus , Neopreno , Nicotiana , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/química , Alcaloides/farmacologíaRESUMEN
In this study, seven novel anthraquinones (1-7) and four described anthraquinones (8-11) were purified from Nicotiana tabacum-derived Aspergillus oryzae YNCA1220. It is worth noting that only analogs of 4 and 5 have been reported as natural products to date, while the nuclei of compounds 1-3, 6 and 7 were isolated for the first time in nature. Among them, compounds 1-3 bear an unusual anthra[2,3-b]furan-9,10-dione nucleus, 4 and 5 possess a rare 3-methyl-1H-pyrrol-2-yl substituent, and 6 and 7 are new framework anthraquinones bearing a 6-methyl-1,7-dihydro-2H-azepin-2-one ring. Interestingly, the in vivo assays indicated that 1, 4 and 5 had inactivation effects against tobacco mosaic virus (TMV) with inhibition rates of 41.6%, 55.4% and 38.6%, respectively, at a concentration of 50 µg/mL, which were better than that of the positive control agent, ningnanmycin (33.8%). Compounds 1, 4 and 5 also had protective effects with inhibition rates of 48.7%, 60.2% and 43.5% at the same concentration, while 4 had a better curative effect than ningnanmycin at a concentration of 100 µg/mL. In addition, mechanistic studies also revealed that a potent direct effect on TMV, the induction of SAR in tobacco plants, and the effective regulation of defense enzymes, defense genes, and defense hormones may be the reasons for the significant effects of 4 against TMV. At the same time, downregulation of the expression of total NtHsp70 protein by inhibiting the related Hsp70 genes may also be involved in tobacco resistance to TMV. To evaluate whether compounds have broader antiviral activities, the antirotavirus activities of new isolates were also evaluated and found to be highly effective with a therapeutic index (TI) value ranging from 11.6 to 17.7. This study suggests that the above anthraquinone compounds, particularly 4, have broad spectrum antiviral activities. The successful isolation and structure identification of the above anthraquinones provide new materials for the screening of anti-TMV agents and contribute to the improved utilization of N. tabacum-derived fungi.
Asunto(s)
Aspergillus oryzae , Virus del Mosaico del Tabaco , Nicotiana , Antraquinonas/farmacología , Bioensayo , Antivirales/farmacologíaRESUMEN
There is growing evidence that bioactive substances produced by microbial endophytes have applicability in medicine, agriculture and industry. To enrich the bioactive substances, in our search for new bioactive metabolites from fungi Aspergillus, the phytochemical reinvestigation on the Aspergillus sp. 0338 was carried out, and this led to the isolation of three new (1-3) and five known alkaloids (4-8). Their structures were elucidated by spectroscopic analysis, including extensive 1D and 2D NMR techniques, as well as comparison with literature values. Additionally, compounds 1-3 were evaluated for their anti-MRSA activities. The results revealed that compounds 1-3 exhibited good inhibitions with IZD of 15.2 ± 1.8, 14.6 ± 2.0, and 13.4 ± 2.2 mm, respectively.
RESUMEN
BACKGROUND: Natural products are important sources of biopesticides to control plant virus, and flavonoids are identified as promising anti-tobacco mosaic virus (TMV) agents. Since Desmodium caudatum is a rich source of flavonoids, this study focuses on the discovery of the new anti-TMV active flavonoids from D. caudatum and their possible mode of action. RESULTS: Three new (compounds 1-3) and nine known (compounds 4-12) C-alkylated flavonoids were isolated from D. caudatum. To the best of our knowledge, the framework of 1-3 was reported in natural products for the first time. In addition, 1-3, 5, and 6 showed notable anti-TMV activity with inhibition rates in the range of 35.8-64.3% at a concentration of 50 µg/mL, and these rates are higher than that of positive control (with inhibition rates of 34.6% ± 2.8). In addition, the structure-activity relationship study revealed that the (pyrrol-2-yl)methyl moiety on flavone can significantly increases the activity. This result is helpful to find new anti-TMV inhibitors. CONCLUSION: C-Alkylated flavonoids showed potent activities against TMV with multiple modes of actions. The increase of defense-related enzyme activities, up-regulate the expression of defense related genes, down-regulate the expression of Hsp70 protein by inhibiting the related Hsp genes that are involved in tobacco resistance to TMV. By the actions mentioned earlier, the infection of TMV was influenced, thereby achieving the effects of control of TMV. The successful isolation of the earlier-mentioned flavonoids provide the new source of biopesticides to TMV proliferation, and also contribute to the utilization of D. caudatum. © 2023 Society of Chemical Industry.
Asunto(s)
Flavonoides , Virus del Mosaico del Tabaco , Flavonoides/farmacología , Agentes de Control Biológico/farmacología , Relación Estructura-Actividad , Nicotiana , Antivirales/farmacologíaRESUMEN
Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical ß-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi.
Asunto(s)
Policétidos , Sintasas Poliquetidas/metabolismo , Aldehídos , CatálisisRESUMEN
Nicotiana tabacum (tobacco) has attracted interest as one of the most economically important industrial crops widely cultivated in China, whose dried leaves are popularly consumed medicinally and recreationally by human societies. In this study, five undescribed alkaloids derivatives, isoaspergillines A-E, together with eight known alkaloids, notoamide D, (1R,4S)-4-benzyl-1-isopropyl-2,4-dihydro-1H-pyrazino-[2,1-b]quinazoline-3,6-dione, protuboxepin K, notoamide C, notoamide M, deoxybrevianamide E, cyclo (D-Pro-L-Trp), and versicolamide B, were obtained from the culture of the Nicotiana tabacum-derived fungus Aspergillus versicolor. Their structures were mainly elucidated through comprehensive analyses of spectroscopic data. Bioactivity evaluation of all isolated compounds revealed that isoaspergilline A and notoamide M exhibited anti-TMV activities with IC50 values of 20.0 and 22.8 µM, respectively. Molecular docking suggested that isoaspergilline A and notoamide M were well located into the active site of anti-TMV by interacting with SER138, SER143, and ASN73 residues. This study enlightens the therapeutic potential of the endophytic fungus A. versicolor and it is helpful to find undescribed anti-TMV activity inhibitors, as well as searching for new anti-TMV candidates from natural sources.
Asunto(s)
Nicotiana , Humanos , Simulación del Acoplamiento Molecular , ChinaRESUMEN
Three new isochromenes, (5-methoxy-7-prenyl-1H-isochromen-3-yl)methanol (1), 3-(3-(hydroxymethyl)-5-methoxy-1H-isochromen-7-yl)propan-1-ol (2), and (5-methoxy-7-methyl-1H-isochromen-3-yl)methanol (3), along with three known analogues (4-6) were isolated from the fermentation products of a Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor. Their structures were elucidated by spectroscopic methods, including extensive 1 D and 2 D NMR techniques. Compounds 1-3 and 6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 46.4%, and this rate is higher than that of positive control. Compounds 1, 3, and 6 also showed potential anti-TMV activity with inhibition rates of 28.6, 30.5, and 26.2%, respectively. The IC50 of compounds 1-3 and 6 were also tested, and showed IC50 values of 49.3, 22.4, 42.2, and 54.1 µM, respectively.
Asunto(s)
Nicotiana , Virus del Mosaico del Tabaco , Nicotiana/química , Metanol , Antivirales/química , Estructura Molecular , AspergillusRESUMEN
In previous studies, several isoindolin-1-one analogs that exhibited significant anti-tobacco mosaic virus (anti-TMV) activities were isolated from Nicotiana tabacum. Since gene-editing mutants provide a new sample for the discovery of active metabolites, we focused on the stems of YN-18-23 (a mutant N. tabacum for gene editing with the alkaloid metabolic pathway cultivated by Yunnan Tobacco Company), which led to the isolation of four new (1-4) and four known (5-8) isoindolin-1-ones. To the best of our knowledge, nicindole C (3) is the first subclass of isoindolin-1-one bearing a pentacyclic ketone, while nicindole D (4) is the first example of isoindolin-1-one bearing a methyl-pyridin-2-(1H)-one moiety. Compounds 1-4 were tested for their anti-TMV activities, and the results revealed that compounds 1, 3, and 4 exhibited high anti-TMV activities at concentrations of 20 µM with inhibition rates of 48.6, 42.8, and 71.5%, respectively. These rates are higher than the inhibition rate of the positive control (33.2%). The mechanistic study of compound 4, which had the highest anti-TMV activity revealed that increased potentiation of defense-related enzyme activities and downregulation of expression of the NtHsp70 protein may induce resistance in tobacco against the viral pathogen TMV. Molecular docking studies also revealed that the isoindolin-1-one substructure is fundamental for anti-TMV activity. The methyl-pyridin-2-(1H)-one moiety in compound 4 and the 2-oxopropyl groups in compounds 1 and 3 at the N-2 position may increase inhibitory activities. This study of the structure-activity relationship is helpful for finding new anti-TMV activity inhibitors. To study whether the isoindolin-1-ones have broader antiviral activities, compounds 1-4 were also tested for their anti-rotavirus activities. Compound 4 exhibited high anti-rotavirus activity with a therapeutic index (TI) value of 20.7. This TI value is close to that of the positive control (20.2).
Asunto(s)
Nicotiana , Virus del Mosaico del Tabaco , Antivirales/química , China , Simulación del Acoplamiento Molecular , Nicotiana/química , Nicotiana/metabolismo , Virus del Mosaico del Tabaco/metabolismoRESUMEN
Indole alkaloids have attracted widespread attention of chemists and biologists. Therefore, the aim of this study is to screen more bioactivities indole alkaloids from the microorganisms. In this study, five undescribed CPA-type indole alkaloids, aspergillines F-J, and three known CPA-type indole alkaloids, aspergilline A, aspergilline C, and cyclopiamide E, were obtained from the Nicotiana tabacum-derived fungus Aspergillus versicolor. Notably, aspergillines F and G represent the first examples of indole alkaloids with a benzo[cd]indol-2(1H)-one skeleton, and aspergilline J is also the firstly obtained indole alkaloids bearing a N-1-(2-(1H-imidazole-5-yl)ethyl) moiety. Aspergillines F-J and cyclopiamide E were tested for their anti-TMV activities, and the results revealed that aspergillines G and J exhibited obvious anti-TMV activities with inhibition rates of 41.2 and 56.8% at the concentration of 20 µM, respectively. These rates are high than that of positive control (with inhibition rate of 32.5%). In addition, the molecular docking studies for the isolated CPA-type indole alkaloids may also reveal that the benzo[cd]indol-2(1H)-one substructure is the fundamental for anti-TMV activity and the oxygen-containing substituent groups at C-19 also increases the inhibitory activity. This study of structure-activity relationship is helpful to find new anti-TMV activity inhibitors.
Asunto(s)
Virus del Mosaico del Tabaco , Aspergillus , Hongos , Alcaloides Indólicos/farmacología , Indoles , Simulación del Acoplamiento Molecular , Estructura Molecular , Nicotiana/químicaRESUMEN
Two new sesquiterpene aryl esters, armimelleolides A and B (1 and 2), and four known ones, were isolated from the EtOAc extract of Armillaria gallica 012 m by column chromatography on silica gel, reversed-phase C18 silica gel and semi-preparative HPLC. Their structures were elucidated on the basis of spectroscopic methods, including extensive 1 D NMR, 2 D NMR and MS. All these compounds showed potential antitumor activities against at least one of the human cancer cell lines (A549, HCT-116, M231 and W256), with IC50 ranging from 2.57 to 19.94 µM.
Asunto(s)
Armillaria , Sesquiterpenos , Ésteres , Estructura Molecular , Sesquiterpenos/farmacologíaRESUMEN
A new isoquinoline alkaloid(1) has been isolated from the whole plant of Thalictrum glandulosissimum by using various chromatographic techniques, including silica gel, sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 1-(6-hydroxy-7-methylisoquinolin-1-yl) ethantone by physicochemical properties and spectroscopic data. This compound was evaluated for anti-tobacco mosaic virus(TMV) activity. The results showed that it had prominent anti-TMV activity with inhibition rates of 28.4%. This rate was closed to that of positive control.
Asunto(s)
Alcaloides , Antivirales , Thalictrum , Virus del Mosaico del Tabaco , IsoquinolinasRESUMEN
Gregatin A (1) is a fungal polyketide featuring an alkylated furanone core, but the biosynthetic mechanism to furnish the intriguing molecular skeleton has yet to be elucidated. Herein, we have identified the biosynthetic gene cluster of gregatin A (1) in Penicillium sp. sh18 and investigated the mechanism that produces the intriguing structure of 1 by in vivo and in vitro reconstitution of its biosynthesis. Our study established the biosynthetic route leading to 1 and illuminated that 1 is generated by the fusion of two different polyketide chains, which are, amazingly, synthesized by a single polyketide synthase GrgA with the aid of a trans-acting enoylreductase GrgB. Chain fusion, as well as chain hydrolysis, is catalyzed by an α/ß hydrolase, GrgF, hybridizing the C11 and C4 carbon chains by Claisen condensation. Finally, structural analysis and mutational experiments using GrgF provided insight into how the enzyme facilitates the unusual chain-fusing reaction. In unraveling a new biosynthetic strategy involving a bifunctional PKS and a polyketide fusing enzyme, our study expands our knowledge concerning fungal polyketide biosynthesis.
Asunto(s)
Policétidos/metabolismo , Estructura Molecular , Sintasas Poliquetidas/química , Sintasas Poliquetidas/metabolismo , Policétidos/química , EstereoisomerismoRESUMEN
A new isobenzoisofuran(1) has been isolated from the whole plant of Cassia pumila using various chromatographic techniques, including silica gel, Sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 9-(2-hydroxyethyl)-2,2-dimethyl-2H-furo[3,4-g]chromen-6(8H)-one. This compound was also evaluated for its antibacterial activity. The results showed that it had prominent antibacterial activity with MIC_(90) value of(45.2±4.2) µg·mL~(-1) for methicillin resistant Staphylococcus aureus(MRSA) strain. This value was closed to that of levofloxacin [with MIC_(90) value(48.5±4.3) µg·mL~(-1)].
Asunto(s)
Antibacterianos/farmacología , Benzofuranos/farmacología , Cassia/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/aislamiento & purificación , Benzofuranos/aislamiento & purificación , Levofloxacino , Pruebas de Sensibilidad Microbiana , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Plantas Medicinales/químicaRESUMEN
A new flavone( 1) has been isolated from the whole plant of Cassia nomame by using various chromatographic techniques,including silica gel,Sephadex,MCI-gel resin,and RP-HPLC,and its structure was determined as 8,4'-dimethoxy-7-( 2-oxopropyl)-flavone based on spectroscopic data. The biological activity test showed that this compound displayed potent cytotoxicity against NB4,SH-SY5 Y,PC3,A549 and MCF-7 cell lines with IC50 values 2. 2,1. 8,3. 4,4. 5 and 1. 6 µmol·L-1,respectively.
Asunto(s)
Cassia , Flavonas , Senna , Cromatografía Líquida de Alta Presión , Humanos , Células MCF-7RESUMEN
Three new diphenyl ethers (1-3), together with four known isopentylated diphenyl ethers derivatives (4-7), were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results revealed that compounds 1 and 2 showed strong inhibitions with inhibition zone diameters (IZD) of 20.2 ± 2.5 mm and 17.9 ± 2.2 mm, respectively. Compound 3 also showed good inhibition with IZD 15.2 ± 1.8 mm. The IZD data of compound 1 is close to that of positive control with IZD 21.9 ± 2.1 mm.
Asunto(s)
Ascomicetos/metabolismo , Endófitos/metabolismo , Fermentación , Éteres Fenílicos/aislamiento & purificación , Éteres Fenílicos/química , Éteres Fenílicos/farmacologíaRESUMEN
A new naphthaldehyde derivative has been isolated from Comastoma pulmonarium by using various chromatographic techniques, including silica gel, Sephadex LH-20, MCI-gel resin and RP-HPLC. This compounds was determined as 5-methoxy-2-methyl-7-(2-oxopropyl)naphthalene-1-carbaldehyde(1) by NMR, MS, IR and UV spectra. This compound was also evaluated for its anti-tobacco mosaic virus (anti-TMV) activity. The result showed that it showed high anti-TMV activity with inhibition rate of 32.8%. The inhibition rate is close to that of positive control (ningnanmycin).
Asunto(s)
Aldehídos/farmacología , Antivirales/farmacología , Gentianaceae/química , Naftalenos/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Aldehídos/aislamiento & purificación , Antivirales/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Naftalenos/aislamiento & purificación , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , NicotianaRESUMEN
A new isobenzofuranone derivative has been isolated from Phlomis betonicoides by using various chromatographic techniques, including silica gel, Sephadex LH-20, MCI-gel resin and RP-HPLC. This compound was determined as 5-(3-hydroxypropyl)-2,2-dimethyl-2H-furo[3,4-h]chromen-7(9H)-one (1) by NMR, MS, IR and UV spectroscopic data. Compound 1 showed potent antibacterial activity with an MIC90 value of (58.4 ± 4.2) mg·L⻹ for methicillin resistant Staphylococcus aureus (MRSA) strain [levofloxacin as a control with MIC90 value of (52.8±4.6) mg·L⻹].
Asunto(s)
Antibacterianos/farmacología , Benzofuranos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Phlomis/química , Antibacterianos/aislamiento & purificación , Benzofuranos/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacologíaRESUMEN
A new isoflavone derivative was isolated from Rosa damascena by using various chromatographic techniques including silica gel, Sephadex LH-20, and preparative RP-HPLC separation. Its structure was identified as 4'-hydroxy-7-(3-hydroxypropanoyl)-6-methoxy-isoflavone using combined examinations of their UV, IR, MS, and NMR spectroscopic data. Biological activity test showed that this compound showed prominent antibacterial activity with MIC90 value of (46±4) mg·L⻹ for methicillin resistant Staphylococcus aureus(MRSA) strain. This value is close to that of levofloxacin [with MIC90 value (53±5) mg·L⻹].
Asunto(s)
Antibacterianos/farmacología , Isoflavonas/farmacología , Rosa/química , Antibacterianos/aislamiento & purificación , Isoflavonas/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacologíaRESUMEN
Three new isopentylated diphenyl ethers, (1-3), together with two known isopentylated diphenyl ethers derivatives (4 and 5) were isolated from the fermentation products of an endophytic fungus Phomopsis fukushii. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Compounds 1-3 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results showed that compounds 1-3 showed strong activity with diameter of inhibition zone (IZD) of 21.8 ± 2.4 mm, 16.8 ± 2.2 mm, and 15.6 ± 2.0 mm, respectively.
Asunto(s)
Antibacterianos/farmacología , Ascomicetos/química , Compuestos de Bifenilo/farmacología , Antibacterianos/biosíntesis , Antibacterianos/aislamiento & purificación , Compuestos de Bifenilo/aislamiento & purificación , Fermentación , Espectroscopía de Resonancia Magnética , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría UltravioletaRESUMEN
A new naphthalene derivative has been isolated from Aloe vera by using various chromatographic techniques, including silica gel, sephadex, MCI-gel resin, and RP-HPLC. The new compound was determined as 3-hydroxy-1-(1,7-dihydroxy-3,6-dimethoxynaphthalen-2-yl)propan-1-one (1). In the biological activity assay, compound 1 disglayed prominent antibacterial activity with a MIC90 value of (48±4) mgâ¢L⻹ for methicillin resistant Staphylococcus aureus (MRSA) strain which was stronger than that of the positive control levofloxacin with a MIC90 value (58±5) mgâ¢L⻹.