In vivo and in vitro antifungal activities of five alkaloid compounds isolated from Picrasma quassioides (D. Don) Benn against plant pathogenic fungi.

Highly active and novel antifungal compounds are continuously researched from natural products for pesticide development. Picrasma quassioides (D. Don) Benn, a species of Simaroubaceae, is used in traditional Chinese medicine to treat colds and upper respiratory infections. In this study, the active ingredients of P. quassioides and their antifungal activities against plant pathogenic fungi are investigated to explore the practical application of the plant in the agricultural field. The results showed that the extracts of P. quassioides exhibited highly significant preventive and curative effects on apple valsa canker (AVC) with a reduction of lesion diameter were 80.28% and 83.63%, respectively, and can improve the resistance of apple trees to a pathogen. Five antifungal compounds, namely, canthin-6-one (T1), nigakinone (T2), 4,5-dimethoxycanthin-6-one (T3), 1-methoxycarbonyl-ß-carboline (T4), and 1-methoxycarbonyl-3-methoxyl-ß-carboline (T5), are isolated from P. quassioides using the bioassay-guided method. This is the first report of 1-methoxycarbonyl-3-methoxyl-ß-carboline as a natural product. Canthin-6-one shows strong in vitro inhibitory activity against 11 species of plant pathogenic fungi, and their EC50 values range from 1.49 to 8.80 mg/L. The control efficacy of canthin-6-one at 2000 mg/L are 87.88% and 94.37% against AVC and 80.10% and 84.73% against apple anthracnose (C. gloeosporioides), respectively. Additionally, V. mali is observed after treatment with cannin-6-one, although microscopic. This is the first study on the control of the secondary metabolites of P. quassioides against plant fungal diseases. The results show that P. quassioides is a potential resource for the development of botanical fungicides.

Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases.

p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.

Investigation on the Antifungal Ingredients of Saccharothrix Yanglingensis Hhs.015, an Antagonistic Endophytic Actinomycete Isolated from Cucumber Plant.

Abstract: Apple tree canker infected by Valsa mali var. mali is a serious and widely distributed disease in China. Saccharothrix yanglingensis Hhs.015 is an endophytic actinomycete isolated from cucumber roots, and it has been proven that this strain is a promising biocontrol agent on apple tree canker in previous studies. The aim of this study was to elucidate the active ingredients in its metabolites. Two pentaene macrolides, WH01 and WH02, were isolated from strain Hhs.015, and their structures were elucidated based on the extensive spectroscopic analysis. WH01 and WH02 were identified as fungichromin and 1'-deoxyfungichromin, among which WH02 is a novel compound. These two compounds showed strong in vitro and in vivo antifungal activity against V. mali. By comparison of the structures of hyphae cells treated by pure compound and fermentation broth, it has been proven that pentaene macrolides are the main active ingredients in the metabolites of strain Hhs.015. This is the first report on the antifungal activity of fungichromin and its analogs on V. mali, and the 28-member pentaene macrolides were also firstly isolated from the genus of Saccharothrix.

SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

Synthesis, antifungal and antitumor activity of two new types of imidazolin-2-ones.

Thirty-six imidazolin-2-ones, including ten pairs of benzimidazolones and sixteen imidazopyridines, were synthesized and subjected for the evaluation of antifungal and antitumor activity. Compounds 4a-01, 6-01, 6-04 and 6-06 could effectively inhibit the spore germination and mycelium growth of Botrytis cinerea. The relationship between structure and antifungal activity revealed that the introducing short-chain aliphatic acyl groups at the moiety of imidazopyridines is favorable for the antifungal activity, whereas aromatic acyl groups are much better than aliphatic acyl groups for the activity of benzimidazolones except for acetyl. Preliminary SRB assay indicated that 6-01 exerted strong antiproliferative effect against Hela and NCM460 cell lines. Further kinases assay revealed that 6-01 could specially inhibit mTOR among 114 human cancer related kinases. Elisa and Western blot analysis testified that 6-01 simultaneously inhibits the phosphorylation of Akt and 4E-BP1, and 6-01 is a novel mTOR inhibitor which targets on both mTORC1 and mTORC2. This investigation provided a valuable chemical structure for the development of antitumor drugs.

Synthesis and herbicidal activities of benzothiazole N,O-acetals.

A new series of N,O-acetals were prepared via a simple one-pot reaction by the condensation of 2-amino-methybenzothiazole with aldehydes and alcohols. The title compounds were obtained in moderate to good yields in the presence of acid catalyst. Bioassay results indicated that some synthesized compounds had good herbicidal activity against both dicotyledon and monocotyledon weeds. This investigation provided a new type of herbicidal lead compounds, as well as its facile preparation method.

Structure and Antibacterial Activity of Ambobactin, a New Telomycin-Like Cyclic Depsipeptide Antibiotic Produced by Streptomyces ambofaciens F3.

A new telomycin-like cyclic depsipeptide, ambobactin (1), was isolated from the metabolites of Streptomyces ambofaciens F3, an endophyte of Platycladus orientalis. Its structure was elucidated on the basis of extensive spectroscopic analysis and advanced Marfey's method. Ambobactin is structurally related with telomycin, except that the configuration of the 3-methyltryptophanes in their structures is different. It exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria. Furthermore, this investigation revealed that S. ambofaciens F3 is a new producer of telomycin-like antibiotics.

[Identification of a kojic-acid producing Aspergillus flavus F52].

OBJECTIVE: We identified an endophytic fungus of Vigna unguiculata, as well as the influence of carbon sources on the production of kojic acid by the isolated fungus. METHODS: This kojic acid producer was identified as Aspergillus flavus F52 according to morphological characteristics and ITS region of rDNA. The metabolite of strain F52 was obtained by recrystallization, and identified as kojic acid based on the spectral data of NMR, HR-ESI/MS and IR. The fungus was cultivated in medium containing various carbon sources, and the production of kojic acid in the fermentation broth was quantified by high performance liquid chromatography. RESULTS: The complex carbon source which was composed of glucose and sucrose was preferential, whereas the presence of lactose was not beneficial to the production of kojic acid. The content of kojic acid in the fermentation broth reached 24.44 g/L. CONCLUSION: Aspergillus flavus F52 might be a potent producer of kojic acid for commercial use.

Synthesis and herbicidal activities of 2-((3-pyridinyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)oxy)propionates.

BACKGROUND: The discovery of lead compounds is fundamental to herbicide innovation, yet the limited availability of valuable lead compounds has impeded their progress in recent years. The study presents a novel molecular scaffold that exhibits remarkably potent herbicidal activity. RESULTS: Through a scaffold-hopping strategy, a highly potent lead compound for herbicides, namely 3-(2-pyridinyl)-benzothiazol-2-one, was unexpectedly discovered during attempts to structurally modify haloxyfop, a commercial aryl-oxy-phenoxy-propionate herbicide. To investigate the structure-activity relationship (SAR) of the newly discovered herbicidal chemicals, a series of 2-(2-oxo-3-(pyridin-2-yl)-2,3-dihydrobenzo[d]thiazol-6-yloxy)propanoic acid derivatives, I-01 ~ I-27, were designed and synthesized. SAR analysis revealed that trifluoromethyl at the 5-position of pyridine is crucial for herbicidal activity, whereas additional fluorine or Cl atom at the 3-position of pyridine significantly enhances activity. Carboxylic ester derivatives exhibit superior herbicidal activity compared with amide derivatives. Moreover, the activity of carboxylic ester derivatives decreases with C chain extension, but the introduction of O atoms in the side chain benefits activity enhancement. Pot experiments conducted in a glasshouse demonstrated that I-01 and I-09 exhibited potent postemergence herbicidal activity against broadleaf weeds, and completely inhibited growth of Amaranthus retroflex, Abutilon theophrasti and Portulaca oleracea at a dosage of 75 g ha-1. CONCLUSION: Despite the initial goal of scaffold-hopping not being achieved, we have successfully identified a novel molecular scaffold exhibiting exceptional herbicidal activity, thereby presenting innovative prospects for herbicide development. © 2024 Society of Chemical Industry.

Synthesis and Herbicidal Activity of 2-(2-Oxo-3-pyridyl-benzothiazol-6-yloxy)hexanoic Acids.

The discovery of a lead compound is fundamental to herbicide innovation, but the limited availability of valuable lead compounds has hindered their development in recent years. By utilizing the structural diversity-oriented inactive group strategy, 3-(2-pyridyl)-benzothiazol-2-one was identified as a promising lead scaffold for herbicides, starting from benzothiazole which is an inactive moiety commonly found in herbicides such as mefenacet, benazolin, benzthiazuron, and fenthiaprop-ethyl. To investigate the structure-activity relationship (SAR) of these chemicals, a series of 2-(2-oxo-3-pyridyl-benzothiazol-6-yloxy)hexanoic acid derivatives (VI01 ∼ VI28) were synthesized through classical nucleophilic SNAr reaction using halogenated pyridines and 6-methoxybenzothiazole-2-one. The chemical structures of all the title compounds were confirmed by NMR and MS analysis. Petri dish assays indicated that many compounds exhibited potent herbicidal activity against both broad-leaf weeds and grass weeds at 1.0 mg/L. The SAR analysis revealed that the presence of a trifluoromethyl group at the 5-position of pyridine is essential for herbicidal activity. Furthermore, carboxylic esters exhibit higher herbicidal activity compared to carboxylic amides and free acids, and the activity decreased with the extension of the carbon chain. The postemergence herbicidal activity of VI03 against 16 species of weeds was tested by pot experiments in a greenhouse. VI03 demonstrated comparable efficacy in controlling broadleaf weeds and superior efficacy in controlling grass weeds compared to carfentrazone ethyl. The present study has unveiled a novel molecular scaffold exhibiting remarkably potent herbicidal activity. These findings are anticipated to provide valuable insights for the advancement of new herbicides and offer an alternative approach for managing resistant weeds.

Discovery of N-benzyl-6-methylpicolinamide as a potential scaffold for bleaching herbicides.

BACKGROUND: In pesticide research, bleaching herbicides have always been a hot topic. Our previous research showed that N-(4-fluorobenzyl)-2-methoxybenzamide is an innovative lead compound for bleaching herbicides. RESULTS: A total of 40 derivatives of picolinamides were prepared and evaluated for their herbicidal activity by Petri dish tests and postemergence trials. The structure-activity relationship (SAR) revealed that introducing electron-withdrawing groups at the 3- or 4-positions of the benzyl significantly enhances herbicidal activity. Furthermore, ZI-04 induced similar symptoms such as bleaching effect in treated weeds and accumulation of biosynthetic precursors for carotenoids as observed with diflufenican. ZI-04 also exhibited significant cross-resistance to diflufenican and had a lower resistance risk than diflufenican. CONCLUSION: N-benzyl-6-methylpicolinamides were discovered as a novel scaffold for bleaching herbicides. The accumulation of phytoene, phytofluene and ζ-Carotene in radish cotyledons, and cross-resistance observed with diflufenican, showed that title compounds can interfere with carotenoid biosynthesis. © 2024 Society of Chemical Industry.

Synthesis of 1-isopropyl-3-acyl-5-methyl-benzimidazolone derivatives and their antimicrobial activity.

A series of N-acylated analogues of 1-isopropyl-3-acyl-5-methyl-benzimidazolone were synthesized. Bioassay results indicated that analogues 5-07 and 5-19 exhibited the most potency against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Analogues 5-02, 5-07, 5-12, 5-15, 5-19, 5-20 and 5-25 could effectively inhibit the spore germination of Botrytis cinerea. The relationship between structure and their antimicrobial activity (SAR) has also been discussed according to aliphatic acids and aromatic acids derivatives, respectively. This implied that the N-acylated derivatives of 5-methyl-benzimidazolone might be potential antimicrobial agents.

[Treatment of premature ovarian failure patients of Shen Yang deficiency syndrome by warming Shen, enhancing Yang, invigorating qi, and nourishing blood method combined artificial cycle therapy: a clinical observation].

OBJECTIVE: To observe the clinical efficacy of warming Shen, enhancing Yang, invigorating qi, and nourishing blood method (WSEYIQNBM) combined artificial cycle therapy in treatment of premature ovarian failure (POF) patients of Shen yang deficiency syndrome (SYDS). METHODS: Totally 96 POF patients of SYDS were randomly assigned to the treatment group and the control group, 48 in each group. Patients in the treatment group were treated with WSEYIQNBM combined artificial cycle therapy, while those in the control group were treated with Western medicine artificial cycle therapy. One month constituted 1 course, a total of 3 courses. The menstruation and main symptoms were observed before and after treatment. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were detected before and after treatment. RESULTS: The total effective rate was 85.43% in the treatment group, higher than that of the control group (79.17%, P < 0.05). Besides, better effect in improving Chinese medical symptoms was obtained in the treatment group (P < 0.05). CONCLUSION: POF patients' serum hormone levels and clinical symptoms could be improved by WSEYIQNBM combined artificial cycle therapy.

N-benzyl-2-methoxy-5-propargyloxybenzoamides, a new type of bleaching herbicides targeting the biosynthesis pathway of plastoquinone.

BACKGROUND: Previously, the herbicidal activity of N-benzyl-2-methoxybenzamides was discovered during a random screening program in our laboratory. The chemicals resulted in bleaching effect of newly grown leaves by interfering with the biosynthesis of ß-carotene in plant. RESULTS: A total of 28 benzamides were synthesized and subjected for the evaluation of herbicidal activity. Structure-activity relationship (SAR) showed that introducing propargyloxy group at 5-position of benzoyl-benzene ring and fluorine or methyl group at 3- or 4-position of benzyl-benzene ring is beneficial for the activity. Post-emergence herbicidal activities of compounds 406 and 412 were comparable to those of mesotrione and diflufenican. Studies on MOA showed that 406 decreased the level of both ß-carotene and plastoquinone (PQ) in treated plants. The bleaching effect in green alga caused by 406 could be reversed by supplying exogenous homogentisic acid (HGA), the precursor of plastoquinone. CONCLUSION: N-benzyl-2-methoxy-5-propargyloxybenzoamides were discovered as new candidates for bleaching herbicides. Preliminary investigation on mechanism of action (MOA) showed that the title compounds might indirectly interfere with carotenoid biosynthesis by blocking the production of PQ. © 2023 Society of Chemical Industry.

Two piperazic acid-containing cyclic hexapeptides from Streptomyces alboflavus 313.

Two novel cyclic hexapeptides, designated NW-G10 (1) and NW-G11 (2), were isolated from the fermentation broth of Streptomyces alboflavus 313. Their relative structures were elucidated on the basis of extensive spectroscopic analysis, and the absolute configurations of several constituent amino acids were determined by Marfey's method. NW-G10 (1) and NW-G11 (2) exhibited significant activity against Gram-positive bacteria, such as Bacillus cereus, Bacillus subtilis and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), but they are not active against gram negatives.

Exploration of diverse hinge-binding scaffolds for selective Aurora kinase inhibitors.

Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.

Isolation and characterization of two novel antibacterial cyclic hexapeptides from Streptomyces alboflavus 313.

Two novel cyclic hexapeptides, designated NW-G08 (1) and NW-G09 (2), were isolated from the fermentation broth of Streptomyces alboflavus 313. Their structures were elucidated on the basis of extensive spectroscopic analysis, MS experiments, and chemical analysis. Their antibacterial activities against several strains of bacteria were evaluated by micro-broth dilution method. NW-G08 (1) and NW-G09 (2) were highly antibacterial against Gram-positive but not active against Gram-negative bactaria. The minimum inhibitory concentrations (MICs) of 1 against Bacillus cereus, Bacillus subtilis, and Staphylococcus aureus were 6.25, 6.25, and 1.56 µg/ml, respectively. It is worth noting that 1 and 2 exhibited much higher activities against methicillin-resistant Staphylococcus aureus (MRSA) than ampicillin, which implies that they might be potential candidates for the development of novel drugs against resistant pathogenic bacteria.

Simultaneous identification of multiple celangulins from the root bark of Celastrus angulatus using high-performance liquid chromatography-diode array detector-electrospray ionisation-tandem mass spectrometry.

INTRODUCTION: Celangulins are a small family of ß-dihydroagarofuran sesquiterpenoids endowed with diverse polyoxygenated polyol esters and various biological properties. Since our research focuses on celangulins, the development of rapid and sensitive online analytical methods to analyse and characterise them is of great significance. OBJECTIVE: To develop an HPLC-DAD-ESI-MS/MS method capable of simple and rapid analysis of celangulins in crude extract of root bark of C. angulatus extracts. METHODOLOGY: High-performance liquid chromatography coupled with a diode array detector and electrospray ionisation tandem mass spectrometry was established for the efficient and rapid identification of the celangulins. Chromatographic separations of celangulins were performed on a Hypersil Gold C(18) reverse-phase column by gradient elution with acetonitrile-water as mobile phase at a flow-rate 0.2 mL/min. RESULTS: ESI/MS/MS analysis of sodium adduct ion ([M + Na](+) ) of each celangulin shows that all the celangulins produced very similar fragmentation profiles, and that the characteristic fragments at m/z 245, m/z 229 and m/z 231 were defined as the diagnostic ions for celangulins. Simultaneously, 46 components in the extracts of this plant were separated, and 36 of them were characterised as celangulins by online ESI/MS/MS and by comparing their retention times, UV and MS spectra with those of authentic compounds. CONCLUSION: HPLC-DAD-ESI-MS/MS was demonstrated to be a powerful tool for the characterisation of minor celangulins in complex samples.

Synthesis and antibacterial activities of 1-alkyl-3-methacryloyl (acryloyl) of benzimidazolone (thione) derivatives.

A series of (28) 1-alkyl-3-methacryloyl (acryloyl)-benzimidazolone (thione) deriv-atives were synthesized. The structures of the new derivatives were confirmed by (1)H-NMR, (13)C-NMR and ESI-MS spectral analysis. The antibacterial activities of these compounds against several strains of bacteria, such as Bacillus cereus, Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, were evaluated by methods of paper disc-diffusion and broth mciro-dilution. Methacryloyl derivatives displayed higher antibacterial activities against tested bacterial strains than those of acryloyl derivatives in in vitro tests. A structure-activity relationship (SAR) study revealed that the presences of the methacryloyl moieties is essential to the antibacterial activities of the compounds.

Enhanced production of a novel cyclic hexapeptide antibiotic (NW-G01) by Streptomyces alboflavus 313 using response surface methodology.

NW-G01, produced by Streptomyces alboflavus 313, is a novel cyclic hexapeptide antibiotic with many potential applications, including antimicrobial activity and antitumor agents. This study developed a system for optimizing medium components in order to enhance NW-G01 production. In this study, Plackett-Burman design (PBD) was used to find the key ingredients of medium components, and then response surface methodology (RSM) was implemented to determine their optimal concentrations. The results of PBD revealed that the crucial ingredients related to the production of NW-G01 were (NH(4))(2)SO(4), peptone and CaCO(3). A prediction model has been built in the experiments of central composite design and response surface methodology, and its validation has been further verified. The optimal medium composition was determined (g/L): corn starch 15, glucose 15, peptone 3.80, (NH(4))(2)SO(4) 0.06, NaCl 1.5, CaCO(3) 1.30, MgSO(4)·7H(2)O 0.015, K(2)HPO(4)·3H(2)O 0.015, MnCl(2)·4H(2)O 0.015, FeSO(4)·7H(2)O 0.015, and ZnSO(4)·7H(2)O 0.015. Compared with NW-G01 production (5.707 mg/L) in non-optimized fermentation medium, the production of NW-G01 (15.564 mg/L) in optimized fermentation medium had a 2.73-fold increase.