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Phthalides represent a notable category of secondary metabolites that are prevalent in various plant species, certain fungi, and liverworts. The significant pharmacological properties of these compounds have led to the synthesis of a novel phthalide derivative. The current study focuses on investigating the binding interactions of a newly synthesized 3-substituted phthalide derivative, specifically 3-((4-chloro-6-methyl pyrimidine-2-yl)amino) isobenzofuran-1(3H)-one (Z11), with double-stranded deoxyribonucleic acid (dsDNA). Research in the pharmaceutical and biological fields aimed at developing more potent DNA-binding agents must take into account the mechanisms by which these newly synthesized compounds interact with DNA. This investigation seeks to explore the binding dynamics between dsDNA and our compound through a variety of analytical techniques, such as electrochemistry, UV spectroscopy, fluorescence spectroscopy, and thermal denaturation. The binding constant (Kb) of Z11 with DNA was determined using both spectroscopic and voltammetric approaches. The research revealed that Z11 employs a groove binding mechanism to associate with dsDNA. To further explore the interactions between Z11 and dsDNA, the study utilized density functional theory (DFT) calculations, molecular docking, and molecular dynamics simulations. These analyses aimed to ascertain the potential for a stable complex formation between Z11 and dsDNA. The results indicate that Z11 is situated within the minor groove of the dsDNA, demonstrating the ability to establish a stable complex. Furthermore, the findings imply that both π-alkyl interactions and hydrogen bonding play significant roles in the stabilization of this complex. [ABSTRACT FROM AUTHOR]

The present study investigated potential application of somatic embryogenesis (SE) for conservation of Kelussia odoratissima Mozaff. As the efficiency of SE greatly varies depending on the culture conditions including light, effects of five light spectrums including a fluorescent light and four types of light - emitting diode (LED) (red, blue, 3red-1blue, and 3blue:1red) for an exposure time of a month on the maturation of K. odoratissima were studied. To better understand the effect of light treatment on conversion of K. odoratissima cultures, two months after treatment, fresh and dry weight and metabolite contents were evaluated. Samples of the same age in-situ plant and air-dry plant were also considered for relative comparison. Study of developmental stage of K. odoratissima under in vitro conditions revealed that a combination of 3red:1blue LED provided the highest number of cotyledonary (mature) embryos per callus. Interestingly, 3red:1blue LED could significantly improve synchronization of somatic embryos. Hence, this light treatment was identified as the best treatment for the maturation of somatic embryos in K. odoratissima. In conversion stage, the highest fresh and dried weights were recorded for tissue culture plantlets grown under 3blue:1red and blue LED treatment. Phthalide content of fresh in-situ plant was significantly greater than other treatments. Interestingly, the phthalide content was significantly higher in leaves of tissue culture plantlets compared to air-dry in situ plants, which suggests tissue culture as an alternative technique for the production of bioactive compounds in K. odoratissima.Key message: LEDs can be effective in micropropagation of Kelussia odoratissima Mozaff, an endangered plant endemic to Iran. Our results could pave the way for the proliferation of plant in bioreactor systems. [ABSTRACT FROM AUTHOR]

BACKGROUND: Peanut southern blight disease, caused by Sclerotium rolfsii, is a destructive soil‐borne fungal disease. The current control measures, which mainly employ succinate dehydrogenase inhibitors, are prone to resistance and toxicity to non‐target organisms. As a result, it is necessary to explore the potential of eco‐friendly fungicides for this disease. RESULTS: Fourteen novel phthalide compounds incorporating amino acid moieties were designed and synthesized. The in vitro activity of analog A1 [half maximal effective concentration (EC50) = 332.21 mg L−1] was slightly lower than that of polyoxin (EC50 = 284.32 mg L−1). It was observed that on the seventh day, the curative activity of A1 at a concentration of 600.00 mg L−1 was 57.75%, while the curative activity of polyoxin at a concentration of 300.00 mg L−1 was 42.55%. These results suggested that our compound exhibited in vivo activity. Peanut plants treated with A1 showed significant agronomic improvements compared to the untreated control. Several compounds in this series exhibited superior root absorption and conduction in comparison to the endothermic fungicide thifluzamide. The growth promotion and absorption‐conduction experiments demonstrated the reason for the superior in vivo activity of the target compound. Cytotoxic assays have demonstrated that this series of targeted compounds exhibit low toxicity levels toward human lo2 liver cells. CONCLUSION: Our results provide a new strategy for the design and synthesis of novel green compounds. Furthermore, the target compound A1 can serve as a lead for further development of green fungicides. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

A versatile and readily available chiral amide directing group has been developed for the ruthenium(II)‐catalyzed asymmetric C−H activation. Asymmetric C−H activation of the related chiral benzamides with various olefins, aldehydes and propargylic alcohols has been accomplished with high stereoselectivities, affording a series of chiral products including 3,4‐dihydroisocoumarins (up to 96 % ee), isocoumarins (up to 92 % ee), phthalides (up to 99 % ee), chiral bicyclo[2.2.1]heptanes (>20 : 1 dr), 4‐alkylidene‐3,4‐dihydroisocoumarins (up to 97 % ee) and allenes (>20 : 1 dr). Importantly, our methodologies enabled concise syntheses of many biologically active compounds and natural products (e.g. Montroumarin, Cyclosporone E, Cyclosporone Q, Concentricolide, Chuangxinol, and Eleutherol). [ABSTRACT FROM AUTHOR]

Antimicrobial compounds were purified from culture filtrates from 2 edible Pleurotus species. Using a bioassay-guided fractionation of the culture filtrate extracts, 3 compounds (1-3) were obtained from Pleurotus ostreatus, and another compound (4) was obtained from Pleurotus pulmonarius . Spectroscopic analysis revealed that 1-3 was identified as 5,7-dimethoxyphthalide, 4,6-dimethoxyphthalide, and cheimonophyllon E, respectively, while 4 were identified as pleuroton A. The minimum inhibitory concentration and minimum bactericidal concentration of these compounds were determined against 6 pathogenic bacterial species, Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae. Compounds 2 and 4 were inhibitory against all tested bacteria, while 1 and 4 were inhibitory against 3 and 2 species, respectively. In addition, 1-4 inhibited tyrosinase, with IC50 values of 0.10-0.30 mg/mL, and α-glucosidase, with IC50 values of 0.12-0.54 mg/mL. However, their antioxidant capacities were marginal. [ABSTRACT FROM AUTHOR]

The excessive use of chemical pesticides in agricultural fields for controlling plant pathogenic microorganisms harms human health, the environment, and other beneficial microorganisms in the soil and plants. To address this challenge, it is essential to isolate and discover bioactive compounds from biological resources that could inhibit plant pathogenic microorganisms. In this study, the culture filtrate of the edible mushroom Pleurotus ostreatus was subjected to bioassay-guided isolation, and two phthalide derivatives--4,6-dimethoxyphthalide (1) and 5,7-dimethoxyphthalide (2)--were identified, along with an oxindole compound--3-hydroxy-3-methyloxindole (3). The inhibitory activities of the three compounds were evaluated against four fungal and five bacterial pathogens. Remarkably, 1 and 2 exhibited the lowest IC50 values against the conidial germination and germ tube elongation of the rice blast fungus Pyricularia oryzae. However, their effectiveness against bacterial pathogens was relatively low. The (S) and (R)-enantiomers of 3-hydroxy-3-methyloxindole showed different activities against plant fungal pathogens and bacterial plant pathogens. [ABSTRACT FROM AUTHOR]

The investigation on the fruits of Pittosporum elevaticostatum Chang et Yan led to the isolation of two undescribed metabolites (1 – 2, named pitelevatin A and B) and twelve known ones (3 – 14), including one phthalide (1), four monoquiterpenoids (2 – 5), two sesquiterpenoids (6 – 7), two diterpenoids (8 – 9), and five phenolic analogues (10 – 14). The structures of 1 and 2 were elucidated based on spectroscopic methods, including high resolution electrospray ionization mass spectroscopy (HR-ESI-MS), one demension (1D) and 2D nuclear magnetic resonance (NMR), ultraviloet (UV), electronic circular dichroism (ECD) spectra and experimental and calculated specific optical rotation (SOR). Compounds 1 – 3 , 7 and 11 showed significant nitric oxide (NO) production inhibitory activity in lipopolysaccharide (LPS)-induced BV-2 microglial cells by inhibiting the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), with IC 50 values ranging from 6.35 to 25.75 μ M. Western blot analysis confirmed the results above. [Display omitted] • First report of chemical constituents of P. elevaticostatum Chang et Yan. • Fourteen compounds, including two undescribed ones were isolated and identified from P. elevaticostatum fruits. • Pitelevatin A (1) showed NO production inhibition in BV-2 cells (IC 50 6.35 µM). Western blot analysis revealed the possible anti-inflammatory mechanism. [ABSTRACT FROM AUTHOR]

Endophytic fungi reside within their host plants with no obvious symptoms. They have been proven as abundant sources of new bioactive compounds with diverse structures. In our continuous search of the new compound from endophytic fungi, a new compound, 5,7-dihydroxy-3(R)-methylphthalide (1), was isolated from Xylaria brevipes PGR1, and three known compounds, (-)-altenuene (2), alternariol (3), and altertoxin I (4), were isolated from Alternaria alternata D-8. Both endophytic fungi were isolated from the branch of an Indonesian medicinal plant, Psidium guajava. Their structures were elucidated using extensive spectroscopy analyses, including 1D/2D NMR, HRESITOFMS, and data comparisons with the literature. Compounds 1-3 exhibited phytotoxicity at IC50 (µg/ml) values of 4.6, 23.07, and 77.28, respectively. Additionally, 1-4 showed significant cytotoxicity in the brine shrimp lethality test (BSLT), with mortality rates at 75%, 50%, 90%, and 80% at the concentration of 0.19 µg/ml, respectively. [ABSTRACT FROM AUTHOR]

Senkyunolide I (SI) is a natural phthalide that has drawn increasing interest for its potential as a cardio-cerebral vascular drug candidate. In this paper, the botanical sources, phytochemical characteristics, chemical and biological transformations, pharmacological and pharmacokinetic properties, and drug-likeness of SI are reviewed through a comprehensive literature survey, in order to provide support for its further research and applications. In general, SI is mainly distributed in Umbelliferae plants, and it is relatively stable to heat, acid, and oxygen, with good blood–brain barrier (BBB) permeability. Substantial studies have established reliable methods for the isolation, purification, and content determination of SI. Its pharmacological effects include analgesic, anti-inflammatory, antioxidant, anti-thrombotic, anti-tumor effects, alleviating ischemia–reperfusion injury, etc. Pharmacokinetic parameters indicate that its metabolic pathway is mainly phase Ⅱ metabolism, and it is rapidly absorbed in vivo and widely distributed in the kidneys, liver, and lungs. [ABSTRACT FROM AUTHOR]

Amestolkins A (1) and B (2), two previously undescribed phthalides sharing the same planar structure of (1, 5-dihydroxyhexyl)-7-hydroxyisobenzofuran-1(3H)-one were isolated from Talaromyces amestolkiae. Their absolute configurations were elucidated by comprehensive analyses of spectroscopic evidences in high-resolution electrospray mass spectra (HRESIMS) and nuclear magnetic resonance (NMR) combined with electronic circular dichroism (ECD) and NMR calculations. 1 and 2 showed anti-neuroinflammatory activity by inhibiting the gene expressions of proinflammatory factors including C-C motif chemokine ligand 2 (CCL-2), tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), as well as attenuating the excretion of inducible nitric oxide synthase (iNOS) in BV-2 microglial cells at the concentration of 30 μM. [ABSTRACT FROM AUTHOR]

Perfluorinated 1-methyl- and 1-ethylbenzocyclobutenes and 2-methyl- and 2-ethylbenzocyclo-butenones reacted with 20% oleum at 150°C to give mixtures of almost equimolar amounts of 3-perfluoroalkyl-4,5,6,7-tetrafluorophthalides and perfluoro-3-hydroxy-3-alkylphthalides. In addition to these products, the reac-tion of perfluoro-2-methylbenzocyclobutenone with oleum at 100°C afforded perfluoro-2-hydroxy-2-methylbenzo-cyclobutenone. The reaction of perfluoro-2-phenylbenzocyclobutenone with oleum produced perfluoro-2-benzoylbenzoic acid, whereas polyfluorobenzocyclobutene-1,2-diols were converted to the corresponding cyclic sulfates. [ABSTRACT FROM AUTHOR]

A highly efficient and convenient procedure for straightforward synthesizing structurally diverse 3-benzofurylsubstituted phthalides is developed with moderate to excellent yields via cyclization reactions of benzofurans with 2-carbonyl-benzoic acid. The reaction features readily available starting materials, a broad scope, and a high atom economy. Besides, an interesting regioselective was observed in some cases. [ABSTRACT FROM AUTHOR]

Two new phthalide derivatives, namely bialowalides A (1) and B (8), and one new isochromanone analogue biourgalide C (11), together with 8 known phthalides (2-7, 9, and 10) as well as two known isochromanones (12 and 13) were discovered from the EtOAc extract of the deep-sea-derived fungus Penicillium bialowiezense A3. The structures were resolved on the basis of extensive spectroscopic analyses (NMR and HRESIMS data), in association with the modified Mosher's method and ECD data for the determination of the absolute configurations. All isolated secondary metabolites (1-13) were tested their antiviral activities against the SARS-CoV-2 trVLP pseudovirus at a concentration of 25 μM. As a result, compounds 1, 5, 11, and 12 exhibited the inhibitory effects against the luminescence at 46.2 %, 39.6 %, 45.5 %, and 48.8 %, respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Mountain celery (MC) is an endemic plant native to Iran. The plant possesses several nutritional and industrial applications bestowed by a wide range of bioactive compounds. The present study investigated some changes in the chemical composition of fresh arial parts of MC at different vegetative stages. The headspace (HS) technique in tandem with GC–MS analysis were implemented to identify bioactive compounds. Results indicated that phthalides, sesquiterpenes, and monoterpenes were the main constituents in MC. It was found that MC had higher concentration and more diverse composition of phthalides at younger age. It seems MC farming has the potential to be commercialized with a decent revenue. [ABSTRACT FROM AUTHOR]

Angelica glauca Edgew, which is an endangered medicinal and aromatic herb, is a rich source of numerous industrially important bioactive metabolites, including terpenoids, phenolics, and phthalides. Nevertheless, genomic interventions for the sustainable utilization and restoration of its genetic resources are greatly offset due to the scarcity of the genomic resources and key regulators of the underlying specialized metabolism. To unravel the global atlas of the specialized metabolism, the first spatial transcriptome sequencing of the leaf, stem, and root generated 109 million high-quality paired-end reads, assembled de novo into 81,162 unigenes, which exhibit a 61.53% significant homology with the six public protein databases. The organ-specific clustering grouped 1136 differentially expressed unigenes into four subclusters differentially enriched in the leaf, stem, and root tissues. The prediction of the transcriptional-interactome network by integrating enriched gene ontology (GO) and the KEGG metabolic pathways identified the key regulatory unigenes that correspond to terpenoid, flavonoid, and carotenoid biosynthesis in the leaf tissue, followed by the stem and root tissues. Furthermore, the stem and root-specific significant enrichments of phenylalanine ammonia lyase (PAL), cinnamate-4-hydroxylase (C4H), and caffeic acid 3-O-methyltransferase (COMT) indicate that phenylalanine mediated the ferulic acid biosynthesis in the stem and root. However, the root-specific expressions of NADPH-dependent alkenal/one oxidoreductase (NADPH-AOR), S-adenosyl-L-methionine-dependent methyltransferases (SDMs), polyketide cyclase (PKC), and CYP72A15 suggest the "root" as the primary site of phthalide biosynthesis. Additionally, the GC-MS and UPLC analyses corresponded to the organ-specific gene expressions, with higher contents of limonene and phthalide compounds in the roots, while there was a higher accumulation of ferulic acid in the stem, followed by in the root and leaf tissues. The first comprehensive genomic resource with an array of candidate genes of the key metabolic pathways can be potentially utilized for the targeted upscaling of aromatic and pharmaceutically important bioactive metabolites. This will also expedite genomic-assisted conservation and breeding strategies for the revival of the endangered A. glauca. [ABSTRACT FROM AUTHOR]

Nur77, an orphan member of the nuclear receptor superfamily, regulates inflammatory diseases and is a therapeutic target for treating inflammation. Phthalides in Angelica sinensis exhibit anti-inflammatory activity. This study aimed to screen compounds from A. sinensis phthalide extract that could exert anti-inflammatory activity by targeting Nur77. To provide new theoretical support for better elucidation of Chinese medicine targeting mitochondria to achieve multiple clinical efficacies. The anti-inflammatory capacity of phthalides was assessed in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells using western blotting. The interaction between phthalides and Nur77 was verified by molecular docking, surface plasmon resonance, and cellular thermal shift assay. Co-immunoprecipitation, western blotting, and immunostaining were performed to determine the molecular mechanisms. The in vivo anti-inflammatory activity of the phthalides was evaluated in a lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute hepatitis and liver injury mouse model of acute hepatitis and liver injury. Finally, the toxicity of phthalide toxicity was assessed in zebrafish experiments. Among the 27 phthalide compounds isolated from A. sinensis , tokinolide B (TB) showed the best Nur77 binding capacity and, the best anti-inflammatory activity, which was induced without apoptosis. In vivo and in vitro experiments showed that TB promoted Nur77 translocation from the nucleus to the mitochondria and interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2) and sequestosome 1 (p62) to induce mitophagy for anti-inflammatory functions. TB substantially inhibited LPS/d-GalN-induced acute hepatitis and liver injury in mice. TB also exhibited significantly lower toxicity than celastrol in zebrafish experiments. These findings suggested that TB inhibits inflammation by promoting Nur77 interaction with TRAF2 and p62, thereby inducing mitophagy. These findings offer promising directions for developing novel anti-inflammatory agents, enhance the understanding of phthalide compounds, and highlight the therapeutic potential of traditional Chinese herbs. [Display omitted] [ABSTRACT FROM AUTHOR]

The behaviour of 14 ortho-functionalised 2-aryloxazolines (11 of them prepared and characterised for the first time) with butyllithium has been examined. Significant limitations to the Wittig rearrangement of such systems are revealed. In terms of asymmetric Wittig rearrangement, good diastereoselectivity is obtained with a valine-derived 4-isopropyl oxazoline, but this is compromised by racemisation upon hydrolysis. More encouraging selectivity is achieved in the Wittig rearrangement of an acyclic phenylalanine-derived ortho-benzyloxy benzamide. [ABSTRACT FROM AUTHOR]

Rapid synthesis of 3-arylphthalides with a quaternary carbon center has been achieved via a cascade [4+1] cycloaddition/nucleophilic 1,4-addition of 2-carbonylcyclohexadienimines with two molecules of isocyanides. The reaction proceeded smoothly under metal-free conditions leading to the formation of multi-functionalized phthalides in moderate to good yields.

In this report, 3-((4,6-dimethylpyrimidin-2-yl)amino)isobenzofuran-1(3H)-one have been synthesized via reaction between phthalaldehydic acid and 2-amino-4,6-dimethylpyrimidine in 90% yields and characterized by Infrared (IR), Nuclear Magnetic Resonance (NMR), Ultraviolet–visible (UV–Vis), X-ray single crystal diffraction techniques. The single-crystal X-ray analysis shows that the title compound crystallizes in the triclinic space group P-1 with unit-cell parameters a = 7.9351(4) Å, b = 11.1687(6) Å, c = 16.1281(9) Å, α = 73.713(5)°, β = 80.362(5)°, γ = 72.882(4)° and Z = 4. A theoretical study with hybrid functional B3LYP 6-311G (d, p) basis set have been used in calculations. The structural and electronic properties have been detailed. The title compound was screened for its antioxidant activity by (1,1-diphenyl-2-picryl hydrazyl) free radical scavenging (DPPH), Ferric ion reducing antioxidant power (FRAP), total phenolic contents (TP) assays and its ferrous ions chelating property. Electronic absorption titration, thermal denaturation measurement and viscosity techniques were used to determine the interaction between double stranded DNA (dsDNA) and compound 1. In three techniques, the mode of binding of compound 1 to dsDNA is minor groove. The UV–Vis measurement results allowed the calculation of the binding constant showing the binding strength of compound 1 to dsDNA was calculated as 8.13 × 104 ± 0.07 L mol−1. Moreover, the molecular docking calculations have been performed to investigate the compound–DNA interactions, computationally. In molecular docking calculations, it was observed that for the title compound, the lowest energy docking pose takes place in the minor groove of DNA and in addition to minor groove binding, interactions between the compound and the consecutive base pairs of DNA which may cause a partial intercalation were also observed. Results showed that title compound – DNA complex is stabilized by several hydrogen bonds, and Pi-alkyl interactions also take part in the stabilization of the complex. Binding affinities of the lowest energy docking pose of the title compound was found to be −8.3 kcal/mol.

Metal‐catalyzed C−H activation/tandem reactions of aromatic acids and functionalized alkenes is profound for constructing phthalide skeleton. However, most of these reactions employ stoichiometric amounts of metal additives and metal oxidants/toxic organic solvents. Herein, we describe a sequential cobalt/rhodium‐catalyzed tandem cyclization of aromatic aldehydes and acrylates for preparing 3‐substituted phthalides in one pot. This protocol features the use of water as a sustainable solvent and oxygen as the singular oxidant free of any additives. The use of aromatic aldehydes instead of aromatic acids as starting materials renders this route high atom economy, and the formation of water as a sole byproduct makes this process practical and environmentally benign. [ABSTRACT FROM AUTHOR]

Kelussia odoratissima Mozaff. (keluss), is an endemic medicinal herb in the central Zagros region of Iran. Due to its excessive harvesting in the early vegetation period and the relatively long time required for seed establishment and production, this plant does not have the opportunity to regenerate and produce seed and is exposed to extinction. Keluss has two groups of essential oils and flavonoids. Flavonoids are one of the important components of the plant that have anti-inflammatory, antiviral, anti-diabetes and anti-cancer effects. The most important ingredient in the essential oil of keluss is butylidene dihydrophthalide, as well as butylamine phthalide. Phthalides are found mainly in plant seeds. The main fatty acids of the plant are petroselinic acid, linoleic acid and palmitic acid. The aerial parts of the keluss have properties such as anti-inflammatory, analgesic, rheumatic treatment and blood purification in traditional medicine. Keluss has antioxidant and and tissue protection effects. In this article, the plant is reviewed from various aspects such as botanical characteristics, cultivation and production, uses in traditional medicine and clinical research.

[Display omitted] • Two new azaphthalide/phthalide compounds were isolated from a marine Aspergillus. • New structures were determined by NMR, OR, calculated ECD and X-ray diffraction. • Melilotigenin B (10) displayed moderate inhibition on pancreatic lipase. A new azaphthalide derivative, (S)-3-hydroxy-2,7-dimethylfuro [3,4- b ]pyridin-5(7 H)-one (1), and a new phthalide derivative, (S)-7-hydroxy-3-((S)-1-hydroxyethyl)isobenzofuran-1(3 H)-one (2), were isolated from the coral-derived fungus Aspergillus sp. SCSIO41405, together with eight known compounds (3–10). Their structures, including absolute configurations, were determined by NMR and MS spectroscopic analyses, optical rotation, calculated electronic circular dichroism (ECD) and X-ray crystal data. The isolated compounds were examined for antibacterial and enzyme inhibition activities. Compounds 7 and 8 exhibited weak antibacterial activities, and 10 displayed moderate inhibition on pancreatic lipase with an IC 50 value of 15.6 μ g/mL. [ABSTRACT FROM AUTHOR]

The Dothideomycete fungal pathogen Pyrenophora tritici-repentis (Ptr) is the causal agent of the tan spot disease of wheat. The proteinaceous necrotrophic effectors ToxA and ToxB are well characterized. A nonproteinaceous effector called ToxC has also been partially characterized. Ptr produces a number of other small molecular weight compounds, but these remain poorly characterized. In this study, two novel compounds, designated ToxE1 and ToxE2, capable of inducing chlorotic symptoms on wheat leaves in a cultivar-specific manner, were purified from Ptr liquid cultures. There is no evidence that these compounds correspond to ToxC. Most isolates produced ToxE1, ToxE2, or both, and both compounds were detected in infected wheat leaves. The structures of both analogues were elucidated by NMR spectroscopy and comprise a phthalide core structure with an amide moiety. We postulate that these compounds have a general phytotoxic effect and may have an ancillary role in disease development.

Abstract In live organisms, there is a balance between the production of reactive oxygen species (ROS) and their neutralization. The increased level of these species leads to a condition called redox imbalance. The aim of this study was to evaluate the protective action of isobenzofuranones in primary cultures of hippocampal neurons subjected to redox imbalance. To accomplish this, MTT and LIVE/DEAD assays were initially performed. In the cultures pretreated with isobenzofuranones 1 and 2, there was a higher number of live cells when compared to that in the untreated ones. Regarding redox imbalance, there was a significant increase in the intracellular levels of ROS. The cultures pretreated with isobenzofuranones showed a reduction in ROS levels. Lipid peroxidation caused by oxidative damage was significantly reduced in the cultures pretreated with isobenzofuranones 1 and 2. Taken together, these data show the ability of isobenzofuranones 1 and 2 to significantly minimize cytotoxicity, cell death, intracellular levels of ROS and lipid peroxidation induced by redox imbalance. These results suggest that isobenzofuranones 1 and 2 represent a possible alternative therapy for the neurodegenerative disturbances that are triggered by ROS production increases.

In this work we report a facile access to a 3,3-disubstituted isobenzofuranone by tandem addition/cyclization reaction to methyl 2-acetylbenzoate in the presence of dimethyl malonate, under basic conditions.

Two new phthalide derivatives, (-)-3-carboxypropyl-7-hydroxyphthalide (1) and (-)-3-carboxypropyl-7-hydroxyphthalide methyl ester (2), were isolated from the endophytic fungus Penicillium vulpinum isolated from the Chinese medicinal plant Sophora tonkinensis. Their structures were elucidated using spectroscopic methods, mainly on 1D and 2D NMR. Compound 1 exhibited medium antibacterial activities against Bacillus subtilis, Shigella dysenteriae and Enterobacter areogenes with MIC values of 12.5-25 μg/mL, and 2 showed a medium inhibition to E. areogenes with MIC value of 12.5 μg/mL. [ABSTRACT FROM AUTHOR]

Rapid synthesis of 3-arylphthalides with a quaternary carbon center has been achieved via a cascade [4+1] cycloaddition/nucleophilic 1,4-addition of 2-carbonylcyclohexadienimines with two molecules of isocyanides. The reaction proceeded smoothly under metal-free conditions leading to the formation of multi-functionalized phthalides in moderate to good yields. [ABSTRACT FROM AUTHOR]

In this report, 3-((4,6-dimethylpyrimidin-2-yl)amino)isobenzofuran-1(3 H)-one have been synthesized via reaction between phthalaldehydic acid and 2-amino-4,6-dimethylpyrimidine in 90% yields and characterized by Infrared (IR), Nuclear Magnetic Resonance (NMR), Ultraviolet–visible (UV–Vis), X-ray single crystal diffraction techniques. The single-crystal X-ray analysis shows that the title compound crystallizes in the triclinic space group P-1 with unit-cell parameters a = 7.9351(4) Å, b = 11.1687(6) Å, c = 16.1281(9) Å, α = 73.713(5)°, β = 80.362(5)°, γ = 72.882(4)° and Z = 4. A theoretical study with hybrid functional B3LYP 6-311G (d, p) basis set have been used in calculations. The structural and electronic properties have been detailed. The title compound was screened for its antioxidant activity by (1,1-diphenyl-2-picryl hydrazyl) free radical scavenging (DPPH), Ferric ion reducing antioxidant power (FRAP), total phenolic contents (TP) assays and its ferrous ions chelating property. Electronic absorption titration, thermal denaturation measurement and viscosity techniques were used to determine the interaction between double stranded DNA (dsDNA) and compound 1. In three techniques, the mode of binding of compound 1 to dsDNA is minor groove. The UV–Vis measurement results allowed the calculation of the binding constant showing the binding strength of compound 1 to dsDNA was calculated as 8.13 × 104 ± 0.07 L mol−1. Moreover, the molecular docking calculations have been performed to investigate the compound–DNA interactions, computationally. In molecular docking calculations, it was observed that for the title compound, the lowest energy docking pose takes place in the minor groove of DNA and in addition to minor groove binding, interactions between the compound and the consecutive base pairs of DNA which may cause a partial intercalation were also observed. Results showed that title compound – DNA complex is stabilized by several hydrogen bonds, and Pi-alkyl interactions also take part in the stabilization of the complex. Binding affinities of the lowest energy docking pose of the title compound was found to be −8.3 kcal/mol. [ABSTRACT FROM AUTHOR]

A new phthalide, namely 7-methoxy-3-propylidenephthalide (1), along with two known compounds (2, 3) were isolated from the roots of the edible herb Levisticum officinale W.D.J. Koch, commonly known as lovage and well known in traditional medicine for its spasmolytic and diuretic effects. The structure of the new compound was established by HRMS and 1D & 2D NMR (1H 1H COSY, HMQC, and HMBC) spectroscopic analysis. All compounds are reported for the first time from L. officinale. Compounds 1-3 were tested against two Gram negative (Escherichia coli, Pseudomonas aeruginosa) and two Gram positive (Staphylococcus aureus and vancomycin-resistant Enterococcus [VRE] faecium) bacteria strains. Compound 3 was active against S. aureus, E. coli and vancomycin-resistant E. faecium with MIC values of 16, 64, and 128 µg/mL, respectively. [ABSTRACT FROM AUTHOR]

Ligusticum sinense Oliv. and L. jeholense Nakai et Kitag. are globally recognized as medicinal botanical species, specifically the rhizomes and roots. These plant parts are collectively referred to as Ligustici Rhizoma et Radix (LReR), which is recorded in the Pharmacopoeia of the People's Republic of China (Ch. P). LReR enjoys widespread recognition in many countries such as China, Russia, Vietnam, and Korea. It is an herbal remedy traditionally employed for dispelling wind and cold, eliminating dampness, and alleviating pain. Numerous bioactive compounds have been successfully isolated and identified, displaying a diverse array of pharmacological activities and medicinal value. This review aims to primarily center on the botanical aspects, ethnopharmacology, phytochemistry, pharmacology, toxicity, quality control, and other applications of LReR to furnish a comprehensive and multidimensional foundation for future exploration and utilization. Relevant information about LReR was acquired from ancient books, doctoral and master's dissertations, Google Scholar, Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), ScienceDirect, classical literature, and clinical reports. Several electronic databases were also incorporated. In traditional usage, LReR had been traditionally employed for the treatment of anemofrigid headaches, colds, and joint pain. It possessed therapeutic properties for facial skin disorders, thereby facilitating skin regeneration. It has been subjected to comprehensive chemical analysis, resulting in the identification and isolation of 190 compounds, including phthalides, phenylpropanoids, flavonoids, phenolic acids, triterpenes, steroids, volatile oil, fatty acids, and other constituents. The pharmacological activities have been in-depth explored through modern in vivo and in vitro studies, confirming its anti-inflammatory, analgesic, and anti-melanin effects. Furthermore, it exhibited pharmacological activities such as antioxidant, anticancer, antibacterial, and vasodilatory properties. This study provides a basic to contribute to the advancement of research, medicinal applications and product development related to LReR. Considering its traditional and contemporary applications, phytochemical composition, and pharmacological properties, LReR was regarded as a valuable botanical resource for pharmaceutical and pest control purposes. While certain constituents had demonstrated diverse pharmacological activities and application potential, further elucidation was required to fully understand their specific actions and underlying mechanisms. Hence, there was a need to conduct additional investigations to uncover its material foundation and mode of action. [Display omitted] • Extensive biological activities and application values of Ligustici Rhizoma et Radix. • Botany, phytochemistry, toxicity and quality control are summarized. • Traditional uses and pharmacology of Ligustici Rhizoma et Radix. • Current challenges and feasible suggestions are provided. [ABSTRACT FROM AUTHOR]

Discribed in this article is a versatile and practical method for the synthesis of C3-perfluoroalkyl-substituted phthalides in a one-pot manner. Upon treatment of KF or triethylamine, 2-cyanobenzaldehyde reacted with (perfluoroalkyl)trimethylsilanes via nucleophilic addition and subsequent intramolecular cyclization to give perfluoroalkylphthalides in good yields.

The extract from Cnidium officinale rhizomes was shown in a prior experiment to markedly recover otic hair cells in zebrafish damaged by neomycin. The current study was brought about to identify the principal metabolite. Column chromatography using octadecyl SiO2 and SiO2 was performed to isolate the major metabolites from the active fraction. The chemical structures were resolved on the basis of spectroscopic data, including NMR, IR, MS, and circular dichroism (CD) data. The isolated phthalide glycosides were assessed for their recovery effect on damaged otic hair cells in neomycin-treated zebrafish. Three new phthalide glycosides were isolated, and their chemical structures, including stereochemical characteristics, were determined. Two glycosides (0.1 μM) showed a recovery effect (p < 0.01) on otic hair cells in zebrafish affected by neomycin ototoxicity. Repeated column chromatography led to the isolation of three new phthalide glycosides, named ligusticosides C (1), D (2), and E (3). Ligusticoside C and ligusticoside E recovered damaged otic hair cells in zebrafish.

Background: Phthalides are privileged constituents of numerous pharmaceuticals, natural products and agrochemicals and exhibit several biological and therapeutic activities. Therefore, the development of new, facile, and sustainable strategies for the construction of these moieties is highly desired.Results: A broad substrate scope for β-keto acids was found to be strongly compatible with this catalytic process, affording a wide variety of 3-substituted phthalides in good to excellent yields.Conclusion: A concise and efficient synthesis strategy of 3-substituted phthalides from 2-formylbenzoic acid and β-keto acids via a catalytic one-pot cascade reaction in glycerol has been accomplished.

Phthalide derivatives bearing indole or indoline moieties were successfully synthesized via eco-friendly method and were evaluated for their antiproliferative activity on HL-60 and HepG2 cell lines in vitro. At a final concentration of 100 μM, most of the compounds showed moderate potency on both the cell lines tested. Compound 3b bearing 5-chloro substituted indoline had the best potency against HL-60 and HepG2 cell lines with IC 50 values of 45.4 and 57.7 μM, respectively. It was also found that replacement of a conjugated indoline to indole moiety gave better antiproliferative activity on HL-60 cells by almost two-fold. Morphological observation demonstrated numerous fragmented nuclei which are indicative of apoptosis. Molecular docking studies predicted non-covalent interactions and H-bonding of selected compounds with the P2 binding hot spot of the anti-apoptotic protein, Bcl-2, formed by Asp108, Phe109, Met112, Leu134, Arg143, Ala146 and Val153. Overall, our work highlights the potential of synthesized phthalide-fused indoles or indolines as antitumor agents. [ABSTRACT FROM AUTHOR]

We report an efficient, catalyst-free, one-pot synthesis of (E)-N′-benzylidene-2-(hydroxymethyl)benzohydrazide derivatives by the one-pot reaction of phthalide, hydrazine hydrate and aldehyde. Advantages of this synthetic approach include mild reaction conditions and environmentally friendly nature, and the ability to provide a wide range of desired compounds in moderate to excellent yields. Here we introduce a green and efficient one-pot three-component protocol for the synthesis of (E)-N′-benzylidene-2-(hydroxymethyl)benzohydrazide derivatives in ethanol without any catalyst. [ABSTRACT FROM AUTHOR]

The BINOL‐derived chiral phosphoric acid (R)‐TRIP is utilized as an organocatalyst in the asymmetric isoprenylboration reaction of aldehydes, wherein hydrogen‐bond interactions play a key role in the control of enantioselectivity. A wide arrays of enantioenriched dienyl homoallyl alcohols, including two natural products (−)‐Ipsdienol and (−)‐Ipsenol, have been successfully constituted. The synthetic application to chiral isoprenylated isobenzofuranone, vinyloxirane and cyclohexene derivatives has also been disclosed. [ABSTRACT FROM AUTHOR]

Fruits of Apium graveolens (celery) are used traditionally in Persian and European medicine for the treatment of uncomplicated urinary tract infections. Aim of the study: The study aimed at identifying potential antiadhesive compounds from celery extracts to provide strategies for improved standardization of the herbal material. Decoction, hydroalcoholic and acetone extracts were prepared from celery fruits. Bioassay-guided fractionation was performed by Fast Centrifugal Partition Chromatography and preparative HPLC, followed by LC-MS and NMR investigations for structure elucidation. The antiadhesive activity of extracts, fractions and purified compounds was assessed by flow cytometry, evaluating the adhesion of fluorescent-labelled uropathogenic bacteria (UPEC NU14) to T24 bladder cells; mannose served as positive control. Influence of the extract on gene expression of selected adhesins and fitness genes was monitored by qPCR. Concentration-dependent antiadhesive activity was found for the hydroalcoholic and even more for the acetone extract AE (IC 50 85 μg/mL) from celery fruits. Bioassay-guided fractionation revealed the presence of the phthalides senkyunolide (1, inactive) and sedanenolide (2, IC 50 790 μM). 2 is assessed as the main antiadhesive compound, which accounts for 4.0% in the water extract, for 18% in the hydroethanolic extract and for 71% in AE. Additionally a similar phthalide, Z-ligustilide (5), was shown to exert an IC 50 of 611 μM. Furthermore, AE caused a significant upregulation of fimH and s faG in free floating, non-attached UPEC and significantly down-regulated these genes in adherent bacteria. Phthalides were identified as the main active compounds in polar and semi-polar extracts, which exert strong antiadhesive activity against uropathogenic E. coli. The current findings support the traditional use in phytotherapy for urinary tract infections and provide a base for standardization of the herbal material. Image 1 [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel 1,3,4-oxadiazole hybrids of 3- n -butylphthalide derivatives have been synthesized as potential anti-ischemic stroke agents. • Compounds 5b , 5d , 5 l , and 5 m exhibited more excellent antiplatelet aggregation activity than the positive controls 3- n -butylphthalic and aspirin. • Compound 5b demonstrated potential antithrombotic activity and anti-ischemic stroke efficacy in the animal model. • Compound 5b had relatively high bioavailability, metabolic stability, and blood–brain barrier permeability. • Compound 5b could effectively reduce the bleeding risk and had better safety profile. In continuation of our program to search for novel potential anti-ischemic stroke agents, a series of 1,3,4-oxadiazole and sulfoxide hybrids of phthalide derivatives was designed and synthesized in this study to evaluate their anti-ischemic stroke activity. Among them, compounds 5b , 5d , 5 l , and 5 m exhibited excellent inhibitory effects on platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA). In particular, compound 5b possessed considerable antithrombotic activity in animal models, as demonstrated by the effective alleviation of carrageenan-induced and FeCl 3 -induced thrombosis in tail and carotid arteries, respectively. Notably, intraperitoneal administration of compound 5b could better protect the brain from injury caused by ischemia/reperfusion in rats compared with precursor 3- n -butylphthalide. Further pharmacokinetics, liver microsomal stability, and PAMPA-BBB assays also indicated that compound 5b had relatively high bioavailability, metabolic stability, and BBB permeability. Moreover, compound 5b showed a safety profile that was superior to the clinical drugs clopidogrel, aspirin, and 3- n -butylphthalide in the mouse-tail bleeding assay. Finally, molecular docking predicted that the potential target of the antiplatelet aggregation activity of compound 5b was P2Y12 receptor. This research provides a novel candidate compound for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

A pair of novel lipopeptide epimers, sinulariapeptides A (1) and B (2), and a new phthalide glycerol ether (3) were isolated from the marine algal-associated fungus Cochliobolus lunatus SCSIO41401, together with three known chromanone derivates (4–6). The structures of the new compounds, including the absolute configurations, were determined by comprehensive spectroscopic methods, experimental and calculated electronic circular dichroism (ECD), and Mo2 (OAc)4-induced ECD methods. The new compounds 1–3 showed moderate inhibitory activity against acetylcholinesterase (AChE), with IC50 values of 1.3–2.5 μM, and an in silico molecular docking study was also performed.

Four series of novel 1,3,4-oxadiazole/1,2,4-triazole hybrids of phthalide derivatives were designed and synthesized to search for novel potential antifungal agents. Preliminary antifungal activity assay results showed that compounds 4 a, 4 b, 4 m, 5 b, 5 f, 5 h, and 7 h exhibited moderate to excellent inhibitory activity against some phytopathogenic fungi. Among them, compound 5 b displayed the most outstanding antifungal effects against V. mali and S. sclerotiorum, with the EC 50 mean of 3.96 μg/mL and 5.60 μg/mL, respectively, which was superior to those of commercial fungicides hymexazol and chlorothalonil. Furthermore, compound 5 b could completely suppress the spore germination of V. mali at a concentration of 10 μg/mL. Finally, molecular docking revealed that the potential target for the antifungal activity of compound 5 b was succinate dehydrogenase (SDH). This research provides novel candidate compounds for the prevention of phytopathogenic fungi., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The chiral transient directing group (TDG) strategy has been successfully introduced to the rhodium(III)‐catalyzed asymmetric C−H activation. In the presence of a catalytic amount of a chiral amine and an achiral rhodium catalyst, various chiral phthalides were synthesized from simple aldehydes with high chemoselectivity, regioselectivity, and enantioselectivity (53 examples, up to 73 % yield and >99 % ee). It is noteworthy that the chiral induction model is different from the previously reported chiral TDG system using amino acid derivatives and palladium salts. The imino group generated in situ from chiral amine and aldehyde acts as the monodentate TDG to promote the C−H activation, stereoselectively generating the chiral rhodacycle bearing a chiral metal center. Moreover, the stereogenic center of the product is created and stereocontrolled during the Grignard‐type addition of the C−Rh bond to aldehyde, rather than during the C−H activation step. C−H activation: The chiral transient directing group (TDG) strategy has been successfully introduced to the rhodium(III) catalyzed asymmetric C−H activation. In the presence of a catalytic amount of chiral amine and an achiral rhodium catalyst, various chiral phthalides were synthesized from simple aldehydes with high chemoselectivity, regioselectivity, and enantioselectivity (53 examples, up to 73 % yield and >99 % ee; see scheme). [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of phthalides using phthalic anhydride derivatives for the first time. • The structure of a desired product was admitted by X-ray crystallography. • Mechanism includes C H bond activation, vinylation, decarboxylation and annulation. • A number of corresponding phthalides were obtained in good yields. Abstract Synthesis of substituted phthalides through a ruthenium-catalyzed reaction of phthalic anhydrides with acrylates is described. The reaction proceeds via C H bond activation and leads to the formation of vinylated phthalides through a successive double vinylation accompanied by decarboxylation and annulation reactions. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Low-intensity absorption bands of phthalide were recorded for the first time. • Solvation effects make it possible to distinguish between nπ* and ππ* transitions. • PCM/TDDFT calculations reproduce the experimental absorption spectrum of phthalide. • Low-intensity absorption bands of phthalide correspond to the T 1 and T 2 states. Abstract The optical absorption spectra of phthalide in polar (methanol) and nonpolar (n -hexane) solvents are recorded. The electronic phthalide spectrum was calculated by TDDFT B3LYP/6-311+G(d, p) using the polarisable continuum model. Based on an analysis of calculation data and the displacement of absorption bands in a polar solvent, it was established that the absorption bands of phthalide at energies of 3.51 and 3.96 eV correspond to singlet-triplet transitions to the T 1 and T 2 states, respectively. [ABSTRACT FROM AUTHOR]

Graphical abstract R N H 2 : 12 examples including bifunctional reagents. *R 2 N H: only cyclic sec -amines, and no reactions for the corresponding acyclic counterpart. Highlights • Facile construction of CF 3 -containing γ-lactams starting from primary amines. • Further cyclization from the product using 2-aminoethanol. • Net substitution reactions from cyclic secondary amines. Abstract Unprecedented isobenzofuran-1-ones (phthalides) with CF 3 and ethoxy groups both at the 3-position were readily synthesized from the corresponding aromatic 1,2-diesters and reacted with a variety of primary amines to find out convenient conversion to the corresponding γ-lactams, while secondary amines behaved in a totally different manner to affect the net substitution reactions for the EtO moiety, where characteristics of the strongly electron-withdrawing CF 3 group was considered to play a significantly important role. [ABSTRACT FROM AUTHOR]

A detailed account on the outcome of the thermal reaction between benzylidene phthalides and various amino acid derivatives is reported. It was discovered that the tricyclic pyrroles as previously described are not the products formed in these reactions. Instead under high-temperature conditions decarboxylated phthalamide adducts are formed within 5-10 minutes. Additionally, an unprecedented alkene transposition mechanism has been identified leading to the final products of these reactions. KeyA detailed account on the outcome of the thermal reaction between benzylidene phthalides and various amino acid derivatives is reported. It was discovered that the tricyclic pyrroles as previously described are not the products formed in these reactions. Instead under high-temperature conditions decarboxylated phthalamide adducts are formed within 5-10 minutes. Additionally, an unprecedented alkene transposition mechanism has been identified leading to the final products of these reactions. [ABSTRACT FROM AUTHOR]

This study reports the effect of explant type and plant growth regulators (PGRs) on callus induction in Cnidium officinale. Compared to stem, root explant showed maximum percent callus formation of 75% on Murashige and Skoog (MS) medium containing 2.3 µM 2,4-dichlorophenoxyacetic acid (2,4-D) and 2.2 µM benzyladenine (BA). At 30th day of callus culture on the said medium, callus fresh weight was sevenfold higher than other tested PGRs treatments. It was noted that MS medium supplemented with 27.1 µM 2,4-D showed the highest 0.30 mg g−1 DW of total phenols, while total flavonoids content reached to a maximum of 0.05 mg g−1 DW on the MS medium supplemented with 4.5 µM 2,4-D and 2.2 µM BA. Conversely, maximum (83.9%) DPPH free radical scavenging activity was observed in calli grown on the MS medium supplemented with 2.3 µM 2,4-D and 2.2 µM BA. The high-performance liquid chromatography (HPLC) analysis revealed higher phthalide content in callus than intact roots of in vitro plants. While 3-butylidenephthalide content in callus was comparable to the intact shoots and roots of in vitro grown C. officinale. The concentrations of 2,4-D played a significant role in the production of phthalide and 3-butylidenephthalide. Additional measures are recommended to further enhance their production in vitro.Graphical abstract: [ABSTRACT FROM AUTHOR]