Dihydroisocoumarin Derivatives Research Articles

In-vitro anti-diabetic, anti-Alzheimer, anti-tyrosinase, antioxidant activities of selected coumarin and dihydroisocoumarin derivatives

Benzo-α-pyrone structured coumarin derivatives are secondary metabolites first obtained from Coumarouna odorata in 1822. Coumarin and its structural isomer dihydroisocoumarin derivatives are found in many different sources in nature. Several different bioactivities of these compounds have been reported. In this study, preliminary activity screening and comparison of four purchased coumarin derivatives (esculetin, esculin monohydrate, umbelliferon, scoparone) and four previously isolated 3-phenyl-3,4-dihydroisocoumarin derivatives (thunberginol C, scorzocreticoside I, scorzocreticoside II, scorzopygmaecoside) from a medicinal plant were carried out by in-vitro methods. α-Glucosidase, acetylcholinesterase, butyrylcholinesterase, tyrosinase inhibitor activities and antioxidant potentials of the compounds were evaluated. Consequently, thunberginol C (free – not glycosylated form of 3,4-dihydroisocoumarin structure) showed better potential in all enzyme inhibitory activities compared to coumarin structure. Particularly, α-glucosidase inhibitory activity of this compound with a very low IC50 value (94.76±2.98 µM) compared to standard acarbose (1036.2±2.70 µM) should be noted. Glycosylation and/or methoxy substitution of 3,4-dihydroisocoumarin structure resulted a significant decrease in all tested enzyme inhibitory activities. The structures of esculin MH, umbelliferone, scoparone, scorzocreticoside I, and scorzopygmaeceoside might be considered in further synthetic studies as selective acetylcholinesterase inhibitors. Thunberginol C has a promising potential in tyrosinase inhibitory activity. Esculetin and thunberginol C showed the best results with high potentials in antioxidant activity via 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical scavenging, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid cation radical decolorization, and cupric ion reducing antioxidant capacity assays compared to the standards.

Development of a novel antioxidant based on a dimeric dihydroisocoumarin derivative

A biaryl dimer based on eurotiumide A, a dihydroisocoumarin-type natural product possessing a 1,4-hydroquinone skeleton, was synthesized herein. The radical scavenging activity and cytotoxicity were evaluated. The prepared biaryl dimer and eurotiumide A displayed comparable potent antioxidant activities to those of α-tocopherol and edaravone. However, the biaryl dimer did not show any cytotoxicity against murine colon and human myeloma cells.

ISOLATION AND CHARACTERISATION OF BERGENIN FROM ETHYL ACETATE EXTRACT OF FLUEGGEA VIROSA LEAVES

Bergenin is an important constituent of Flueggea virosa (Euphorbiaceae), a tropical plant with several traditional uses. While there are numerous reports on the isolation and characterization of bergenin, a rapid, high-throughput, readily accessible method for the isolation and characterization of the compound locally has not been reported. Isocratic elution of ethyl acetate extract via vacuum liquid chromatography (VLC) with methanol produced a white amorphous solid (100 mg), which was successfully isolated from 250 g of the plant. On the basis of spectral data (1H, C NMR, COSY, HSQC and HMBC) and comparison with literature reports, the structure of this solid was shown to be bergenin, a dihydroisocoumarin derivative of glucopyranosyl gallic acid.

The genus Tragopogon (Asteraceae): A review of its traditional uses, phytochemistry, and pharmacological properties.

Species of Tragopogon are used in traditional medicine, and consumed as vegetables across the world. In terms of the medicinal uses of Tragopogon, different species have found use in traditional medicine, including uses for wound-healing, treatment of gastrointestinal and hepatic complaints, cancer, kidney and liver dysfunction, inflamed skin and certain cutaneous diseases, as well as constipation, fatigue and anoxia. The aim of this review is to highlight and critically summarize those species of the genus that have been studied as a source of interesting lead compounds, and their traditional uses and bioactivities. A comprehensive and systematic review of literature on traditional uses, phytochemicals and pharmacological properties of the genus Tragopogon was carried out. Information was retrieved from secondary databases such as Scopus, Chemical Abstracts Services (Scifinder), Pubmed, Google Scholar and ScienceDirect, in addition to primary sources including books, PhD and MSc dissertations, and official websites. Species names were validated using "The Plant List" (www.theplantlist.org). The taxa of the genus Tragopogon are known for their local and traditional uses as medicine for treatment of various diseases, and have been consumed as vegetables and snacks for generations in Eurasia, the Mediterranean, Caucasus, Europe and North America. From the approximately 110 species of Tragopogon, only twelve species have been scientifically evaluated for their bioactivity and/or phytochemical composition. Tragopogon species are a rich source of phytochemical constituents and among those that have been identified are 19 flavonoids, 35 terpenoids, seven bibenzyl derivatives, five benzylphtalides, six stilbenes, nine dihydroisocoumarin derivatives, nine phenylmethane derivatives, three hydroxyphenylacetic acid derivatives, four phenylpropane derivatives, four esters of phenylpropanoic acids, a coumarin derivative, and a spermine derivative. Various extracts of the taxa, in addition to the isolated compounds, demonstrated pharmacological properties such as antitumor, antimicrobial, anti-inflammatory and enzyme inhibitory activities, in addition to hepatoprotective, antihyperlipidaemic and wound-healing properties. This review highlights the traditional uses, phytochemistry and pharmacological properties of the few studied taxa of the genus Tragopogon. Some of the reviewed papers were not of an appropriate methodological standard. For instance, phytochemical profiles were not determined, and the fundamental requirements of the pharmacological properties were not defined such as including appropriate positive and negative controls, and calculating the MIC values. Furthermore, these studies did not provide an in depth evaluation of bioactivity of the extracts and the isolated compounds or in vivo experiments which could indicate therapeutic relevance. From a phytopharmacological point of view, this review recommends more high quality evidence-based research on Tragopogon species for further development of plant-derived remedies and compounds.

Diaporone A, a new antibacterial secondary metabolite from the plant endophytic fungus Diaporthe sp.

Diaporone A (1), one new dihydroisocoumarin derivative and four known α-dibenzopyrones, alternariol (2), 5'-hydroxyalternariol (3), alternariol 4,10-dimethyl ether (4), and alternariol 4-methyl ether (5) were isolated from the crude extract of the plant endophytic fungus Diaporthe sp. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as HRESIMS and comparison with data from the literature. The absolute configuration of 1 was assigned by electronic circular dichroism (ECD) calculations. Compound 1 showed moderate antibacterial activity against Bacillus subtilis with the MIC value of 66.7 μM, and exhibited weak cytotoxicity against human cervical carcinoma (HeLa) cell line with IC50 value of 97.4 μM.

Dihydroisocoumarins produced by Diaporthe cf. heveae LGMF1631 inhibiting citrus pathogens.

Citrus black spot (CBS) and post-bloom fruit drop (PFD), caused by Phyllosticta citricarpa and Colletotrichum abscissum, respectively, are two important citrus diseases worldwide. CBS depreciates the market value and prevents exportation of citrus fruits to Europe. PFD under favorable climatic conditions can cause the abscission of flowers, thereby reducing citrus production by 80%. An ecofriendly alternative to control plant diseases is the use of endophytic microorganisms, or secondary metabolites produced by them. Strain LGMF1631, close related to Diaporthe cf. heveae 1, was isolated from the medicinal plant Stryphnodendron adstringens and showed significant antimicrobial activity, in a previous study. In view of the potential presented by strain LGMF1631, and the absence of chemical data for secondary metabolites produced by D. cf. heveae, we decided to characterize the compounds produced by strain LGMF1631. Based on ITS, TEF1, and TUB phylogenetic analysis, strain LGMF1631 was confirmed to belong to D. cf. heveae 1. Chemical assessment of the fungal strain LGMF1631 revealed one new seco-dihydroisocoumarin [cladosporin B (1)] along with six other related, already known dihydroisocoumarin derivatives and one monoterpene [(-)-(1S,2R,3S,4R)-p-menthane-1,2,3-triol (8)]. Among the isolated metabolites, compound 5 drastically reduced the growth of both phytopathogens in vitro and completely inhibited the development of CBS and PFD in citrus fruits and flowers. In addition, compound 5 did not show toxicity against human cancer cell lines or citrus leaves, at concentrations higher than used for the inhibition of the phytopathogens, suggesting the potential use of (-)-(3R,4R)-cis-4-hydroxy-5-methylmellein (5) to control citrus diseases.

Enantioselective Total Synthesis of (+)-Monocerin, a Dihydroisocoumarin Derivative with Potent Antimalarial Properties.

We describe here the enantioselective synthesis of (+)-monocerin and its acetate derivative. The present synthesis features an efficient optically active synthesis of the β-hydroxy-γ-lactone derivative with high enantiomeric purity using Sharpless dihydroxylation as the key step. The synthesis also highlights a tandem Lewis acid-catalyzed, oxocarbenium ion-mediated diastereoselective syn-allylation reaction, and a methoxymethyl group promoted methylenation reaction. We investigated this reaction with a variety of Lewis acids. A selective CrO3-mediated oxidation of isochroman provided the corresponding lactone derivative. The synthesis is quite efficient and may be useful for the preparation of derivatives.

3,4-Dihydroisocoumarins, Interesting Natural Products: Isolation, Organic Syntheses and Biological Activities.

3,4-dihydroisocoumarins are an important small group belonging to the class of naturally occurring lactones isolated from different bacterial strains, molds, lichens, and plants. The structures of these natural compounds show various types of substitution in their basic skeleton and this variability influences deeply their biological activities. These lactones are structural subunits of several natural products and serve as useful intermediates in the synthesis of different heterocyclic molecules, which exhibit a wide range of biological activities, such as anti-inflammatory, antiplasmodial, antifungal, antimicrobial, antiangiogenic and antitumoral activities, among others. Their syntheses have attracted attention of many researchers reporting many synthetic strategies to achieve 3,4-dihydroisocoumarins and other related structures. In this context, the isolation of these natural compounds from different sources, their syntheses and biological activities are reviewed, adding the most recent advances and related developments. This review aims to encourage further work on the isolation and synthesis of this class of natural products. It would be beneficial for synthetic as well as the medicinal chemists to design selective, optimized dihydroisocoumarin derivatives as potential drug candidates, since dihydroisocoumarin scaffolds have significant utility in the development of therapeutically relevant and biologically active compounds.

New bioactive chlorinated cyclopentene derivatives from the marine-derived Fungus Phoma sp

The new halogenated metabolites cryptophomic acid (1), cryptodiol (2), and cryptotriol (3) and the known dihydro-isocoumarin derivative 4, were isolated from the marine-derived fungus Phoma sp.135. The structural elucidation of these compounds was achieved by extensive analysis of spectroscopic data including 1D- and 2D-NMR, HRMS, optical rotation, UV, and IR. The absolute configuration of cryptophomic acid (1) was determined by using circular dichroism and TD-DFT ECD calculations of the solution conformers. The relative configurations of cryptodiol (2) and cryptotriol (3) were elucidated by a detailed analysis of the spectroscopic data and quantum mechanical calculation of NMR chemical shifts, based also on the newly reported + approach. The dihydro-isocoumarin derivative 4 was also produced by the same fungus and its structure was established as (R)-8-hydroxy-6-methoxy-3-methy-3,4-dihydro-isocoumarin (4), often referred to 6-methoxymellein and its chemical structure and absolute configuration were further confirmed through X-ray diffraction analysis. We report here the new compounds 1–3 and the crystallographic data of compound 4 for the first time. Additionally, we report significant antimicrobial activity of compounds 1–3 against Escherichia coli, Bacillus subtilis, Mycobacterium phlei, and Staphylococcus aureus and they showed no lethality against brine shrimp.

CpxR negatively regulates the production of xenocoumacin 1, a dihydroisocoumarin derivative produced by Xenorhabdus nematophila.

Xenocoumacin 1 (Xcn1), a major antimicrobial compound produced by Xenorhabdus nematophila, has great potential for use in agricultural productions. In this study, we evaluated the effects of CpxR, a global response regulator associated with the mutualism and pathogenesis of X. nematophila, on the antimicrobial activity and Xcn1 production. The mutation of cpxR could promote the production of Xcn1 significantly with its level in ΔcpxR mutant being 3.07 times higher than that in the wild type. Additionally, the expression levels of xcnA‐L genes, which are responsible for the production of Xcn1, were increased in ΔcpxR mutant while the expression levels of xcnMN, which are required for the conversion of Xcn1 into Xcn2 was reduced. Noticeably, Xcn2 was also enhanced on account of the conversion of excessive Xcn1 in spite of low expression levels of xcnM and xcnN in ΔcpxR mutant. The transcriptional levels of ompR and lrp, encoding the global response regulators OmpR and Lrp which negatively and positively regulate the production of Xcn1 were concurrently decreased and increased, respectively. Correspondingly, ΔcpxR mutant also exhibited increased antimicrobial activities in vitro and in vivo. Together, these findings suggest that CpxR negatively regulates xcnA‐L genes expression while positively regulating xcnMN expression in X. nematophila YL001, which led to a high yield of Xcn1 in ΔcpxR mutant.

A Dihydroisocoumarin from the Rhizome of Aloe pulcherrima

Chromatographic separation of the chloroform/methanol (1:1) extract of the Aloe pulcherrima rhizome afforded a new dihydroisocoumarin derivative (1) along with six anthraquinone derivatives (2-7). The chemical structures of the compounds were established based on spectroscopic analyses including NMR (1H and 13C NMR, 1H-1H COSY, HMQC, HMBC, NOESY), MS and comparison with reported literature. The isolated compounds were evaluated for in vitro antibacterial and antiplasmodial activities. Almost all compounds showed antibacterial activity with the highest activity observed for compound 5 against Enterococcus faecalis. Whereas, only compound, 3, 4, 5 and 6 showed antiplasmodial activity against chloroquine-resistant (W2) strain of Plasmodium falciparum.

A New Dihydroisocoumarin Derivative from the Extract of the Fungus Monascus-Fermented Rice

Examination of the EtOAc-soluble fraction from a 70% ethanolic extract of red yeast rice fermented with the yellow mutant of the fungus Monascus sp. (Eurotiaceae) yielded a new dihydroisocoumarin derivative, monascusmellein (1). The structure of compound 1 was determined by spectroscopic methods, including UV, IR, HR-ESI-MS, and extensive 1D and 2D NMR analysis.

Penicisimpins A⿿C, three new dihydroisocoumarins from Penicillium simplicissimum MA-332, a marine fungus derived from the rhizosphere of the mangrove plant Bruguiera sexangula var. rhynchopetala

Three new dihydroisocoumarin derivatives, penicisimpins A⿿C (1⿿3), were isolated and identified from Penicillium simplicissimum MA-332, a fungus derived from the rhizosphere of the marine mangrove plant Bruguiera sexangula var. rhynchopetala. Their structures and absolute configurations were elucidated by extensive spectroscopic methods in combination with X-ray diffraction experiment. Compounds 1⿿3 exhibited brine shrimp (Artemia salina) lethality as well as broad-spectrum antimicrobial activities.

Dihydroisocoumarin Derivatives from Marine-Derived Fungal Isolates and Their Anti-inflammatory Effects in Lipopolysaccharide-Induced BV2 Microglia.

Chemical investigation of the EtOAc extracts of marine-derived fungal isolates Aspergillus sp. SF-5974 and Aspergillus sp. SF-5976 yielded a new dihydroisocoumarin derivative (1) and 12 known metabolites. The structures of the isolated metabolites were established by extensive spectroscopic analyses, including 1D and 2D NMR spectra and MS data. Among the metabolites, the absolute configuration of 5'-hydroxyasperentin (6) was determined by single-crystal X-ray diffraction analysis. The in vitro antineuroinflammatory effects of the metabolites were also evaluated in lipopolysaccharide (LPS)-stimulated microglial cells. Among the isolated metabolites, dihydroisocoumarin derivatives 1-6 (10-80 μM) were shown to inhibit LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by suppressing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively, in LPS-stimulated BV2 microglia. Further, 1 (20-80 μM) was found to suppress the phosphorylation of the inhibitor of nuclear factor kappa B-α (IκB-α), interrupt the nuclear translocation of nuclear factor kappa B (NF-κB), and decrease the activation of p38 mitogen-activated protein kinase (MAPK).

Isocoumarin derivatives from the marine-derived fungus Phoma sp. 135

The dihydro-isocoumarin derivatives 1–2 were isolated from the marine-derived fungus Phoma sp. 135. Structural elucidation was achieved through extensive spectroscopic evaluation including 1D- and 2D-NMR, accurate mass measurements, and single crystal X-ray diffraction analysis. We report herein the structure and absolute configuration of the known compound 1 using X-ray diffraction, and the structural elucidation of the new dihydro-isocoumarin derivative 2.

Dihydroisocoumarin derivatives with antifouling activities from a gorgonian-derived Eurotium sp. fungus

Five pairs of new dihydroisocoumarin enantiomers, (±)-eurotiumides A–E, and two related racemates, (±)-eurotiumides F and G, were isolated from a gorgonian-derived fungus, Eurotium sp. XS-200900E6. The enantiomeric separations for (±)-eurotiumides A–E were achieved by chiral-HPLC, and their absolute configurations were determined by ECD spectra. All of the isolated compounds are rare dihydroisocoumarin derivatives with a methoxy at C-4. (+)- And (−)-eurotiumides B and D with cis configurations of H-3/H-4 exhibited potent antifouling activities against the larval settlement of the barnacle Balanus amphitrite with the EC50 values ranging from 0.7 to 2.3 μg/mL, and displayed high therapeutic ratios (LC50/EC50 >15). The tested compounds also showed extensive antibacterial activities. It was the first report of antifouling activities for dihydroisocoumarin derivatives.

New production of (R)-(–)-5-bromomellein, a dihydroisocoumarin derivative from the marine-derived fungus Aspergillus ochraceus

The addition of NaBr to the fermentation of a marine isolate of the fungus Aspergillus ochraceus resulted in induced production of a new brominated mellein analogue. A new radical-scavenging halogenated isocoumarin, (R)-(–)-5-bromomellein (1), and three known compounds, (R)-(–)-mellein (2), clavatol (3), and circumdatin A (4), were isolated from the culture. The structure of 1 was assigned through a combination of spectroscopic data analyses. Compounds 1–4 exhibited mild radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH). The IC50 values of each compounds (1–4) were 24, 25, 30, and 32 μM, respectively, which were less active than the positive control, L-ascorbic acid (IC50, 20.0 μM).

Two new dihydroisocoumarins from the endophytic fungus Aspergillus sp. collected from the south china sea

Two new dihydroisocoumarin derivatives, aspergillumarins A and B (1 and 2), were isolated from the culture broth of a marine-derived fungus Aspergillus sp., which was isolated from the fresh leaf of the mangrove tree Bruguiera gymnorrhiza collected from the South China Sea. The structures of compounds 1 and 2 were established by comprehensive analysis of the spectral data, especially 2D NMR spectra results. Compounds 1 and 2 showed weak antibacterial activity against Staphylococcus aureus and Bacillus subtilis at a concentration of 50 μg/mL.

Secondary metabolites from the liverwort Heteroscyphus coalitus

A new dihydroisocoumarin derivative, R-(−)-heteroscyphide (1), together with three known terpenoid derivatives (2–4), were isolated from the liverwort Heteroscyphus coalitus. Their structures were elucidated by spectroscopic methods and the biogenetic pathway of compound 1 was proposed. Cytotoxic test revealed that they exhibited moderate inhibitory activity to three human tumor cell lines.

An Enantioselective Approach toward 3,4-Dihydroisocoumarin through the Bromocyclization of Styrene-type Carboxylic Acids

A facile and enantioselective approach toward 3,4-dihydroisocoumarin was developed. The method involved an amino-thiocarbamate catalyzed enantioselective bromocyclization of styrene-type carboxylic acids, yielding 3-bromo-3,4-dihydroisocoumarins with good yields and ee's. 3-Bromo-3,4-dihydroisocoumarins are versatile building blocks for various dihydroisocoumarin derivatives in which the Br group can readily be modified to achieve biologically important 4-O-type and 4-N-type 3,4-dihydroisocoumarin systems. In addition, studies indicated that, by refining some parameters, the synthetically useful 5-exo phthalide products could be achieved with good yields and ee's.