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Three phthalide-derived analogues, oxaspiroangelioic acids A–C (1–3), were isolated as minor components of an aqueous extract of the Angelica sinensis root heads (guitou). Oxaspiroangelioic acids A and B were racemates separated into enantiomers by chiral HPLC. Their structures including absolute configurations were determined by spectroscopic data analysis, single crystal X-ray diffraction, exciton chirality method and electronic circular dichroism (ECD) calculation. These compounds share an undescribed carbon skeleton, for which biosynthetic pathways are proposed. Compound 1 and its enantiomers showed almost identical activity inhibiting Tandem of P domains in a weak inwardly rectifying K+ channel 1 (TREK-1).

The thermal polymerization of styrene in the presence of polymer initiators, copoly(arylene phthalides) of the diphenyl oxide series with different ratios of two adjacent (“head-to-head”) and single (“head-to-tail”) phthalide groups, was studied. Depending on the composition of copoly(arylene phthalides), either copolymers enriched in styrene units, or copolymers with prevailing arylphthalide groups are formed. Diphilic macromolecules of the copolymers form micelles in solutions, the size of which is determined by the ratio of styrene and phthalide units.

Electrospun polyimide (PI) ultrafine non-woven fibrous mats (UFMs) with good heat-fusibility via hot press procedure were successfully fabricated. For this purpose, two organo-soluble PI resins were prepared via a two-step chemical imidization procedure from two isomeric oxydiphthalic dianhydrides, including the asymmetrical ODPA (2,3,3′,4′-oxydiphthalic dianhydride, or aODPA) and symmetrical ODPA (4,4′-oxydiphthalic dianhydride, or ODPA) with an aromatic diamine containing phenolphthalein unit in the main chain, 3,3-bis[4-(4-aminophenoxy)phenyl]phthalide (BAPPT), respectively. The derived PI-1 (aODPA-BAPPT) and PI-2 (ODPA-BAPPT) resins showed high numerical average molecular weights (Mn) over 105 g/mol and were easily soluble in polar aprotic solvents, such as N-methyl-2-pyrrolidinone (NMP) and N, N-dimethylacetamide (DMAc). PI-1 and PI-2 UFMs were successfully prepared from the PI solutions in DMAc via the one-step electrospinning procedure. Different rotating speeds of 500–2500 round per minute (rpm) for the cylindrical collector were set to investigate the effects of the fiber morphologies on the properties of the PI UFMs. The derived PI UFMs showed good thermal stability with the glass transition temperatures (Tg) over 280 °C and 5 % weight loss temperatures (T5%) higher than 510 °C in nitrogen. The PI UFMs could be successfully heat-sealed via the hot-press temperature at 320 °C (about 40 °C higher than Tg) for 60s with the pressure of 0.5 MPa.

A convenient approach for the synthesis of 3-difluoroalkyl phthalides has been developed from phthalaldehydic acids and difluoroenoxysilanes by using relatively inexpensive p-toluenesulfonic acid monohydrate (PTSA) as a catalyst. A series of 3-difluoroalkyl phthalides and cyclic difluoroalkyl ethers were obtained in up to 99% yield. The products obtained could be readily converted into difluoroalkyl phthalide derivatives by simple modifications.

A mild and practical C(sp3)-H lactonization protocol has been achieved by merging photocatalysis and magnesium (iron, nickel) catalysis. A diverse range of 2-alkylbenzoic acids with a variety of substitution patterns could be transformed into the corresponding phthalide products. Based on the mechanistic experimentation and reported prior studies, a possible mechanism for the benzylic oxidative lactonization reaction was proposed with the hypothetic photoactive ternary complex formed between the 2-alkylbenzoic acid substrate, magnesium ion, and bromate anion.

A new azaphthalide derivative, (S)-3-hydroxy-2,7-dimethylfuro [3,4-b]pyridin-5(7H)-one (1), and a new phthalide derivative, (S)-7-hydroxy-3-((S)-1-hydroxyethyl)isobenzofuran-1(3H)-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 IC50 value of 15.6 μg/mL.

Five new polyketides were isolated from the rare filamentous fungus Aspergillus californicus IBT 16748 including calidiol A (1); three phthalide derivatives califuranones A1, A2, and B (2-4); and a pair of enantiomers (-)-calitetralintriol A (-5) and (+)-calitetralintriol A (+5) together with four known metabolites (6-9). The structures of the new products were established by extensive spectroscopic analyses including HRMS and 1D and 2D NMR. The absolute configurations of two diastereomers 2 and 3 and the enantiomers (-5) and (+5) were assigned by comparing their experimental and calculated ECD data, whereas the absolute configuration of 4 was proposed by analogy. Compound 1 showed moderate activity against methicillin-resistant Staphylococcus aureus.

The interbicopolycondensation of 3,3'-bis(4-phenoxyphenyl)-3,3'-diphthalide and diphenyl oxide with intermonomer, 4,4'-bis(2-carboxybenzoyl)diphenyl oxide pseudoacid dichloride, proceeding by the Friedel–Crafts electrophilic substitution mechanism is used for the synthesis of a number of new diphenyl oxide copolyarylenephthalides with different ratios of phthalide and diphthalide groups in the polymer chain. It is shown that the ratio of diphthalide (meso and racemic) and common phthalide groups in the main chain significantly affects the morphological structure of the copolymers. A side “rephthalidation” reaction is found, which consists in the catalytic cleavage of the diphthalide group accompanied by the generation of two phthaloyl carbocations, which, along with the intermonomer, interact with diphenyl oxide, participating in the polymer-forming reaction.

A practical and efficient method is established for the direct oxidative lactonization of the C(sp3)–H bonds relying on visible-light-induced photoredox catalysis. This protocol expediently allows the delivery of diverse phthalides using oxygen as the sole terminal oxidant under metal-free conditions at room temperature. Notably, the choice of an appropriate hydrogen atom transfer (HAT) cocatalyst is revealed to be critical for the success of this process.

Three new ophiobolin sesterterpenoids, (6R)-16,17,21,21-O-tetrahydroophiobolin G (1), (6R)-16,17-dihydroophiobolin H (2), and (5S,6S)-16,17-dihydroophiobolin H (3), and three new farnesylated phthalide derivatives farnesylemefuranones D-F (9-11), along with five known ophiobolin analogues (4-8), were isolated and identified from the culture extract of Aspergillus insuetus SD-512, a deep-sea-derived fungus obtained from cold seep sediments collected at a depth of 1331 m. Among them, compounds 9-11 are rare examples of phthalide derivatives linked with farnesyl moieties via ether bonds. Their structures were established on the basis of detailed interpretation of the NMR spectroscopic and mass spectrometric data. X-ray crystallographic analysis, ECD calculations, and DP4+ probability analysis were performed to confirm the structures and establish the relative and absolute configurations of compounds 1-4. Compounds 3 and 9-11 showed broad-spectrum antibacterial activities, and differences in potencies could be assigned to structural modifications. This is the first report of secondary metabolites obtained from a deep sea cold-seep-derived fungus.

Objective: The study aims at the derivatization of “Phthalides” and synthesizes 3- arylaminophthalides & 3-indolyl-phthalides compounds, and evaluates their anti-tubercular and antioxidant activities. The study has also intended to employ the in silico methods for the identification of possible drug targets in Mycobacterium and evaluate the binding affinities of synthesized compounds. Methods: This report briefly explains the synthesis of phthalide derivatives using ammonium chloride. The synthesized compounds were characterized using spectral analysis. Resazurin Microtiter Assay (REMA) plate method was used to demonstrate the anti-mycobacterial activity of the synthesized compounds. An in-silico pharmacophore probing approach was used for target identification in Mycobacterium. The structural level interaction between the identified putative drug target and synthesized phthalides was studied using Lamarckian genetic algorithm-based software. Results and Discussion: In the present study, we report an effective, environmentally benign scheme for the synthesis of phthalide derivatives. Compounds 5c and 5d from the current series appear to possess good anti-mycobacterial activity. dCTP: deaminasedUTPase was identified as a putative drug target in Mycobacterium. The docking results clearly showed the interactive involvement of conserved residues of dCTP with the synthesized phthalide compounds. Conclusion: On the eve of evolving anti-TB drug resistance, the data on anti-tubercular and allied activities of the compounds in the present study demonstrates the enormous significance of these newly synthesized derivatives as possible candidate leads in the development of novel anti-tubercular agents. The docking results from the current report provide a structural rationale for the promising anti-tubercular activity demonstrated by 3-arylaminophthalides and 3-indolyl-phthalides compounds.

A cross-dehydrogenative coupling of arene carboxylic acids with olefins is reported with ruthenium(II) catalyst employing air and water as green oxidant and solvent, respectively. It offers a robust synthesis of valuable phthalide molecules. A one-pot sequential strategy is also disclosed to access Heck-type products that are apparently difficult to make directly from arene carboxylic acids.

2-Ferrocenyl­carbonyl­benzoic acid (C18H14FeO3) was synthesized from the Friedel–Crafts acyl­ation of ferrocene with phthalic anhydride, and the product was reduced to 3-ferrocenylphthalide (C18H14FeO2) using Zn(Cu) in aqueous sodium hydroxide. Both compounds were characterized using IR, NMR, and single-crystal X-ray analysis., The title compounds, 2-(ferrocenylcarbon­yl)benzoic acid, [Fe(C5H5)(C13H9O3)], 1, and 3-ferrocenylphthalide [systematic name: 3-ferrocenyl-2-benzo­furan-1(3H)-one], [Fe(C5H5)(C13H9O2)], 2, have been synthesized and structurally characterized by single-crystal X-ray diffraction. The crystal structure of compound 1 was solved recently at room temperature [Qin, Y. (2019 ▸). CSD Communication (CCDC deposition number 1912662). CCDC, Cambridge, England]. Here we report a redetermination of its crystal structure at 90 K with improved precision by a factor of about three. The mol­ecular structures of both compounds exhibit a typical sandwich structure. In the crystal packing of compound 1, each mol­ecule engages in inter­molecular hydrogen bonding, forming a centrosymmetric dimer with graph-set notation R 2 2 (8) and an O⋯O distance of 2.6073 (15) Å. There are weak C—H⋯O and C—H⋯π inter­actions in the crystal packing of compound 2. The phthalide moiety in 2 is oriented roughly perpendicular to the ferrocene backbone, with a dihedral angle of 77.4 (2)°.

Background: Stachys (Lamiaceae) is a genus with varied effects and applications in traditional medicine. The essential oil (EO) of different species of genus Stachys has received much attention in different studies. According to previous evidence, the components of EO in different species have diversity although there is no previous data regarding investigating Stachys fruticulosa for EO. Considering the importance of the plants of genus Stachys, vast types of compounds in the EO of the genus, the aim of the present study was to evaluate the components of EO of S. fruticulosa M. Bieb. Methods: The EO of the aerial parts from S. fruticulosa was obtained by hydrodistillation and then the oil was analyzed by gas chromatography/mass spectrometry (GC/MS) and 95% of the oil (17 components) was identified accordingly. The identity of the components was assigned by comparing their mass spectra and retention indices with those of authentic samples. Results: Most oil components were α-terpinyl acetate (24.6%), 3-n-Butyl phthalide (20.5%), p-cymene (18.2%), and β-phellandrene (18.2%). Conclusion: The components of essential oil from S. fruticulosa were identified for the first time, and these substances may be responsible for the biological effects of these essential oils.

A facile and convenient synthesis of the chiral phthalide framework catalyzed by cationic iridium was developed. The method utilized cationic iridium/bisphosphine-catalyzed asymmetric intramolecular carbonyl hydroacylation of 2-keto benzaldehydes to furnish the corresponding optically active phthalide products in good to excellent enantioselectivities (up to 98% ee). The mechanistic studies using a deuterium-labelled substrate suggested that the reaction involved an intramolecular carbonyl insertion mechanism to iridium hydride intermediate. In addition, we investigated the kinetic isotope effect (KIE) of intramolecular hydroacylation with deuterated substrate and determined that the C-H activation step is not included in the turnover-limiting step.

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74–88% ee). The enantiomeric purity could be substantially enhanced to 94–95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

Three previously undescribed metabolites named argyrotoxins A-C, were isolated, together with the well known porritoxinol, its closely related phthalide, a phthalide derivative, zinniol, alternariol and its 4-methyl ether from Alternaria argyroxiphii E.G. Simmons & Aragaki, the causal agent of leaf spot on African mahogany trees, Khaya senegalensis A. Juss. (Meliaceae). The known compounds were identified comparing their physical and spectroscopic properties to those previously reported in literature. Argyrotoxins A-C were characterized essentially by NMR (1H, 13C, COSY, HSQC, HMBC and NOESY NMR spectra) and HRESIMS spectra as 4-(7-methoxy-6-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yloxy)-2-methyl-butyric acid, 5-but-2-enyloxy-N-(2-hydroxyethyl)-2-hydroxymethyl-3-methoxy-4-methyl-benzamide and 1-(5-(hydroxymethyl)-3-methoxy-4-(methoxymethyl)-2-methylphenoxy)-3-methylbutane-2,3-diol, respectively. The absolute configuration of argyrotoxin A was determined through electronic circular dichroism, by applying the biphenyl chiroptical probe approach. The phytoxicity of all metabolites isolated was evaluated by leaf puncture assay at concentration of 1 mg/mL. Zinniol proved to be the most active compound causing necrotic lesions on young leaves of Hedera elix L., Phaseolus vulgaris L. and Quercus ilex L. Argirotoxins A and B were found active, to a minor extent, on Phaseolus vulgaris L. leaves, while porritoxinol exhibited activity on holm oak leaves. The other secondary metabolites herein reported for A. argyroxiphii were inactive.

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.

Two new phthalide derivatives, rhytidhylides A (1) and B (2), together with ten known compounds (3–12) were isolated from cultures of Rhytidhysteron sp. BZM-9, an endophyte isolated from the leaves of Leptospermum brachyandrum. Their structures were identified by an extensive analysis of NMR, HRESIMS, ECD, and through comparison with data reported in the literature. In addition, the cytotoxic activities against two human hepatoma cell lines (HepG2 and SMMC7721) and antibacterial activities against MRSA and E. coli were evaluated.

Cardo- phenolphthalein formaldehyde resin was studied as a binder of antifriction organoplastics. The role of the phthalide cycle in the structure of the polymer during its curing process is shown. Experimental data on the effect of processing temperature on the tribological and thermofriction properties of organoplastics reinforced with polyoxadiazole fiber are presented.

(+)-6-3'a,7-6'-Isowallichilide and (−)-6-3'a,7-6'-isowallichilide, a pair of enantiomeric phthalide dimers featuring new 6-3'a,7-6' dimerization sites, were isolated from Ligusticum chuanxiong. The structures were elucidated by NMR spectroscopy and X-ray diffraction analysis. Furthermore, the absolute configurations were assigned using experimental and theoretical electronic circular dichroism methods. Their nitric oxide inhibition, antiplatelet aggregation and antioxidant activities were investigated.

The temperature dependence of the resistivity of thin poly(diphenylene phthalide) films in a highly conductive state is studied. A metallic type of conductivity in the range of low temperatures is observed, suggesting the possibility of charge transfer in the films along a narrow conduction band in the band gap.

The use of polymer dielectrics as a matrix for fullerene derivatives allows photoconductive properties of fullerene-containing materials to be induced. Results are presented from studying the properties of poly(diphenylene phthalide) (PDP) doped with fullerene derivatives.

The roots of Ligusticum porteri J.M. Coult. & Rose, Apiaceae, are used in Mexican traditional medicine for the treatment of gastrointestinal disorders. The dimeric phthalide (Z´)-diligustilide found in their organic extracts is associated with the gastroprotective properties. In this study, the gastroprotective effect of nanoemulsion of the volatile oil from the roots of L. porteri (at doses of 1, 3, 10, and 30 mg/kg) in the indomethacin-induced gastric damage model was tested, and nitric oxide (NO) and hydrogen sulfide (H2S) gastric levels were determinate. The volatile oil obtained by steam distillation (0.63% yield) contained 37 constituents, as assessed by GC-MS analysis, where the significant compounds were 4-phenyl-3-buten-2-ol (20.54%) and (Z)-3-butylidenephthalide (20.54%) that correspond to phthalide monomers. These results demonstrate that nanoemulsion of the volatile oil from L. porteri (at 10 and 30 mg/kg) shows a significant gastroprotective effect (72 and 92% respectively) against indomethacin-induced gastric damage, which is not different from the gastroprotective effect of omeprazole (69%) (p

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 IC50 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. Keywords: Phthalide, Indole, Indoline, Antiproliferative activity, Molecular docking

Indole and phthalide are privileged heterocyclic scaffolds in numerous natural products and bioactive molecules. The synthesis and biological evaluation of the compounds combining these two scaffolds have rarely been reported. Herein, we repot the first palladium-catalyzed ligand-free double cyclization reactions that enable efficient synthesis of 3-(1'-indolyl)-phthalides (42 examples, up to 96% yield) under mild conditions. Notably, only 1.0 mol % of catalyst loading is used, suggesting high efficiency. Late-stage elaborations give highly functionalized analogues.

Phtalides are secondary metabolites found in several fungi with a wide range of biological activities. A novel phthalide analog was synthesized by Diels-Alder reaction between cyclopentadiene and 3,4-dichlorofuran-2(5H)-one. Quantum mechanical calculations were used in conjunction with the spectrometric methods to determine the structure of the title compound. The calculated NMR chemical shifts for eight candidate pairs of enantiomers were compared with the experimental NMR chemical shifts applying the DP4 probability and mean absolute errors methodology. DP4 analysis using 1 H and 13 C NMR chemical shifts without assignment of the signals presented 100% probability for the correct candidate structure 3d, proving the consistency of the method even without spectra interpretation. Results from theoretical calculation and NMR spectra interpretation were in agreement to the structure of rac-(3aR,4S,4aS,5R,8S,8aR,9R,9aS)-3a,9a-dichloro-3a,4,4a,5,8,8a,9,9a-octahydro-4,9:5,8-dimethanonaphtho[2,3-c]furan-1(3H)-one.

We have provided a critical review that focuses on key developments in the area of 3-substituted phthalides and their role in the development of important biologically active natural products. 3-Substituted phthalides are vital molecules owing to their fascinating biological activity. The scope, isolation, and characterization of various naturally occurring racemic and chiral 3-substituted phthalides have been covered. We have put significant emphasis on recently developed research methodologies for the synthesis of racemic and chiral 3-substituted phthalides. These newer approaches are essential for the development of newer and elegant strategies for the synthesis of phthalide-based or similar molecular architecture with broader substrate scope and higher stereoselectivities. Also, we have discussed the application of 3-substituted phthalides as a precursor for the synthesis of natural products and their analogs.

Herein, facile and enantioselective approaches to synthesize the core phthalide tetrahydroisoquinoline scaffold of (−)-β-hydrastine via both a CF3COOH-catalyzed (86% ee) and KHMDS-catalyzed (78% ee) epoxide ring-opening/transesterification cascade cyclization from chiral epoxide under very mild conditions are described. The key elements include a highly enantioselective epoxidation using the Shi ketone catalyst and an intramolecular CF3COOH-catalyzed cascade cyclization in one pot, and a late-stage C-3′ epimerization under MeOK/MeOH conditions as the key steps to achieve the first total synthesis of (−)-β-hydrastine (up to 81% ee).

Flash vacuum pyrolysis of methyl N-methyl-N-nitrosoanthranilate leads to elimination of nitric oxide and disproportionation of the formed N-radical to 7-(methylamino)phthalide and methyl N-methylanthranilate. This transformation was found to be a convenient, solvent-free method for the preparation of 7-(methylamino)phthalides. An alternative route through pyrolysis of N-benzyl-N-methyl anthranilates was also investigated.

The first tolan derivative-based viscosity sensor (5d) has been synthesized, and its fluorescence intensity and lifetime increase when the viscosity of the solvent increases in methanol–glycerol mixtures. Phthalide (5d) was selected among structurally diverse tolan derivatives through systematic modifications of a simple tolan. To test 5d as a viscosity sensor, fluorescence lifetime imaging (FLIM) images of HeLa cells were obtained upon treatment with 5 μM of 5d to map the viscosity of the HeLa cells.

Mechanistic studies relating to the photochemistry of 3-hydroxy-2-phenyl-4H-chromen-4-one (3HF) and 6-chloro-3-hydroxy-2-phenyl-4H-chromen-4-one (Cl-3HF) have been reinvestigated in selected solvents. The UV-visible spectra of the photoproduct(s) of 3HF and Cl-3HF have been computed in situ via subtracting the spectra of unreacted substrates, with acetonitrile (ACN) and methanol (MeOH) as solvents. These spectra turn out to be different from the spectra of the corresponding isolated photoproducts: 3-hydroxy-3-phenyl-indan-1,2-dione and 6-chloro-3-hydroxy-3-phenyl-indan-1,2-dione (referred to as dione ). Analyses of the photoproduct(s) via GC-MS show the formation of a single detectable product, i.e., the corresponding dione. On the basis of some experimental observations, it is proposed that the primary photoproduct in situ is 2,3-epoxy-2-hydroxy-1-indanone (referred to as epoxide) instead of dione as reported in previous years. Earlier, epoxide has been proposed to be the intermediate in the mechanism for the formation of dione. This is the first report where the formation of epoxide has been directly detected in the selected solvents. On the other hand, both dione and epoxide (2 : 1) are shown to be formed with MeOH as solvent. The second important finding is that epoxide and dione interconvert in the dark, depending upon the environment. With ACN as solvent, pure dione in the dark is kinetically and partially converted to epoxide. With MeOH as solvent, epoxide is instantly and partially converted to dione until both are in equilibrium. However, a solution of dione in MeOH remains stable in the dark. The photoformation of epoxide is quantitative with ACN as solvent and it is sufficiently stable. It has been further observed that epoxide solutions of 3HF and Cl-3HF in ACN are quantitatively converted into 3-phenylisobenzofuran-1(3H)-one and 6-chloro-3-phenylisobenzofuran-1(3H)-one, i.e., the corresponding phthalides, through the loss of CO when kept in the dark for some days. A mechanism has been proposed where epoxide has been shown to give dione and/or phthalide via selective C-O or C-C bond cleavage in the oxiranyl ring, respectively. The selection of this cleavage depends mainly on the solvent system and the substituents in the parent flavones.

Four new meroterpenoids, austalides V-X (1-3) and a farnesylated phthalide derivative (4), were isolated from the culture of the marine fungus Penicillium rudallense, together with eight known meroterpenoids derivatives (5-12). Their structures, including absolute configurations, were determined by spectroscopic methods. All of the isolated compounds were evaluated for their inhibitory activities on the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. Compounds 1, 2, 5-7, and 10 exhibited potent osteoclast differentiation inhibitory activity with ED50 values of 1.9-2.8 μM.

Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy Papaver somniferum, is traditionally being used as an anticough drug. With a safe in vitro toxicological profile, noscapine and its analogues have been explored to show microtubule-regulating properties and anticancer activity against various mammalian cancer cell lines. Since then, our group and other research groups worldwide are working on developing new noscapinoids to tap its potential as the leading drug molecule. With our continuing efforts, we herein present synthesis and anticancer evaluation of a series of imidazothiazole-coupled noscapinoids 7a–o and 11a–o. Natural α-noscapine was N-demethylated to nornoscapine 4 and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant noscapinoid 5 was coupled with various bromomethyl ketones 10a–o to give N-imidazothiazolyl noscapinoids 7a–o in very good yields. Similarly, natural α-noscapine 1 was O-demethylated using sodium azide/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones 10a–o to result in O-imidazothiazolyl noscapinoids 11a–o. All the new analogues 7a–o and 11a–o were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds 5, 7a–o, 9, and 11a–o against four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these conjugates, 5, 7a, 9, 11b, 11c, 11e, and 11o showed potent cytotoxicity with low IC50 values. Further, flow cytometry analysis revealed that MIA PaCa-2 cells treated with these compounds induced cell cycle G2/M-phase arrest. In addition, Western blot analysis revealed that the cells treated with these conjugates accumulate tubulin in the soluble fraction and also elevate cyclin-B1 protein expression levels. Moreover, the conjugates also increased the expression of caspase-3 and PARP levels which is indicative of apoptotic cell death. In silico molecular docking studies showed several noncovalent interactions like van der Waals and hydrogen-bonding with tubulin protein and with good binding energy. The results indicated that these noscapine analogues may serve as novel compounds that can possibly inhibit tubulin protein and can be considered for further optimization as a clinical candidate for treating pancreatic cancer.

Several phthalides were semisynthesized, including a 3,8-dihydrodiligustilide with progesterone-like activity, previously isolated from Ligusticum chuanxiong, the structure of which was earlier assigned to a semisynthetic product with nonidentical spectroscopic constants. The structure of this natural phthalide was reassigned with a proposal of its absolute configuration. Phthalides acted as progestins in cell viability assays, immunofluorescence microscopy, and docking analysis. Therefore, the structures for natural and semisynthetic phthalides with potential use in hormone-related therapies were reassigned.

The thermally stimulated luminescence (TSL) of poly(diphenylene phthalide) (PDP) films with terminal acid and diphenyl groups was studied using mathematical modeling methods. An adequate description (relative mean deviation, 6%) of the kinetic curves of TSL was obtained and the activation parameters of individual steps were determined by solving an inverse kinetic problem within the framework of a three-center four-step reaction scheme. The kinetics of TSL indicated the existence of two independent channels leading to the generation of an electronically excited diphenylene fragment of the polymer chain. The photoexcitation of PDP leads to the formation of a system of separated ion–radical states and, as a result, to the activation of individual polymer fragments. The subsequent recombination processes with the participation of the most active states occur through successive stages, and they are characterized by relatively low activation energies (Ea2 = 23 kJ/mol and Ea3 = 42 kJ/mol), which are traditionally interpreted in terms of the theory of mechanical relaxation as the vibrations of the smallest structural elements of the polymer (supposedly, the triarylmethyl-type side fragments of PDP). The high-temperature TSL (>370 K) is described in terms of the Randall–Wilkins model, and it is probably caused by the segmental mobility of the polymer (Ea1 = 70.5 kJ/mol). The data obtained indicate that the mid-chain units of the polymer mainly participate in the generation of electronically excited states: an analysis of activation parameters estimated from the kinetics of TSL of PDP films with different terminal units showed no significant differences in the described recombination processes.

Synthetically derived (Z)-ligustilide (1) has been subjected to photochemically-promoted dimerization processes under a range of conditions. By such means, varying distributions of the dimeric natural products tokinolides A–C (4, 3, and 6, respectively) and riligustilide (5) as well certain related (isomeric) compounds have been obtained. The structures of three of them have been confirmed by single-crystal X-ray analysis. The biosynthetic implications of the outcomes of this study are discussed.

The [4 + 1] annulation of benzamides and aldehydes for phthalide synthesis was achieved via rhenium-catalyzed C-H activation, which demonstrates an unprecedented reaction pattern distinct from those of other transition-metal catalyses. The reaction also features readily available starting materials, a wide scope for both electro-rich and electro-deficient substrates, and the elimination of homoannulation byproducts.

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.

The photoluminescence (PL) method has been used to study the change in the PL spectra of poly(diphenylene phthalide) (PDP) films under the influence of such factors as the wavelength of the exciting light, the duration of exposure to UV light, and annealing. The contribution to the change in the PL spectra of pretreatment of the samples and the structure of the terminal units of the polymer chain has been estimated. The recombination mechanism of experimentally observed processes in PDP films upon UV irradiation and annealing is discussed. These processes include, in particular, the processes of transformation of the lateral and defective fragments of polymer chains, and the reasons for the appearance of the long-wavelength emission band and the change in the ratio of the intensities of the emission bands with maximums at 344 and ~500 nm.

Ethnopharmacological relevance 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. Materials and methods 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. Results Concentration-dependent antiadhesive activity was found for the hydroalcoholic and even more for the acetone extract AE (IC50 85 μg/mL) from celery fruits. Bioassay-guided fractionation revealed the presence of the phthalides senkyunolide (1, inactive) and sedanenolide (2, IC50 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 IC50 of 611 μM. Furthermore, AE caused a significant upregulation of fimH and sfaG in free floating, non-attached UPEC and significantly down-regulated these genes in adherent bacteria. Conclusions 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.

Acetyl-benzoic acid transformed into its phthalide form (so called Ph-2ABA) when it is crystalized. Also, in the crystalline structure is concerned, it contains four molecules in a unit cell including a dimer. The present study focuses the monomer and dimer structures of Ph-2ABAand their vibrational characteristics and electronic transitions. The FT-IR spectrum of Ph-2ABA was recorded in the region 4000-400 cm−1 and the bands were assigned by using potential energy distribution. The UV–vis absorption spectrum of the molecule in the water solution was recorded in the region 190-300 cm−1 and the molecular orbital contributions associated with the absorption bands were identified. TD-DFT calculations were also performed to elucidate the solvent effect on the electronic transitions. Moreover, the hidden bands (vibrational contributions) in the UV-absorption spectrum is resolved theoretically. Quantum topological atoms in molecule parameters of the molecule and FT-IR spectrum validates the dimer formation in the crystal structure. The charge transfer species corresponding to the hydrogen bonding interactions were identified by natural bond orbital analysis. The experimental results are well supported by the theoretical parameters.

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.

Highly regioselective 5- exo bromolactonizations of stilbene-type carboxylic acids bearing electron-withdrawing substituents are achieved for the first time via the use of chiral bifunctional sulfide catalysts possessing a urea moiety. The chiral phthalide products are obtained in moderate to good enantioselectivities as the result of 5- exo cyclizations., Synlett, 30(14), art.no.st-2019-w0187-c, pp.1662-1666; 2019

A 70% ethanol extract from the root portion of Reynoutria japonica afforded one new and three known juglone derivatives, namely, 2-methoxy-6-acetyl-7-methyljuglone (1), 2-ethoxy-6-acetyl-7-methyljuglone (2), 2-methoxy-7-acetonyljuglone (3), and 3-acetyl-7-methoxy-2-methyljuglone (4) together with two phenolics (5 and 6), an anthraquinone (7), a stilbene (8) and a phthalide (9). Their structures were elucidated on the basis of comprehensive spectroscopic studies including IR, MS, and 1H, 13C, 2D NMR spectra. Compound 3 is a new compound in nature, and compounds 4–6 have been isolated for the first time from R. japonica. The isolates were evaluated for their antibacterial activity against three strains (43504, 51, and 26695) of Helicobacter pylori. The four isolated juglone derivatives (1–4) showed potent growth inhibitory activity. Among them, compounds 1–3 exhibited stronger inhibitory activity than those of the positive controls, juglone and metronidazole, for the three strains and that of another reference, clarithromycin, for the 43504 and 51 strains. Specifically, the new juglone compound 3 displayed the most potent antibacterial activity against all three strains, 43504, 51, and 26695, with MIC values of 0.06, 0.06 and 0.13 μM, respectively, and MIC50 values of 0.14, 0.11 and 0.15 μM, respectively.

A voltammetric sensor based on a composite of polyarylene phthalide and graphitized carbon black Carboblack C modified with chelate complexes of L-argenato-L-alaninate of copper (II) has been developed for the recognition and selective determination of tryptophan enantiomers. The conditions for modifying the sensor are optimized, the effective surface area (A = 4.38 ± 0.06 mm2) and the effective resistance (Ret = 1.29 ± 0.08 kΩ) are calculated. The optimal conditions for recording voltammograms of tryptophan enantiomers are selected: the range of operating potentials is 0.5-1.2 V, the potential sweep rate is 20 mV/s, the holding time of the electrode in the test solution is 5 s. The electrochemical and analytical characteristics of the sensor were studied when registering differential pulse voltammograms of tryptophan enantiomers. It is shown that the dependence of the analytical signal on the concentration is linear in the range from 1.25·10-6 to 1·10-3 M with detection limits of 0.90·10-6 M for L-Trp and 0.66·10-6 M for D-Trp. The developed sensor shows the greatest sensitivity to D-Trp. The sensor has been successfully tested to determine the content of L- and D-Trp in enantiomer solutions in the presence of excipients that are part of medicines and biologically active additives. The proposed sensor allows the determination of tryptophan enantiomers in human urine and blood plasma. To evaluate the analytical capabilities of the sensor, the "entered-found" method was used. When determining tryptophan enantiomers in model solutions, the relative standard deviation does not exceed 2.3 %, and the relative error is 1.7 %. When determining D- and L-Trp in biological fluids, the relative standard deviation ranges from 0.3-1.7 %, and the relative error ranges from 0.3-5.6 %. The research results show that there is no significant systematic error.Keywords: voltammetry, modified electrodes, enantiomers, amino acids, tryptophan, polyarylenephthalide, biologically active additives, sports nutrition. DOI: http://dx.doi.org/10.15826/analitika.2021.25.3.006R.A. Zilberg, Yu.B. Teres, L.R. Zagitova, Yu.A. Yarkaeva, T.V. Berestova Bashkir State University, Department of Chemistry,Validy Str., 32, Ufa, 450076, Russian Federation, Разработан вольтамперометрический сенсор на основе композита полиариленфталида (ПАФ) и графитированной сажи Carboblack C, модифицированной хелатными комплексами L-аргенато-L-аланинат меди (II), для распознавания и селективного определения энантиомеров триптофана (Трп). Оптимизированы условия модифицирования сенсора, рассчитана площадь эффективной поверхности (А = 4.38 ± 0.06 мм2) и сопротивление переноса электрона (Ret= 1.29 ± 0.08 кОм). Подобраны оптимальные условия регистрации вольтамперограмм энантиомеров Трп: диапазон рабочих потенциалов 0.5-1.2 В, скорость сканирования потенциала 20 мВ/с, время выдерживания электрода в исследуемом растворе 5 с. Изучены электрохимические и аналитические характеристики сенсора при регистрации дифференциально-импульсных вольтамперограмм (ДИВ) энантиомеров Трп. Показано, что зависимость аналитического сигнала от концентрации L-Трп и D-Трп линейна в диапазоне от 1.25·10-6 до 1.00·10-3 М с пределами обнаружения (ПО) 0.90·10-6 М для L-Трп и 0.66·10-6 М для D-Трп. Наибольшую чувствительность разработанный сенсор проявляет к D-Трп. Сенсор успешно апробирован для определения содержания L- и D-Трп в растворах энантиомеров в присутствии вспомогательных веществ, входящих в состав лекарственных препаратов и биологически активных добавок. Предложенный сенсор позволяет проводить определения энантиомеров Трп в моче и плазме крови человека. Для оценки правильности определения D- и L-Трп использован метод "введено-найдено". При определении энантиомеров Трп в модельных растворах (n = 5; P = 0.95) относительное стандартное отклонение не превышает 2.3 %, а относительная погрешность – 1.7 %. При определении D- и L-Трп в биологических жидкостях (n = 5; P = 0.95) относительное стандартное отклонение колеблется в пределах 0.3-1.7 %, а относительная погрешность в пределах 0.3-5.6 %. Результаты исследований показывают отсутствие значимой систематической погрешности.Ключевые слова: вольтамперометрия, модифицированные электроды, энантиомеры, аминокислоты, триптофан, полиариленфталид, биологически активные добавки, спортивное питаниеDOI: http://dx.doi.org/10.15826/analitika.2021.25.3.006

The rhizome of Ligusticum chuanxiong Hort. has been widely used for the therapy of diabetic nephropathy (DN) in traditional Chinese medicine (TCM). The nuclear transcription factor erythroid 2-related factor (Nrf2) is a potential target for treating DN. The purpose of this research was to study the chemical constituents from the rhizome of L. chuanxiong, evaluate their Nrf2 inducing activity, and find the molecules with potential therapeutic effect against DN. In this study, two new phthalides (1-2) along with twenty-seven known constituents were obtained from the rhizome of L. chuanxiong. Their structures were elucidated through various spectroscopic methods. Twelve constituents, including eight phthalides (2, 5, 6, 10-13, 14) and four other compounds (17, 18, 20, 28), stimulated NAD(P)H: quinone reductase (QR) activity, suggesting that these bioactive constituents were potential Nrf2 activators. Among the isolated compounds, phthalide levistolide A (LA, 14) upregulated the protein levels of Nrf2, NQO1, and γ-GCS in a dose-dependent manner. Our results implied that the clinical application of the rhizome of L. chuanxiong as an anti-DN drug in TCM might be attributed to the Nrf2 inducing effect of phthalides. Thus, phthalides is a group of promising leading molecules for discovering anti-DN agents.