Isocoumarin Derivatives Research Articles

Ruthenium(II)-Catalyzed Homocoupling of α-Carbonyl Sulfoxonium Ylides Under Mild Conditions: Methodology Development and Mechanistic DFT Study.

A mild ruthenium(II)-catalyzed homocoupling of α-carbonyl sulfoxonium ylides was developed and the detailed mechanism was understood based on DFT calculations in the current report. The catalytic system utilizes the α-carbonyl sulfoxonium ylide as both the directing group for ortho-sp2 C-H activation and the acylmethylating reagent for C-C coupling. Various substituents are compatible in the transformation and a variety of isocoumarin derivatives were synthesized at room temperature without any protection. The theoretical results disclosed that the full catalytic cycle contains eight elementary steps, and in all the cationic Ru(II) monomer is involved as the catalytic active species. The acid additive is responsible for protonation of the ylide carbon prior to the intramolecular nucleophilic addition and C-C bond cleavage. Interestingly, the intermediacy of free acylmethylation intermediate or its enol isomer is not necessary for the transformation.

One‐Pot Two‐Step Synthesis of Isochromene‐Fused CF3‐Substituted Pyrazoles

An efficient one‐pot, two step method for fusing two biologically active motifs, CF3‐substituted pyrazoles and isochromenes, was developed. Selective O‐benzylation of CF3‐substituted pyrazolones and subsequent Pd‐catalyzed direct C–H arylation generate a fused tricycle. For the synthesized compounds through‐space 13C–19F spin–spin coupling was revealed. In addition, the synthesis of three thioisochromene analogues, and one isocoumarin derivative, was accomplished.

Facile access to isocoumarin-based D-A-D triad: A thermally activated delayed-fluorescence host for efficient red phosphorescent OLEDs

Abstract Isocoumarin (ICO) is a natural occurring and well-documented π-conjugated structure due to its electron-withdrawing property and thermal stability. Herein, a novel donor-acceptor-donor (D-A-D) triad type of TADF host using ICO as the acceptor has been developed for the first time via a facile Ru(II) catalytic self-annulation of α-benzoyl sulfoxonium ylides. The high electron-deficiency and planar geometry of ICO structure may also be in favour of compact π-π stacking, thus providing fast transporting pathways for electrons, while the lone pair electrons of oxygen atom in ICO structure would offer a favourable condition to form intramolecular C–H⋯O hydrogen bonding, thus potentially reducing exciton quenching due to the inhibited structural relaxation. The resulting D-A-D triad (PXZ-ICO) exhibits significant thermally activated delayed fluorescence and well-balanced bipolar transporting property. The OLED devices utilizing this triad as a host exhibit outstanding electroluminescence with low driving voltage, high efficiency and small efficiency roll-off. This work would probably give us helpful inspiration for discovering organic functional materials using ICO derivatives.

Talarolactone A, an Isocoumarin Derivative Fused with Dihydrothiophene with Selective Antimigratory Activity from the Endolichenic Fungus Talaromyces sp.

A 3,4-dihydroisocoumarin derivative fused with dihydrothiophene, talarolactone A (1), and two known compounds, terreusinone (2) and 4,6-dihydroxy-5-methylphthalide (3), were isolated from Talaromyces sp. associated with Xanthoparmelia angustiphylla. The structure of 1 was deduced from extensive spectroscopic data, electronic circular dichroism calculations, and X-ray diffraction analyses. A plausible biosynthetic pathway of 1 was further proposed. Compound 1 showed selective antimigratory activity in a wound-healing assay without appreciable cytotoxic activity.

Three new isocoumarin derivatives from the mangrove endophytic fungus Penicillium sp. YYSJ-3.

Three new isocoumarin derivatives, (S)-6,8-dihydroxy-5-(methoxymethyl)-3,7-dimethylisochroman-1-one (1), (S)-6,8-dihydroxy-3,5,7-trimethyl-isochroman-1-one (2) and (R)-2-chloro-3-(8-hydroxy-6-methoxy-1-oxo-1H-isochromen-3-yl) propyl acetate (3), along with four known compounds (4-7) were isolated from a mangrove endophytic fungus Penicillium sp. YYSJ-3. Their structures were established on the basis of the extensive spectroscopic data and HR-ESI-MS analysis. The absolute configurations of 1-3 were further determined by X-ray diffraction analysis and optical rotations. Compounds 3, 6 and 7 showed promising inhibitory activity against α-glucosidase, which were stronger than that of the positive control 1-deoxynojirimycin (IC50 141.2 μmol·L-1).

Atomic Resolution Analyses of Isocoumarin Derivatives for Inhibition of Lysyl-tRNA Synthetase.

Aminoacyl-tRNA synthetases, the essential enzyme family for protein translation, are attractive targets for developing antibacterial, antifungal, and antiparasitic agents and for treating other human diseases. The antimalarial natural product cladosporin was discovered recently as a novel lysyl-tRNA synthetase (LysRS) specific inhibitor. Here, we report a thorough analysis of cladosporin derivatives using chemical synthesis, biophysical, and biochemical experiments. A series of isocoumarin derivatives with only one nonhydrogen atom/bond change per compound was synthesized. These changes include replacements of methyltetrahydropyran moiety by methylcyclohexane or cyclohexane, lactone by lactam, hydroxyl groups by methoxyl groups, and dismission of the chiral center at C3 with a Δ3,4 double bond. We evaluated these compounds by thermal shift assays and enzymatic experiments and further studied their molecular recognition by the Plasmodium falciparum LysRS through total five high-resolution crystal structures. Our results showed that the methyltetrahydropyran moiety of cladosporin could be replaced by a more stable methylcyclohexane without reducing binding ability. Removing the methyl group from the methylcyclohexane moiety slightly decreased the interaction with LysRS. Besides, the replacement with a lactam group or a conjugated Δ3,4 double bond within the scaffold could be two more options to optimize the compound. Lastly, the two phenolic hydroxyl groups were critical for the compounds to bind LysRS. The detailed analyses at atomic resolution in this study provide a foundation for the further development of new antibiotics from cladosporin derivatives.

Synthetic Methods of Isocoumarins and Phosphaisocoumarins through CH Activation

The synthetic methods of isocoumarins and phosphaisocoumarins from the C‐H activation reaction of aromatic compounds having carboxylic acid and phosphoryl groups as directing groups activation with alkynes, vinyl acetates, cyclic 2‐diazo‐1,3‐diketones, benzoquinone‐1,3‐dienes, bromoalkynes, and epoxides were reviewed. CH activation followed by oxidative cyclization using aromatic carboxylic acids affords isocoumarin derivatives in good to excellent yields in the presence of a variety of transition metal catalysts such as rhodium, iridium, cobalt, ruthenium, and palladium. In addition, the synthetic methods used for obtaining phosphaisocoumarins were accessed using phosphoryl groups as directing groups through CH activation catalyzed by rhodium, ruthenium, and palladium.

2H-pyranone and isocoumarin derivatives from the endophytic fungus Pestalotiopsis microspora SC3082 derived from Scaevola taccada (Gaertn.) Roxb

Two new 2H-pyranones (1 and 2), two new isocoumarins (4 and 5), and two known compounds (3 and 6) were obtained from solid cultures of the endophytic fungus Pestalotiopsis microspora SC3082. Their structures and revision of the absolute stereochemistry of 6 were established by spectroscopic analyses and computational calculations. Compounds 2, 4 and 6 displayed moderate antifungal activities against Candida albicans ATCC 10321 with MIC values of 25.0, 25.0, and 12.5 μg/mL, respectively.

Cyclonerane sesquiterpenes and an isocoumarin derivative from the marine-alga-endophytic fungus Trichoderma citrinoviride A-WH-20-3

Two new cyclonerane sesquiterpenes, (10E)-isocyclonerotriol (1) and (10Z)-isocyclonerotriol (2), and one new isocoumarin derivative, trichophenol A (3), were isolated from Trichoderma citrinoviride A-WH-20-3, an endophyte from the marine red alga Laurencia okamurai. Their structures and relative configurations were assigned by spectroscopic techniques, highlighted by using Sarotti's DP4+ sheet to confirm the cyclopentane ring. The absolute configuration of 1 was established by comparison of experimental and calculated specific rotation data. Compounds 1 and 2 represent the first occurrence of ring-isomerized cycloneranes. Compound 3 is the first 3-phenylisocoumarin derivative from Trichoderma and features inhibition of several marine-derived bacteria and phytoplankton species.

New azaphilone, isocoumarin and α-pyrone derivatives from the marine-derived gut fungus Paraphaeosphaeria sp. XZD2-1

Six new compounds including two azaphilones, lunatoic acids D–E (1, 2), three isocoumarins, lunatinins B–D (3-5), and one α-pyrone derivative, lunatinin E (6), as well as four known ones, lunatoic acid A (7), lunatinin (8), penicipyran D (9) and chaetoquadrin F (10) were isolated from the rice medium of the gut fungus Paraphaeosphaeria sp. XZD2-1. Their planar structures were elucidated by analysis of 1D and 2D NMR as well as HRESIMS spectroscopic data. The absolute configurations of compounds 1-3 were assigned by experimental and calculated ECD data and an ester hydrolysis reaction. Compounds 4 and 5 were a pair of enantiomeric excess mixture. Structure of compound 6 was further confirmed by comparing optical rotation with known compounds according to literature. The antimicrobial activity and cytotoxicity of compounds 1-10 were examined.

Palladium complexes with an annellated mesoionic carbene (MIC) ligand: catalytic sequential Sonogashira coupling/cyclization reaction for one-pot synthesis of benzofuran, indole, isocoumarin and isoquinolone derivatives.

Two Pd(ii) complexes (1 and 2) featuring a fused π-conjugated imidazo[1,2-a][1,8]naphthyridine-based mesoionic carbene ligand have been synthesized and structurally characterized. Both complexes effectively catalyze the one-pot synthesis of benzofuran starting from phenylacetylene and 2-iodophenol under mild conditions. Complex 1 is found to be an excellent catalyst for the straightforward access to a library of benzofuran, indole, isocoumarin and isoquinolone derivatives by the reaction of terminal alkynes with 2-iodo derivates of phenol, N-methyl aniline, benzoic acid and N-methyl benzamide, respectively. The general utility of the catalytic method is demonstrated using a variety of diversely substituted terminal alkynes and the corresponding desired products are obtained in good to excellent yields. On the basis of control experiments, a two-cycle mechanism is proposed which involves the Sonogashira coupling of 2-iodo derivatives with alkynes and the subsequent cyclization of the corresponding 2-alkynyl compounds.

Chromone and isocoumarin derivatives from the endophytic fungus Xylomelasma sp. Samif07, and their antibacterial and antioxidant activities

Five chromone derivatives, including 2,6-dimethyl-5-methoxyl-7-hydroxylchromone (1), 6-hydroxymethyleugenin (2), 6-methoxymethyleugenin (3), chaetoquadrin D (4), and isoeugenitol (5), and three isocoumarin congeners, namely diaporthin (6), 8-hydroxy-6-methoxy-3-methylisocoumarin (7), and 6-methoxymellein (8), were isolated from the culture of the endophytic fungus Xylomelasma sp. Samif07 derived from the medicinal plant Salvia miltiorrhiza Bunge. Among them, compound 1 was a new natural product. Their structures were determined by spectroscopic methods and comparison with the literature. The isolated compounds were evaluated for their antibacterial and antioxidant activities. Compound 5 showed notable antitubercular activity against Mycobacterium tuberculosis with MIC value of 10.31 µg/mL, while compounds 1–3, and 5–7 displayed inhibitory activities against the other bacteria with MIC range of 25 ∼ 100 µg/mL. Meanwhile, compound 6 showed potent hydroxyl radical-scavenging activity with EC50 value of 15.1 µg/mL, while compounds 5–7 showed certain ferric reducing ability.

Divergent Synthesis of Isoquinolone and Isocoumarin Derivatives by the Annulation of Benzoic Acid with N-Vinyl Amide.

A simple and efficient method for the synthesis of isoquinolone and isocoumarin derivatives is reported. The method for the first time provides a one-step divergent synthesis of important isoquinolone and isocoumarin skeletons from benzoic acid by switching the coupling partners. In addition, a reliable mechanism has been proposed on the basis of experimental investigations, including kinetic isotope effect experiments, 13C labeling experiments, time-tracking experiments, and competitive experiments, as well as DFT calculation studies.

New phenolic glycosides from Polygonum cuspidatum

Two new isobenzofuranone derivatives, polyphthaliside A (1) and polyphthaliside B (2), and a new isocoumarin derivative, polyisocoumarin (3), were isolated from Polygonum cuspidatum. Their structures were elucidated by detailed spectroscopic analysis and chemical methods. The cytotoxicity activity and PTP1B inhibitory activity of compounds 1–3 were estimated and none of them exhibited activities at a concentration of 10 μM.

Crystal structures of two new isocoumarin derivatives: 8-amino-6-methyl-3,4-diphenyl-1H-isochromen-1-one and 8-amino-3,4-diethyl-6-methyl-1H-isochromen-1-one.

The title compounds, 8-amino-6-methyl-3,4-diphenyl-1H-isochromen-1-one, C22H17NO2, (I), and 8-amino-3,4-diethyl-6-methyl-1H-isochromen-1-one, C14H17NO2, (II), are new isocoumarin derivatives in which the isochromene ring systems are planar. Compound II crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In I, the two phenyl rings are inclined to each other by 56.41 (7)° and to the mean plane of the 1H-isochromene ring system by 67.64 (6) and 44.92 (6)°. In both compounds, there is an intra-molecular N-H⋯O hydrogen bond present forming an S(6) ring motif. In the crystal of I, mol-ecules are linked by N-H⋯π inter-actions, forming chains along the b-axis direction. A C-H⋯π inter-action links the chains to form layers parallel to (100). The layers are then linked by a second C-H⋯π inter-action, forming a three-dimensional structure. In the crystal of II, the two independent mol-ecules (A and B) are linked by N-H⋯O hydrogen bonds, forming -A-B-A-B- chains along the [101] direction. The chains are linked into ribbons by C-H⋯π inter-actions involving inversion-related A mol-ecules. The latter are linked by offset π-π inter-actions [inter-centroid distances vary from 3.506 (1) to 3.870 (2) Å], forming a three-dimensional structure.

Fungal mycotoxins and natural antioxidants: Two sides of the same coin and significance in food safety

Fungi have a long and intimate connection with humankind, particularly at the chemical level as a source of both harmful and beneficial compounds. Their worldwide occurrence in various food and feeds poses a major health threatening risk for human and animal and, as a consequence, mycotoxins represent an economic burden. Fortunately, not all fungal secondary metabolites are toxic to humankind such as; antibiotics, phytotoxines, enzymes and antioxidants, which represent the other side of the coin. Endophytes are now considered as an important component of biodiversity, and act as reservoirs of novel bioactive secondary metabolites, such as alkaloids, flavanoids, phenols, phenolic acids, quinones, steroids, saponins, tannins, terpenoids, isocoumarin derivatives, peptides and enzymes, beside their ability to produce the same or similar kind of compounds of their host plants. Today’s world challenge is ensuring the safety of food, which has been a major focus of international and national action over the last years. Legislative limits for a range of mycotoxins continue to develop worldwide, due to being carcinogenic to animals and humans, resulting in an increased number of official controls monitoring in the food supply chain deriving from national food safety plans and for food trade purposes. This review brings about the harmful (mycotoxins) and beneficial (antioxidants, antibiotics, enzymes) fungal metabolites in industrial and pharmaceutical applications. It also provides a perspective about mechanism of how can endophytic fungi metabolites play a reverse role as one of the main strategies of mycotoxin deactivation and prevention representing the other side of the coin.

Regioselective cyclization of 2-alkynylbenzoic acid in water for the synthesis of isocoumarin

In this work, a regioselective synthesis of isocoumarins from 2-alkynylbenzoic acid is reported. The transformations proceed smoothly with good yields in water via a metal-free radical pathway. When catalytic TBAB is employed, the reaction provides various isocoumarin derivatives according to the structures of the corresponding precursors. It is believed that TBAB serves as a phase transfer catalyst and radical initiator in the reaction. Compared to previous methodologies, the synthetic procedure reported herein provides a more environmentally benign route for the synthesis of isocoumarins.

Ultrasound Assisted Synthesis of 3-(het)aryl Isocoumarin Derivatives and their in vitro Pharmacological Evaluation.

In view of numerous biological activities of 3-substituted isocoumarins a number of analogues based on this scaffold were synthesized for their in vitro pharmacological evaluation. The syntheses of 3-substituted isocoumarins were carried out via a Pd/C-catalyzed Suzuki- Miyaura coupling of 3-chloroisochromen-1-one with a range of boronic acid derivatives. This C-C bond forming reaction was facilitated by ultrasound irradiation to afford the desired products in good yields. A number of 3-(het)aryl isocoumarin derivatives were prepared by using this methodology and subsequently tested for their TNF-α inhibitory properties in vitro followed by cytotoxicities via the MTT assay. Several compounds showed inhibition of TNF-α with one compound showing an IC50 value of 9.01±1.25 µM. Three compounds also showed promising cytotoxic properties against two cancer cell lines with IC50 ~ 0.9-2.7 µM. The isocoumarin framework could be an effective template for the design and discovery of new inhibitor of TNF-α for the potential treatment of related diseases.

New lactone and isocoumarin derivatives from the marine mangrove-derived endophytic fungus Penicillium coffeae MA-314

A new δ-lactone (penicoffeazine A, 1) and two pairs of new isocoumarin derivatives (penicoffrazins B and C, 2 and 3), along with five known isocoumarin derivatives (4−8), were isolated from Penicillium coffeae MA-314, an endophytic fungus obtained from the fresh inner tissue of the leaf of marine mangrove plant Laguncularia racemosa. The structures of all these compounds were elucidated by spectroscopic analysis and the absolute configuration of compound 1 was determined by ECD experiments and compared with that of calculated ECD spectrum. The relative configurations of compounds 2 and 3, which were two pairs of enantiomers, were confirmed by NOESY experiments. Compound 1 was tested for antibacterial activity and the other compounds were tested for antioxidant activity. This is the first report on the natural products of the fungus Penicillium coffeae.

Bioprospecting of Novel and Bioactive Metabolites from Endophytic Fungi Isolated from Rubber Tree Ficus elastica Leaves.

Endophytic fungi are an important component of plant microbiota, and have the excellent capacity for producing a broad variety of bioactive metabolites. These bioactive metabolites not only affect the survival of the host plant, but also provide valuable lead compounds for novel drug discovery. In this study, forty-two endophytic filamentous fungi were isolated from Ficus elastica leaves, and further identified as seven individual taxa by ITS-rDNA sequencing. The antimicrobial activity of these endophytic fungi was evaluated against five pathogenic microorganisms. Two strains, Fes1711 (Penicillium funiculosum) and Fes1712 (Trichoderma harzianum), displayed broad-spectrum bioactivities. Our following study emphasizes the isolation, identification and bioactivity testing of chemical metabolites produced by T. harzianum Fes1712. Two new isocoumarin derivatives (1 and 2), together with three known compounds (3-5) were isolated, and their structures were elucidated using NMR and MS. Compounds 1 and 2 exhibited inhibitory activity against Escherichia coli. Our findings reveal that endophytic fungi from the rubber tree F. elastica leaves exhibit unique characteristics and are potential producers of novel natural bioactive products.