Isobenzofuranone Derivatives Research Articles

Synergistic effect of hydrogen bonding and C–H…π interactions to modulate the supramolecular assemblies of isobenzofuranones: X-ray crystallography, DFT analysis and antihyperglycemic potential

This manuscript reports the synthesis, X-ray characterization and antihyperglycemic potential of two isobenzofuranone derivatives. The Suzuki-Miyaura cross-coupling of 5-bromoisobenzofuran-1(3H)-one with phenylboronic acid and p-tolylboronic acid under the action of palladium catalysis afforded the desired compounds in good yields. The structures were fully established using FTIR and NMR spectroscopy and X-ray crystallography. The study further delves into the synergistic effects of hydrogen bonding and C–H…π interactions on the supramolecular assemblies of isobenzofuranones, leveraging a holistic approach that combines X-ray crystallography, Density Functional Theory (DFT) analysis, and evaluation of antihyperglycemic activity. Focusing on two isobenzofuranone derivatives, we meticulously elucidate their structural features and how noncovalent interactions shape their crystal packing. Our exploration extends to assessing the antihyperglycemic potential of these compounds, underpinned by α-glucosidase inhibitory assays and augmented by molecular docking analysis. Compound 3b showed the best potency with an IC50 value of 13 ± 0.01 µM which is 67-folds strong inhibition than acarbose (IC50 = 870.2 ± 1.54 µM). Furthermore, the admetSAR and ProTox-II demonstrated that compound 3b follows the druggable criteria with a safe toxicity profile. Overall, these findings highlight the pivotal role of noncovalent interactions in modulating the supramolecular architectures of isobenzofuranones, thereby offering insights into their therapeutic potential against diabetes mellitus.

Identification of isobenzofuranone derivatives as promising antidiabetic agents: Synthesis, in vitro and in vivo inhibition of α-glucosidase and α-amylase, computational docking analysis and molecular dynamics simulations

Diabetes mellitus, one of the major health challenges of the 21st century, is associated with numerous biomedical complications including retinopathy, neuropathy, nephropathy, cardiovascular diseases and liver disorders. To control the chronic hyperglycemic condition, the development of potential inhibitors of drug targets such as α-glucosidase and α-amylase remains a promising strategy and focus of continuous efforts. Therefore, in the present work, a concise library of isobenzofuranone derivatives (3a-q) was designed and synthesized using Suzuki-Miyaura cross-coupling approach. The biological potential of these heterocyclic compounds against carbohydrate-hydrolyzing enzymes; α-glucosidase and α-amylase, was examined. In vitro inhibitory results demonstrated that the tested isobenzofuranones were considerably more effective and potent inhibitors than the standard drug, acarbose. Compound 3d having an IC50 value of 6.82 ± 0.02 μM was emerged as the lead candidate against α-glucosidase with ⁓127-folds strong inhibition than acarbose. Similarly, compound 3g demonstrated ⁓11-folds higher inhibition strength against α-amylase when compared with acarbose. Both compounds were tested in vivo and results demonstrate that the treatment of diabetic rats with α-amylase inhibitor show more pronounced histopathological normalization in kidney and liver than with α-glucosidase inhibitor. The Lineweaver-Burk plot revealed an uncompetitive mode of inhibition for 3d against α-glucosidase whereas compound 3g exhibited mixed inhibition against α-amylase. Furthermore, in silico molecular docking and dynamics simulations validated the in vitro data for these compounds whereas pharmacokinetics profile revealed the druglike properties of potent inhibitors.

A New Isobenzofuranone Derivative from Arctic Fungus Gyoerffyella sp. CPCC 401434

A New Isobenzofuranone Derivative from Arctic Fungus Gyoerffyella sp. CPCC 401434

DPPH Radical Scavenging Activity of New Phenolics from the Fermentation Broth of Mushroom Morehella importuna.

In recent years, wild morel mushroom species have begun to be widely cultivated in China due to their high edible and medicinal values. To parse the medicinal ingredients, we employed the technique of liquid-submerged fermentation to investigate the secondary metabolites of Morehella importuna. Two new natural isobenzofuranone derivatives (1-2) and one new orsellinaldehyde derivative (3), together with seven known compounds, including one o-orsellinaldehyde (4), phenylacetic acid (5), benzoic acid (6), 4-hydroxy-phenylacetic acid (7), 3,5-dihydroxybenzoic acid (8), N,N'-pentane-1,5-diyldiacetamide (9), and 1H-pyrrole-2-carboxylic acid (10), were obtained from the fermented broth of M. importuna. Their structures were determined according to the data of NMR, HR Q-TOF MS, IR, UV, optical activity, and single-crystal X-ray crystallography. TLC-bioautography displayed that these compounds possess significant antioxidant activity with the half DPPH free radical scavenging concentration of 1.79 (1), 4.10 (2), 4.28 (4), 2.45 (5), 4.40 (7), 1.73 (8), and 6.00 (10) mM. The experimental results would shed light on the medicinal value of M. importuna for its abundant antioxidants.

Acid/Base-Steered Cascade Cyclization: An Efficient One-Pot Access to Diverse Isobenzofuranone and Isoindolobenzoxazinone Derivatives.

We herein report the acid/base-steered two distinct reaction pathways of 2-acylbenzoic acids with isatoic anhydrides. In the presence of Na2CO3, the cascade process consists of the cyclization of 2-acetylbenzoic acid and nucleophilic ring-opening reaction of isatoic anhydride to furnish isobenzofuranone derivatives with high efficiency. However, p-toluenesulfonic acid can promote the product isobenzofuranones to undergo sequential intramolecular rearrangment, nucleophilic addition and cyclization reaction to produce diverse isoindolobenzoxazinones in good yields. The synthetic utility of this method was further demonstrated by the gram-scale preparation of the desired products and the facile transformations of the resulting products.

Isobenzofuran-1(3H)-one derivatives: Amoebicidal activity and program cell death in Acanthamoeba castellanii Neff.

The genus Acanthamoeba is characterized by being a group of ubiquitous and free-living amoebae that inhabit a variety of environments. Generally, human infections by this parasite are associated with Acanthamoeba keratitis, especially in contact lens wearers, and with chronic but fatal granulomatous amoebic meningoencephalitis. Current treatments used for eradication of amoeba from infection sites represent a challenge for pharmacotherapy, due to the lack of effective treatment and the amoebae highly resistant to anti-amoebic drugs. In this study, we describe the results of the assessment of the IC50 of 10 isobenzofuran-1(3H)-one derivatives (QOET) against four Acanthamoeba strains. The compounds QOET-3 and QOET-9 were the selected derivatives with the lowest IC50 in A. castellanii Neff trophozoites (73.71±0.25 and 69.99±15.32µM, respectively). Interestingly, analysis of the compound effects on the cell apoptosis-like features showed that both active molecules triggered programmed cell death (PCD) in A. castellanii Neff. The results obtained in this study highlights that isobenzofuranone derivatives could represent an interesting source for developing novel antiamoebic drugs.

Two New Isobenzofuranone Derivatives from Phyllanthus emblica and Their Bioactivity

Two new isobenzofuranone derivatives, 5-(2-hydroxyethyl)-2,2-dimethyl-2H-furo[3,4-h]chromen-7(9H)-one (1) and 2,2-dimethyl-5-(2-oxopropyl)-2H-furo[3,4-h]chromen-7(9H)-one (2), were isolated from the fruit of Phyllanthus emblica. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were also tested for their antioxidant activity, and they show good antioxidant activity with an IC50 value of 4.5 and 4.2 μg/mL, respectively.

A new isobenzofuranone derivative from Chaenomeles sinensis and its antibacterial activity

A new isobenzofuranone derivative was isolated from Chaenomeles sinensis by using various chromatographic techniques,including silica gel,Sephadex LH-20,MCI-gel resin and RP-HPLC. This compound was determined as 2,2-dimethyl-5-( 2-oxopropyl)-2 H-furo[3,4-h]chromen-7( 9 H)-one( 1) by NMR,MS,IR and UV spectra,and was also evaluated for its antibacterial activity. The results showed that it showed prominent antibacterial activity with MIC90 value of( 53. 7±4. 5) mg·L-1 for methicillin resistant Staphylococcus aureus( MRSA) strain. This value is close to that of levofloxacin [with MIC90 value( 50. 2± 4. 2) mg·L-1].

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.

Isobenzofuranone Derivatives from the Roots of Phlomis betonicoides and Their Bioactivity

Isobenzofuranone Derivatives from the Roots of Phlomis betonicoides and Their Bioactivity

A new isobenzofuranone derivative from Phlomis betonicoides and its antibacterial activity

A new isobenzofuranone derivative has been isolated from Phlomis betonicoides by using various chromatographic techniques, including silica gel, Sephadex LH-20, MCI-gel resin and RP-HPLC. This compound was determined as 5-(3-hydroxypropyl)-2,2-dimethyl-2H-furo[3,4-h]chromen-7(9H)-one (1) by NMR, MS, IR and UV spectroscopic data. Compound 1 showed potent antibacterial activity with an MIC₉₀ value of (58.4 ± 4.2) mg·L⁻¹ for methicillin resistant Staphylococcus aureus (MRSA) strain [levofloxacin as a control with MIC₉₀ value of (52.8±4.6) mg·L⁻¹].

Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites

Kinetoplast DNA (kDNA) bearing unusual mitochondrion of trypanosomatid parasites offers a new paradigm in chemotherapy modality. Topoisomerase II of Leishmania donovani (LdTopII), a key enzyme associated with kDNA replication, is emerging as a potential drug target. However, mode of action of LdTopII targeted compounds in the parasites at sub-cellular level remains largely unknown. Previously, we reported that an isobenzofuranone derivative, namely 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3), targets LdTopII and induces apoptosis-like cell death in L. donovani. Here, we elucidate the phenotypic changes and the events occurring at sub-cellular level caused by JVPH3 in L. donovani. In addition, we have evaluated the cytotoxicity and ultrastructural alterations caused by JVPH3 in two brazilian trypanosomatid pathogens viz. L. amazonensis and Trypanosoma cruzi. Despite killing these parasites, JVPH3 caused significantly different phenotypes in L. donovani and L. amazonensis. More than 90% population of parasites showed altered morphology. Mitochondrion was a major target organelle subsequently causing kinetoplast network disorganization in Leishmania. Altered mitochondrial architecture was evident in 75–80% Leishmania population being investigated. Quantification of mitochondrial function using JC-1 fluorophore to measure a possible mitochondrial membrane depolarization further confirmed the mitochondrion as an essential target of the JVPH3 corroborating with the phenotype observed by electron microscopy. However, the impact of JVPH3 was lesser on T. cruzi than Leishmania. The molecule caused mitochondrial alteration in 40% population of the epimastigotes being investigated. To our knowledge, this is the first report to evaluate the proliferation pattern and ultrastructural alterations caused in Brazilian kinetoplastid pathogens by a synthetic LdTopII inhibitor previously established to have promising in vivo activity against Indian strain of L. donovani.

Carboxylate-Directed Addition of Aromatic C–H Bond to Aromatic Aldehydes under Ruthenium Catalysis

We report that ruthenium complexes effectively catalyzed the carboxylate-directed addition of aromatic C–H bonds to aldehydes. The reactions of aromatic acids with a variety of aromatic aldehydes including unactivated ones proceeded efficiently to give the corresponding isobenzofuranone derivatives in high yields. The combination of ruthenium(II) complexes with tricyclohexylphosphine led to highly nucleophilic aryl–metal species, which enabled versatile [3 + 2] cycloaddition in the absence of a Lewis acid. This paper also demonstrates the application of supported ruthenium catalysts to the title reaction.

Aniline-Promoted Synthesis of Isobenzofuranone Derivatives

Aniline-Promoted Synthesis of Isobenzofuranone Derivatives

Two new isobenzofuranone derivatives from the fruiting bodies of Hericium erinaceus

Two new isobenzofuranone derivatives erinaceolactones G and H (1 and 2) were isolated from the ethanolic extract of fruiting bodies of Hericium erinaceus. Their structures were characterized on the basis of spectroscopic evidences. Compound 2 was suggested to be racemic by specific rotation, which was resolved by chiral HPLC into enantiomers.

Three new isobenzofuranone derivatives from the fruiting bodies of Hericium erinaceus

Three new isobenzofuranone derivatives erinaceolactones D-F (1–3), together with four known ones (4–7), were isolated from the fruiting bodies of Hericium erinaceus. Their structures were determined on the basis of comprehensive spectroscopic analyses including UV, 1D, 2D NMR and HR-TOF-MS. The absolute configuration of erinaceolactone D (1) and erinaceolactone E (2) were assigned by comparing their specific rotation with those of analogs in literatures. The four known compounds were isomers with each other and were isolated simultaneously for the first time.

Isobenzofuranone derivatives exhibit antileishmanial effect by inhibiting type II DNA topoisomerase and inducing host response.

Leishmania, a protozoan parasite, causes a wide range of human diseases ranging from the localized self-healing cutaneous lesions to fatal visceral leishmaniasis. Toxicity of traditional first line drugs and emergence of drug-resistant strains have worsened the situation. DNA topoisomerase II in kinetoplastid protozoan parasites are of immense interest as drug target because they take part in replication of unusual kinetoplast DNA network. In this study, we have taken target-based therapeutic approaches to combat leishmaniasis. Two isobenzofuranone compounds, viz., (1) 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3) and (2) (4-bromo)-3′-hydroxy-5′-(4-bromophenyl)-benzophenone(JVPH4) were synthesized chemically and characterized by NMR and mass spectrometry analysis. Activity of type II DNA topoisomerase of leishmania (LdTOPII) was monitored by decatenation assay and plasmid cleavage assay. The antiparasitic activity of these compounds was checked in experimental BALB/c mice model of visceral leishmaniasis. Isobenzofuranone derivatives exhibited potent antileishmanial effect on both antimony (Sb) sensitive and resistant parasites. Treatment with isobenzofuranone derivatives on promastigotes caused induction of reactive oxygen species (ROS)-mediated apoptosis like cell death in leishmania. Both the compounds inhibited the decatenation activity of LdTOPII but have no effect on bi-subunit topoisomerase IB. Treatment of LdTOPII with isobenzofuranone derivatives did not stabilize cleavage complex formation both in vitro and in vivo. Moreover, treatment with isobenzofuranone derivatives on Leishmania donovani-infected mice resulted in clearance of parasites in liver and spleen by induction of Th1 cytokines. Taken together, our data suggest that these compounds can be exploited as potential antileishmanial agents targeted to DNA topoisomerase II of the parasite.

Pseudaboydins A and B: novel isobenzofuranone derivatives from marine fungus Pseudallescheria boydii associated with starfish Acanthaster planci.

Two novel isobenzofuranone derivatives, pseudaboydins A (1) and B (2), along with five known compounds, including (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-hydroxybenzofuran (3), (R)-2-(2-hydroxypropan-2-yl)-2,3-dihydro-5-methoxybenzofuran (4), 3,3′-dihydroxy-5,5′-dimethyldiphenyl ether (5), 3-(3-methoxy-5-methylphenoxy)-5-methylphenol (6) and (−)-regiolone (7), were isolated from the culture broth of the marine fungus, Pseudallescheria boydii, associated with the starfish, Acanthaster planci. Their structures were elucidated primarily based on NMR and MS data. The absolute configurations of 1–4 were determined by CD spectroscopy and single-crystal X-ray diffraction studies. The cytotoxic and antibacterial activities of 1–4 were evaluated. Pseudaboydin A (1) showed moderate cytotoxic activity against human nasopharyngeal carcinoma cell line HONE1, human nasopharyngeal carcinoma cell line SUNE1 and human glandular lung cancer cell line GLC82 with IC50 values of 37.1, 46.5 and 87.2 μM, respectively.

3-(Di-phenyl-amino)-isobenzo-furan-1(3H)-one.

In the title isobenzo­furan­one derivative, C20H15NO2, the planar fused-ring system (r.m.s. deviation for the 10 fitted atoms = 0.031 Å) forms dihedral angles of 63.58 (6) and 63.17 (8)° with the N-bound phenyl rings; the dihedral angle between the planes of these phenyl rings is 85.92 (7)°. In the crystal, mol­ecules are linked by weak C—H⋯O inter­actions, involving both O atoms, forming helical supra­molecular chains along [001].

A Spotlight on Chemical Constituents and Pharmacological Activities of Nigella glandulifera Freyn et Sint Seeds

Plants belonging to the Ranunculaceae family, and particularly their seeds, have been a hot research topic in numerous pharmacognosy laboratories. Nigella glandulifera Freyn et Sint (NG) is one of the promising, but relatively insufficiently studied, plants from this family. In this review, we summarize the recently isolated chemical constituents from the seeds of this plant including alkaloids, flavonol glycosides, isobenzofuranone derivatives, saponins, terpenes, terpenoids, and fatty acids. We put also a spotlight on the recently studied therapeutic potentials of such amazing herb seeds as antidiabetes, melanogenesis inhibition, anticancer, anti‐inflammatory, antithrombosis, and antiplatelet aggregation effects. Herein, we illustrate certain properties and potentials via selected examples, and thus we suggest more studies to confirm the therapeutic hypotheses, find out new compounds, and eventually to discover novel properties.