Benzofuran Derivatives Research Articles

Synthesis and Cytotoxic Activity of Quinazoline-benzofuran Conjugates.

In order to study on structure-activity relationships of benzofurans. Benzofuran is a kind of natural compound widely existing in nature with pharmacological effects. The development of new anticancer benzofuran derivatives has attracted more and more attention. We have introduced an active quinazoline unit into piperazine-substituted benzofuran, prepared a series of quinazoline-benzofuran compounds, and evaluated cytotoxic activity against a panel of human tumor cell lines by MTT assay. 48 novel quinazoline-substituted benzofuran derivatives have been prepared, and in vitro, cytotoxic activity against five human tumor cell lines was evaluated. The results indicated that some quinazoline-benzofuran conjugates showed selective inhibitory activity against tumor cell lines. We have found that compound 14x displayed excellent cytotoxic activity, which could be considered a potential anticancer agent.

Base-Mediated Annulation of ortho-Iminophenols and ortho-Vinylphenols with MBH Carbonates of Isatins: Straightforward Access to Dihydrobenzofuran and Benzofuran Derivatives.

We have developed a convenient synthetic protocol for efficient construction of significant dihydrobenzofuran and benzofuran scaffolds by Lewis base-mediated annulation reaction ortho-iminophenols and ortho-vinylphenols with MBH carbonates of isatins under mild and metal-free conditions. The selective generation of different kinds of dihydrobenzofuran and benzofuran derivatives was successfully achieved by employing different substituted isatin-derived MBH carbonates with ortho-N-tosyliminophenols and ortho-vinylphenols. The features included broad substrate scopes, excellent functional group compatibility, high molecular diversity, and atomic economy.

Synthesis, biological evaluation, molecular docking and dynamic simulation of novel benzofuran derivatives as potential agents against Alzheimer's disease

We have synthesized novel benzofuran derivatives (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives showed inhibitory activities having IC50 values ranging from 0.70 ± 0.01 to 28.10 ± 0.50 µM (against AChE), while 0.80 ± 0.01 to 31.20 ± 0.60 µM (against BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 and 4.50 ± 0.10 µM, respectively). Except derivative 5, all other derivatives of the series showed good inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, but some analogues like 2, 4, 7, 14, 15, and 16 displayed many folds better inhibitory activity than the standard drug donepezil. The influences of substituents on inhibitory activity were superficially resonated via the structure-activity relationship. We established molecular docking and MD simulation studies to confirm the binding interaction between potent derivatives and active sites of enzymes.

Synthesis, Antimicrobial Evaluation, and Computational Study of Novel Fluorinated Benzofuran Derivatives

Synthesis, Antimicrobial Evaluation, and Computational Study of Novel Fluorinated Benzofuran Derivatives

An exploration into CTEPH medications: Combining natural language processing, embedding learning, in vitro models, and real-world evidence for drug repurposing.

In the modern era, the growth of scientific literature presents a daunting challenge for researchers to keep informed of advancements across multiple disciplines. We apply natural language processing (NLP) and embedding learning concepts to design PubDigest, a tool that combs PubMed literature, aiming to pinpoint potential drugs that could be repurposed. Using NLP, especially term associations through word embeddings, we explored unrecognized relationships between drugs and diseases. To illustrate the utility of PubDigest, we focused on chronic thromboembolic pulmonary hypertension (CTEPH), a rare disease with an overall limited number of scientific publications. Our literature analysis identified key clinical features linked to CTEPH by applying term frequency-inverse document frequency (TF-IDF) scoring, a technique measuring a term's significance in a text corpus. This allowed us to map related diseases. One standout was venous thrombosis (VT), which showed strong semantic links with CTEPH. Looking deeper, we discovered potential repurposing candidates for CTEPH through large-scale neural network-based contextualization of literature and predictive modeling on both the CTEPH and the VT literature corpora to find novel, yet unrecognized associations between the two diseases. Alongside the anti-thrombotic agent caplacizumab, benzofuran derivatives were an intriguing find. In particular, the benzofuran derivative amiodarone displayed potential anti-thrombotic properties in the literature. Our in vitro tests confirmed amiodarone's ability to reduce platelet aggregation significantly by 68% (p = 0.02). However, real-world clinical data indicated that CTEPH patients receiving amiodarone treatment faced a significant 15.9% higher mortality risk (p<0.001). While NLP offers an innovative approach to interpreting scientific literature, especially for drug repurposing, it is crucial to combine it with complementary methods like in vitro testing and real-world evidence. Our exploration with benzofuran derivatives and CTEPH underscores this point. Thus, blending NLP with hands-on experiments and real-world clinical data can pave the way for faster and safer drug repurposing approaches, especially for rare diseases like CTEPH.

Palladium-Catalyzed Denitrative α-Arylation of Heteroarenes with Nitroarenes via C-H and C-NO2 Bond Activations.

A general approach for the α-arylation of heteroarenes with nitroarenes via denitrative coupling is reported for the first time. Various heteroarenes, including derivatives of furan, benzofuran, pyrrole, indole, thiophene, and benzothiophene, can be arylated at the α-position in moderate to good yields. Mechanistic studies demonstrate that the reaction proceeds via a CMD pathway, with C-H bond activation as the rate-determining step. Furthermore, the scalability and applicability in the synthesis of a drug molecule exemplify the utility of this protocol.

Synthesis of Benzofuran Derivatives via a DMAP-Mediated Tandem Cyclization Reaction Involving ortho-Hydroxy α-Aminosulfones.

An efficient cascade cyclization strategy was developed to synthesize aminobenzofuran spiroindanone and spirobarbituric acid derivatives utilizing 2-bromo-1,3-indandione, 5-bromo-1,3-dimethylbarbituric acid, and ortho-hydroxy α-aminosulfones as substrates. Under the optimized reaction conditions, the corresponding products were obtained with high efficiency, exceeding 95% and 85% yields for the respective derivatives. This protocol demonstrates exceptional substrate versatility and robust scalability up to the Gram scale, establishing a stable platform for the synthesis of 3-aminobenzofuran derivative. The successful synthesis paves the way for further biological evaluations with potential implications in scientific research.

Catalytic coupling of 1-(2-(allyloxy)phenyl)-2-yn-1-ols and isonitriles for the synthesis of 2-(benzofuran-2-yl)acetamides: A combined experimental and theoretical study

A new catalytic approach to the synthesis of an important sub-class of benzofuran derivatives (namely, 2-(benzofuran-2-yl)acetamides, known to possess significant biological activities) has been developed. The new method is based on the use of Pd(PPh3)4 as simple and commercially available catalyst, readily prepared 1-(2-(allyloxy)phenyl)-2-yn-1-ols, and commercially available isonitriles. Formation of benzofuran-2-yl)acetamides derives from a mechanistic pathway involving an ordered sequence of steps, that are, oxidative addition of the phenoxyallyl moiety to Pd(0), isonitrile insertion, water attack to the ensuing (allyl)(imidoyl)palladium complex, β-H elimination from the H-O-C-Pd(allyl) moiety with formation of an allylpalladium hydride species and a 2-(3-hydroxybenzofuran-2(3H)-ylidene)acetamide intermediate, followed by reduction of the latter by (allyl)PdH and MeOH. This mechanistic proposal has been corroborated by DFT studies, while the structures of representative products have been confirmed by X-ray diffraction analysis.

Synthesis of Cytotoxic Benzofurans and Ethers Derivatives of Paeonol.

Paeonol is a broadly studied natural product due to its many biological activities. Using a methodology previously employed by our research group, 11 derivatives of paeonol were synthesized (seven of them are unpublished compounds), including four ethers and seven benzofurans. Additionally, we determined the crystal structure of one of these ether derivatives (1 a) and of five benzofuran derivatives (2 a, 2 b, 2 c, 2 f and 2 g) by single crystal X-ray diffraction. To continue studying the cytotoxicity of this natural product and its derivatives, all compounds were tested against two cancer cell lines, HCT116 and MCF-7. Compounds 2 b, 2 e, and 2 g were considered active against the colorectal adenocarcinoma cells HCT116 (Growth inhibition >60 %). Compound 2 e showed an IC50 of 0.2 μM and was selected for further analysis, results reinforce its anticancer potential.

Identification of new benzofuran derivatives as STING agonists with broad-spectrum antiviral activity

The Stimulator of Interferon Genes (STING) is involved in cytosolic DNA sensing and type I Interferons (IFN-I) induction. Aiming to identify new STING agonists with antiviral activity and given the known biological activity of benzothiazole and benzimidazole derivatives, a series of benzofuran derivatives were tested for their ability to act as STING agonists, induce IFN-I and inhibit viral replication. Compounds were firstly evaluated in a gene reporter assay measuring luciferase activity driven by the human IFN-β promoter in cells expressing exogenous STING (HEK293T). Seven of them were able to induce IFN-β transcription while no induction of the IFN promoter was observed in the presence of a mutated and inactive STING, showing specific protein-ligand interaction. Docking studies were performed to predict their putative binding mode. The best hit compounds were then tested on human coronavirus 229E replication in BEAS-2B and MRC-5 cells and three derivatives showed EC50 values in the μM range. Such compounds were also tested on SARS-CoV-2 replication in BEAS-2B cells and in Calu-3 showing they can inhibit SARS-CoV-2 replication at nanomolar concentrations. To further confirm their IFN-dependent antiviral activity, compounds were tested to verify their effect on phospho-IRF3 nuclear localization, that was found to be induced by benzofuran derivatives, and SARS-CoV-2 replication in Vero E6 cells, lacking IFN production, founding them to be inactive. In conclusion, we identified benzofurans as STING-dependent immunostimulatory compounds and host-targeting inhibitors of coronaviruses representing a novel chemical scaffold for the development of broad-spectrum antivirals.

Deprotonative Metallation of Benzofuran and Benzothiophene Derivatives for the Formation of Tetracyclic and Pentacyclic Heteroaromatic Compounds

AbstractN,N‐dialkylbenzofuran‐ and N,N‐dialkylbenzothiophene‐2‐carboxamides were readily prepared from bare benzofuran and benzothiophene by deprotocupration followed by trapping with N,N‐dialkylcarbamoyl chlorides. They were reacted with 2‐benzofuryl‐ and 2‐benzothienyllithiums to form symmetrical and unsymmetrical diarylketones, or underwent deprotolithiation‐electrophilic trapping sequences at their 3 position. From 3‐iodinated derivatives, copper‐catalysed N‐arylation of azoles was performed, followed by lithium amide‐promoted cyclisation, to give ‘tripentone’ analogues. The diarylketones were also iodinated at their 3,3’ positions and then engaged in the copper‐promoted double N‐arylation of anilines, giving rise to a family of original pentacyclic derivatives. A preliminary assessment of their electrochemical and biological properties was carried out, showing promising results against the proliferation of melanoma cells.

Exploring the potential therapeutic role of benzofuran derivatives in cancer treatment

Benzofuran serves as the primary active pharmaceutical ingredient (API) in a plethora of both naturally occurring and synthetic drugs known for their potent biological activities. The diverse array of biological effects demonstrated by benzofuran and its analogues encompasses anticancer, anti-microbial, anti-inflammatory, anti-fungal, analgesic, anti-parasitic, anti-hyperglycemic, anti-hyperlipidemic, anti-convulsant, antipyretic, anti-tubercular, anti-Alzheimer, and antioxidant properties, among others. Given this extensive range of therapeutic potentials, benzofuran and its derivatives have garnered significant attention and are extensively utilized in pharmaceutical research and development. This review article focuses specifically on the anti-cancer properties of benzofuran and its derivatives, underscoring the pivotal role of benzofuran as a prominent and versatile scaffold for designing and developing novel therapeutic agents.

Enantio- and Diastereoselective Copper-Catalyzed Borylative Coupling of Styrenes and Azadienes.

Here we disclose a CuB-catalyzed reaction between aurone-derived α,β-unsaturated imines and styrenes to produce 2-substituted benzofuran derivatives bearing both the γ-boryl functionality and α,β-unsymmetric stereogenic centers. The reaction represents the first transition-metal-catalyzed unsymmetric 1,4-Michael additions of azadienes, which would enrich the arsenal of CuB catalysis in organic synthesis. In addition, the synthetically versatile boron-alkylated products can be elaborated by chemical transformations to useful optically active benzofuran heterocycles.

Antitumor aspochalasin and antiviral benzofuran derivatives from a marine-derived fungus Aspergillus sp. SCSIO41032

Chemical investigation of the EtOAc extract of a deep-sea derived fungus Aspergillus sp. SCSIO41032 resulted in the isolation of ten known compounds, including eight aspochalasins. Their structures were elucidated by using extensive NMR spectroscopic, mass spectrometric and single crystal X-ray diffraction analysis. The detailed crystallographic data for structures 1, 2, and 4, along with the relative configurations of aspochalasin E (3) determined by its acetonide derivative were reported for the first time. The results of antitumor and antiviral activities showed that 3 displayed moderate antitumor activities against 22Rv1, PC-3, A549, and HCT-15 cell lines with IC50 values ranged from 5.9 ± 0.8 to 19.0 ± 7.7 μM, and 9 exhibited moderate antiviral activities against HSV-1/2 with EC50 values of 9.5 ± 0.5 and 5.4 ± 0.6 μM, respectively. Plate clone formation assays results indicated that 3 inhibited the 22Rv1, PC-3 cells growth in a dose-dependent manner.

Streamlined Synthesis of Varied Heteroarene-Condensed Benzofuran Derivatives via [4 + 2] Annulation of Benzofuran-Derived Azadienes and N-Alkyl Quinolinium Salts.

Herein we have pioneered an innovative synthetic strategy for the efficient assembly of various heteroarene-condensed benzofuran derivatives, utilizing benzofuran-derived azadienes (BDAs) and quinolines as the starting materials. This method functions with transition-metal catalysis and uses cost-effective formic acid as the reducing agent. Mechanistic investigations indicate that this transformation would involve a [4 + 2] annulation cascade process. This approach demonstrates a high tolerance to various functional groups and yields excellent results.

Synthesis and characterization of Cu-modified ox-g-C3N4 nanosheets as an electrode for green synthesis of phenyl Benzofuran derivatives via C–H functionalization to C–O and C–C bond formation with an electrochemical oxidation system

Synthesis and characterization of Cu-modified ox-g-C3N4 nanosheets as an electrode for green synthesis of phenyl Benzofuran derivatives via C–H functionalization to C–O and C–C bond formation with an electrochemical oxidation system

Palladium-Catalyzed Three-Component Cascade Carbonylation Reaction to Construct Benzofuran Derivatives.

A novel three-component cyclization carbonylation reaction of iodoarene-tethered propargyl ethers with amine and CO is reported. This palladium-catalyzed cascade reaction undergoes a sequence of oxidative addition, unsaturated bond migration, carbonyl insertion, and nucleophilic attack to deliver the benzofuran skeleton. Both aromatic amines and aliphatic amines could proceed smoothly in this transformation under one atm of CO.

Undescribed Cyclohexene and Benzofuran Alkenyl Derivatives from Choerospondias axillaris, a Potential Hypoglycemic Fruit.

The fruit of Choerospondias axillaris (Anacardiaceae), known as south wild jujube in China, has been consumed widely in several regions of the world to produce fruit pastille and leathers, juice, jam, and candy. A comprehensive chemical study on the fresh fruits led to the isolation and identification of 18 compounds, including 7 new (1-7) and 11 known (8-18) comprised of 5 alkenyl (cyclohexenols and cyclohexenones) derivatives (1-5), 3 benzofuran derivatives (6-8), 6 flavonoids (9-14) and 4 lignans (15-18). Their structures were elucidated by extensive spectroscopic analysis. The known lignans 15-18 were isolated from the genus Choerospondias for the first time. Most of the isolates exhibited significant inhibitory activity on α-glucosidase with IC50 values from 2.26 ± 0.06 to 43.9 ± 0.96 μM. Molecular docking experiments strongly supported the potent α-glucosidase inhibitory activity. The results indicated that C. axillaris fruits could be an excellent source of functional foods that acquire potential hypoglycemic bioactive components.

A Comprehensive Review on Benzofuran Synthesis Featuring Innovative and Catalytic Strategies.

Benzofurans have intrigued both pharmaceutical researchers and chemists owing to the medicinal usage of their derivatives against copious disease-causing agents (i.e., bacteria, viruses, and tumors). These heterocyclic scaffolds are pervasively encountered in a number of natural products and drugs. The ever-increasing utilization of benzofuran derivatives as pharmaceutical agents persuaded the chemists to devise novel and facile methodological approaches to assemble the biologically potent benzofuran nucleus. This review summarizes the current developments regarding the innovative synthetic routes and catalytic strategies to procure the synthesis of benzofuran heterocycles with their corresponding mechanistic details, reported by several research groups during 2021-2023.

Benzofurans as Acetylcholinesterase Inhibitors for Treating Alzheimer's Disease: Synthesis, in vitro Testing, and in silico Analysis.

Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia worldwide. It is characterized by a progressive decline in cholinergic neurotransmission. During the development of AD, acetylcholinesterase (AChE) binds to β-amyloid peptides to form amyloid fibrils, which aggregate into plaque deposits. Meanwhile, tau proteins are hyperphosphorylated, forming neurofibrillary tangles (NFTs) that aggregate into inclusions. These complexes are cytotoxic for the brain, causing impairment of memory, attention, and cognition. AChE inhibitors are the main treatment for AD, but their effect is only palliative. This study aimed to design and synthesize novel benzofuran derivatives and evaluate their inhibition of AChE in vitro and in silico. Results: The seven synthesized benzofuran derivatives inhibited AChE in vitro. Benzofurans hydroxy ester 4, amino ester 5, and amido ester (±)-7 had the lowest inhibition constant (Ki) values and displayed good affinity for EeAChE in molecular docking. Six derivatives showed competitive inhibition, while the best compound (5: Ki=36.53 μM) exhibited uncompetitive inhibition. The amino, hydroxyl, amide, and ester groups of the ligands favored interaction with the enzyme by hydrogen bonds. Conclusion: Three benzofurans were promising AChE inhibitors with excellent Ki values. In future research on their their application to AD, 5 will be considered as the base structure.