Benzofuran Moiety Research Articles

Synthesis and in vitro study of nitro- and methoxy-2-phenylbenzofurans as human monoamine oxidase inhibitors

A new series of 2-phenylbenzofuran derivatives were designed and synthesized to determine relevant structural features for the MAO inhibitory activity and selectivity. Methoxy substituents were introduced in the 2-phenyl ring, whereas the benzofuran moiety was not substituted or substituted at the positions 5 or 7 with a nitro group. Substitution patterns on both the phenyl ring and the benzofuran moiety determine the affinity for MAO-A or MAO-B. The 2-(3-methoxyphenyl)-5-nitrobenzofuran 9 was the most potent MAO-B inhibitor (IC50 = 0.024 µM) identified in this series, whereas 7-nitro-2-phenylbenzofuran 7 was the most potent MAO-A inhibitor (IC50 = 0.168 µM), both acting as reversible inhibitors. The number and position of the methoxyl groups on the 2-phenyl ring, have an important influence on the inhibitory activity. Molecular docking studies confirmed the experimental results and highlighted the importance of key residues in enzyme inhibition.

Antiproliferative potential, quantitative structure-activity relationship, cheminformatic and molecular docking analysis of quinoline and benzofuran derivatives

Quinoline and benzofuran moieties are commonly used for the synthesis of therapeutically beneficial molecules and drugs since they possess a wide range of pharmacological activities including potent anticancer activity as compared to other heterocyclic compounds. Many of well-known antimalarial, antimicrobial, anti-helminthic, analgesic, anti-inflammatory, antiprotozoal, and antitumor compounds contain quinoline/benzofuran skeleton. The aim of this study was to analyze ten new quinoline and eighteen benzofuran derivatives for carcinoma cell line growth inhibition and to predict possible interactions with the target. The anticancer activity of these compounds against colon cancer (HCT-116) and triple-negative breast cancer (MDA-MB-468) cell lines was determined and performed molecular docking to predict the possible interactions. Among ten quinoline derivatives, Q1, Q4, Q6, Q9, and Q10 were found to be the most potent against HCT-116 and MDA-MB-468 with IC50 values ranging from 6.2-99.6 and 2.7-23.6 μM, respectively. Using the IC50 values, a model equation with quantitative structure activity relationship (QSAR) was generated with their descriptors such as HBA1, HBA2, kappa (1, 2 and 3), Balaban index, Wiener index, number of rotatable bonds, log S, log P and total polar surface area (TPSA). The effect of benzofuran derivatives was moderate in cytotoxicity tests and hence only quinolines were considered for further analysis. The molecular docking indicated the mammalian / mechanistic target of rapamycin (mTOR), Topoisomerase I and II as possible targets for these molecules. The predicted results obtained from QSAR and molecular docking analysis of quinoline derivatives showed high correlation in comparison to the results of the cytotoxic assay. Overall, this study indicated that quinolines are more potent as anticancer agents compared to benzofurans. Further, compound Q9 has emerged as a lead molecule which could be the base for further development of more potent anticancer agents.

In vitro cytotoxicity and druglikeness of pyrazolines and pyridines bearing benzofuran moiety

In vitro cytotoxicity and druglikeness of pyrazolines and pyridines bearing benzofuran moiety

Using the Cancer Dependency Map to Identify the Mechanism of Action of a Cytotoxic Alkenyl Derivative from the Fruit of Choerospondias axillaris.

An extract prepared from the fruit of Choerospondias axillaris exhibited differential cytotoxic effects when tested in a panel of pediatric cancer cell lines [Ewing sarcoma (A-673), rhabdomyosarcoma (SJCRH30), medulloblastoma (D283), and hepatoblastoma (Hep293TT)]. Bioassay-guided fractionation led to the purification of five new hydroquinone-based metabolites, choerosponols A-E (1-5), bearing unsaturated hydrocarbon chains. The structures of the natural products were determined using a combination of 1D and 2D NMR, HRESIMS, ECD spectroscopy, and Mosher ester analyses. The purified compounds were evaluated for their antiproliferative and cytotoxic activities, revealing that 1, which contains a benzofuran moiety, exhibited over 50-fold selective antiproliferative activity against Ewing sarcoma and medulloblastoma cells with growth inhibitory (GI50) values of 0.19 and 0.07 μM, respectively. The effects of 1 were evaluated in a larger panel of cancer cell lines, and these data were used in turn to interrogate the Project Achilles cancer dependency database, leading to the identification of the MCT1 transporter as a functional target of 1. These data highlight the utility of publicly available cancer dependency databases such as Project Achilles to facilitate the identification of the mechanisms of action of compounds with selective activities among cancer cell lines, which can be a major challenge in natural products drug discovery.

Spiroindolone analogues bearing benzofuran moiety as a selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors.

To design and discover a new compound can used as a COX with TNF-α and IL-6 inhibitors is highly challenge. A series of spiroindolone-bearing benzofuran moieties were resynthesized from the chalcone-based benzo[b]furan with substituted isatin, and amino acids. The requisite spiroindolone analogues were tested for their potential inhibitory activities against lipid metabolizing enzymes such as cyclooxygenase COX-1, COX-2, and the release of pro-inflammatory cytokines interleukin IL-6, and tumor necrosis factor TNF-α. Among the tested compounds, 5a, 5c, 5h, 5i, 5l, and 5p exhibited COX-1 inhibitor selectively with percent of inhibition 40.81–83.4% and IC50 values ranging from 20.42 µM to 38.24 µM. In addition, all the synthesized target compounds possessed lipopolysaccharide-induced TNF-α, and IL-6 expression with a varying degree of COX-1 inhibition. Compounds 5d, 5e, 5f, 5g, and 5k markedly inhibited TNF-α, and IL-6 release in WI-38 fibroblast cells. Molecular docking of the most effective and highly selective compounds were investigated and shown important binding mechanisms which could affect pro-inflammatory enzymes and cytokines via the inhibition of COX-1, COX-2, IL-6, and TNF-α.

Synthesis, Characterization and in vitro Antimicrobial Screening of Some Novel Series of 2-Azetidinone Derivatives Integrated with Quinoline, Pyrazole and Benzofuran Moieties

A series of 5-(benzofuran-2-yl)-N-(3-chloro-4-(2-(p-tolyloxy) substituted quinolin-3-yl)-2-oxoazetidin-1-yl)-1-phenyl-1H-pyrazole-3-carboxamide derivatives (4a-f) were synthesized with excellent yields by cyclocondensation reaction of 5-(benzofuran-2-yl)-N′-(2-(p-tolyloxy) substituted quinolin-3-yl)methylene)-1-phenyl-1H-pyrazole-3-carbohydrazide (3a-f) with chloroacetyl chloride in presence of triethylamine in DMF. One pot condensation of 5-(benzofuran-2-yl)-1-phenyl-1H-pyrazole-3-carbohydrazide (1) with 2-(p-tolyloxy) substituted quinoline-3-carbaldehyde (2a-f) in ethanol solvent in presence of catalytic amount of acetic acid gave intermediate compounds (3a-f). The structures of newly synthesized compounds have been substantiated through elemental analysis and spectral studies viz. 1H NMR, 13C NMR, IR and mass spectra. All the synthesized compounds were screened for their in vitro antibacterial activity against pathogenic bacteria such as S. aureus and E. coli at different concentrations.

Synthesis of diarylalkanes through an intramolecular/intermolecular addition sequence by auto-tandem catalysis with strong Brønsted base.

An auto-tandem catalysis with a strong Brønsted base enabled the synthesis of diarylalkanes containing a benzofuran moiety. Potassium tert-butoxide efficiently catalyzed both the intramolecular cyclization of less acidic ortho-alkynylaryl benzyl ethers and the following intermolecular addition of diarylmethanes to styrenes, demonstrating the high potential of the catalysis in organic synthesis.

Benzofuran‐isatin conjugates as potent VEGFR‐2 and cancer cell growth inhibitors

AbstractA series of benzofuran‐isatin conjugates 6a‐l and 7a,b tethered by various alkyl linkers were synthesized and evaluated for their VEGFR‐2 inhibitory activity and in vitro activity against a panel of cancer cell lines. Seven of them were comparable with or better than Sunitinib against all tested cancer cells, demonstrating benzofuran‐isatin conjugates were potential anticancer candidates. The mechanism study revealed that VEGFR‐2 was at least one of the targets for this kind of conjugates. The structure‐activity relationship demonstrated that the carbon spacer between benzofuran and isatin moieties, substituents on the C‐2 position of benzofuran moiety, and substituents on C‐3 as well as C‐5 position of isatin motif influenced the anticancer activity significantly, and the enriched structure‐activity relationship may provide an insight for rational design of more effective conjugates.

Absolute Configuration and Biological Activities of Meroterpenoids from an Endophytic Fungus of Lycium barbarum.

Eleven new meroterpenoids, bipolahydroquinones A-C (1-3), cochlioquinones I-N (4-8 and 11), and isocochlioquinones F and G (9 and 10), together with six known ones, were obtained from an endophytic fungus Bipolaris sp. L1-2 from Lycium barbarum. Compound 2 is the first example of cochlioquinone derivatives possessing a benzofuran moiety. The structures and absolute configurations of the new compounds were elucidated by spectroscopic data interpretation, single-crystal X-ray diffraction analysis, chemical transformations, and biosynthetic considerations. Compounds 3, 4, and 6-8 showed cytotoxicity against NCI-H226 and/or MDA-MB-231 with IC50 values ranging from 5.5 to 9.5 μM.

Crystal structures of butyl 2-amino-5-hy-droxy-4-(4-nitro-phen-yl)benzo-furan-3-carboxyl-ate and 2-meth-oxy-ethyl 2-amino-5-hy-droxy-4-(4-nitro-phen-yl)benzo-furan-3-carboxyl-ate.

The title benzo-furan derivatives 2-amino-5-hy-droxy-4-(4-nitro-phen-yl)benzo-furan-3-carboxyl-ate (BF1), C19H18N2O6, and 2-meth-oxy-ethyl 2-amino-5-hy-droxy-4-(4-nitro-phen-yl)benzo-furan-3-carboxyl-ate (BF2), C18H16N2O7, recently attracted attention because of their promising anti-tumoral activity. BF1 crystallizes in the space group P . BF2 in the space group P21/c. The nitro-phenyl group is inclined to benzo-furan moiety with a dihedral angle between their mean planes of 69.2 (2)° in BF1 and 60.20 (6)° in BF2. A common feature in the mol-ecular structures of BF1 and BF2 is the intra-molecular N-H⋯Ocarbon-yl hydrogen bond. In the crystal of BF1, the mol-ecules are linked head-to-tail into a one-dimensional hydrogen-bonding pattern along the a-axis direction. In BF2, pairs of head-to-tail hydrogen-bonded chains of mol-ecules along the b-axis direction are linked by O-H⋯Ometh-oxy hydrogen bonds. In BF1, the butyl group is disordered over two orientations with occupancies of 0.557 (13) and 0.443 (13).

A Simple and Efficient Process for the Synthesis of Novel Heterocycles Containing Benzofuran Moiety Using Thiocarbohydrazide as a Precursor

A simple and efficient process for the synthesis of novel heterocycles starting from thiocarbohydrazide was reported. Reaction of 2‐acetylbenzofuran (1) and thiocarbohydrazide (2) in ethanol containing acetic acid produced the corresponding thiocarbohydrazone 3 in 86% yield. Reaction of 3 and isatin (4) gave N,2‐bis(2‐oxoindolin‐3‐ylidene)hydrazine‐1‐carbothiohydrazine (6) in 65% yield, rather than the expected product, 3‐[(1‐methyl‐1‐benzofur‐2‐ylmethylidene)amino]‐1‐{[(3Z)‐2‐oxo‐2,3‐dihydro‐1H‐indol‐3‐ylidene]amino}thiourea (5). Reaction of 2‐((3‐(benzofuran‐2‐yl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)methylene)hydrazine carbothioamide (9) and chloroacetic acid or hydrazonoyl chloride 11 in basic medium gave (Z)‐2‐((E)‐((3‐(benzofuran‐2‐yl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)methylene)hydrazono)thiazolidin‐4‐one (10) or 2‐((E)‐2‐((3‐(benzofuran‐2‐yl)‐1‐ phenyl‐1H‐pyrazol‐4‐yl)methylene)hydrazinyl)‐4‐((E)‐(4‐fluorophenyl)diazenyl)‐5‐methylthiazole (12) in 62% or 74%, respectively.

Regioselective synthesis of novel antibacterial pyrazole-benzofuran hybrids: 2D NMR spectroscopy studies and molecular docking

The acetyl derivative bearing benzofuran moiety, its enaminone and different hydrazines are used as synthons for the regioselective synthesis of substituted pyrazoles. Their structures were elucidated by 2D 1H-1H COSY, 1H-1H NOESY and 1H-13C HMBC NMR, spectrometry. Also, a series of novel pyrazole-benzofuran hybrids have been synthesized by the regioselective cycloaddition of enaminone to hydrazonyl chlorides. The series was elucidated by IR, 1H-NMR, 13C-NMR, 2D1H-1H COSY, 1H-1H NOESY and 1H-13C HMBC NMR spectrometry as well as elemental analyses. The series was subjected for testing their antimicrobial activities. Pyrazole derivative 12c showed the highest inhibitory activity against all different bacterial strains with minimum inhibitory concentration values of 7.81, 15.6, 15.6 and 3.91 μg/mL against Staphylococcus aureus, Streptococcus mutans, Escherichia coli and Klebsiella pneumonia, respectively, as compared to standard drugs for gram-positive and negative bacterial strains. The structure-activity relationship studies and molecular docking were performed to explain the inhibitory activities.

Enantioselective Synthesis of Atropisomers Featuring Pentatomic Heteroaromatics by Pd-Catalyzed C–H Alkynylation

Due to the lower rotational barriers, the catalytic asymmetric construction of atropisomeric species featuring a five-membered ring remains a formidable challenge. Herein, we describe a Pd-catalyzed atroposelective C–H alkynylation to synthesize such atropisomers. A wide range of atropisomers displaying either a stereogenic C–N or C–C bond featuring one or even two five-membered rings were obtained (up to 98% yield and up to >99% ee). Various five-membered heteroarenes, including pyrroles, thiophenes, benzothiophenes, and benzofurans were compatible with this protocol. Notably, this strategy offers the catalytic asymmetric synthesis of axially chiral 3,3′-bisbenzothiophene with good ee (93% ee). Computational studies revealed the key structural elements that differentiate the rotational barriers of benzothiophene and benzofuran moieties.

Novel aryloxyphenoxypropionate derivates containing benzofuran moiety: Design, synthesis, herbicidal activity, docking study and theoretical calculation

A series of novel aryloxyphenoxypropionate (APP) herbicides containing benzofuran moiety were designed, synthesized and tested for herbicidal activity. The bioassay results indicated that most of target compounds possessed moderate to good herbicidal activity against monocotyledonous weeds. Compounds 5a-5d and 6a-6d showed 100% control efficiency against crabgrass (Digitaria sanguinalis) and barnyard grass (Echinochloa crus-galli) in both pre-emergence and post-emergence treatments at the dosage of 1500 g a.i. ha−1. Compound 6c was the most promising, with herbicidal activity better than clodinafop-propargyl. Molecular docking for compound 6c and its hydrolysis acid 1c were performed. ACCase activities of some compounds were also tested. Theoretical calculations for corresponding hydrolysis products 1a-1ewere carried out. Based on the results of molecular docking, enzyme activity test and theoretical calculation, the potential mechanism for herbicidal activity of these compounds was evaluated.

Synthesis and study of benzofuran-pyran analogs as BMP-2 targeted osteogenic agents

Twenty-four novel benzofuran-pyran derivatives were synthesized and evaluated for their anti-osteoporotic activity in primary cultures of rat calvarial osteoblasts in vitro. Among all the compounds screened for the alkaline phosphatase activity, three compounds 4e, 4j and 4k showed potent activity at picomolar concentrations in osteoblast differentiating stimulation. Additionally, these compounds were found effective in mineralization, assessed by alizarin red-S staining assay. Compounds were again validated through a series of other in vitro experiments. Moreover, molecular dynamics simulations demonstrated that both benzofuran and pyran moieties are requisite to fit into the active site of BMP-2 receptor, a key target of the osteogenic agents. The obtained results strongly convey that compound 4e is a potential bone anabolic agent among synthesized series, which can be further explored as a drug lead for treating osteoporosis.

A Convergent Total Synthesis of the Biologically Active Benzo­furans Ailanthoidol, Egonol and Homoegonol from Biomass-Derived­ Eugenol

An efficient, general synthetic protocol for the synthesis of the biologically active benzofurans ailanthoidol, egonol and homoegonol was developed. The key starting material, eugenol, is a naturally occurring and abundant precursor. The protocol, involving sequential acylation and intramolecular Wittig reaction, provides a convenient method for building the benzofuran moiety in good yield.

Benzofuran-pyran hybrids: A new class of potential bone anabolic agents

Benzofuran moiety is an important pharmacophore showing positive effects on bone health. In the present study, sixteen benzofuran-pyran hybrids were synthesized and were evaluated for their osteogenic effects on primary osteoblast cells isolated from calvaria. Compounds 22 and 24 were found potent in stimulating osteoblast differentiation as assessed by the alkaline phosphatase activity. These compounds were also found to be nontoxic to osteoblast cells as compared to the control cells in MTT assay. Further, Alizarin Red-S staining for visualization of calcium nodules demonstrated compounds 22 and 34 as active in enhancing mineralization in osteoblast cells. Additionally, transcriptional analysis of these compounds on osteoblast cells revealed that compound 22 up-regulated the expression of osteogenic genes RUNX2, BMP-2, COL-1, thus substantiating that compound 22 having two geminal methyl groups in its R3 position is a potent osteogenic agent. Additionally, compound 22 enhanced the ability of bone marrow stromal cells to differentiate towards osteoblast lineage and therefore can be further studied in vivo in bone loss model.

Application of differential reactivity towards synthesis of lamellarin and 8-oxoprotoberberine derivatives: Study of photochemical properties of aryl-substituted benzofuran-8-oxoprotoberberines

A unique differential reactivity between dihydroisoquinolines and 3-nitrocoumarins was observed and was exploited for the efficient construction of lamellarins and their isomeric benzofuran-8-oxoprotoberberine derivatives under acid-catalyzed or base-promoted conditions. Further, these prepared aryl-substituted benzofuran-8-oxoprotoberberine derivatives bearing electron-donating substituents on benzofuran moiety are found to be benchtop stable but light-sensitive, and can undergo oxidative ring-opening reaction to give the corresponding keto products when exposed to visible light under aerobic conditions.

Synthesis and Antimicrobial Assay of Some Novel 4-Thiazolidinone Derivatives Possessing Benzofuran, Quinoline and Pyrazole Moieties

Synthesis and Antimicrobial Assay of Some Novel 4-Thiazolidinone Derivatives Possessing Benzofuran, Quinoline and Pyrazole Moieties

Benzofuran-dihydropyridine hybrids: A new class of potential bone anabolic agents

A series of novel benzofuran-dihydropyridine hybrids were designed by molecular hybridization approach and evaluated for bone anabolic activities. Among the screened library, ethyl 4-(7-(sec-butyl)-2-(4-methylbenzoyl)benzofuran-5-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (compound 21) significantly enhanced the ALP production and mineralized nodule formation, which are primary requisites in the process of in vitro osteogenesis. Oral administration of compound 21 at 10 mg.kg−1 day−1 for two weeks led to restoration of trabecular bone microarchitecture in drill hole fracture model by significantly increasing BV/TV and Tb.N. Furthermore, histological and molecular studies showed compound 21 triggering the new bone regeneration in a drill hole defect site by increasing BMP expression. Furthermore, molecular modeling studies were performed to gain insight into the binding approach, which revealed that both benzofuran and dihydropyridine moieties are essential to show similar binding interactions to fit into the active site of BMP2 receptor, an important target of the osteogenic agents. Our results suggest that compound 21 stimulates BMP2 synthesis in osteoblast cells that promotes new bone formation (∼40%) at the fracture site which helps in shorten the healing period.