Series Of Benzofuran Derivatives Research Articles

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.

Design, synthesis and computational study of new benzofuran hybrids as dual PI3K/VEGFR2 inhibitors targeting cancer

Design and synthesis of a new series of benzofuran derivatives has been performed. 1H-NMR, 13C-NMR, elemental analysis, and IR were used to confirm the structures of the produced compounds. Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), epithelioid carcinoma cervical cancer (Hela), and human prostate cancer are used to test anticancer activity (PC3). In compared to DOX (4.17–8.87 µM), Compound 8 demonstrated the highest activity against HePG and PC3 cell lines, with an IC50 range of 11–17 µM. Compound 8 inhibited PI3K and VEGFR-2 with IC50 values of 2.21 and 68 nM, respectively, compared to 6.18 nM for compound LY294002 and 31.2 nM for compound sorafenib as PI3K and VEGFR-2 reference inhibitors, selectively. The molecular docking and binding affinity of the generated compounds were estimated and studied computationally utilizing molecular operating environment software as a PI3K and VEGFR-2 inhibitor (MOE). In conclusion, compound 8 exhibited significant action against hepatocellular and cervical cancer cell lines. Mechanistic study showed that it had a dual inhibitory effect against PI3K and VEGFR-2.

Friedel-Crafts alkylation oxidative cyclization catalyzed by co-oxidation of SeO2 and FeCl3: a simple synthesis of benzo[b]furan from acetophenone and anisole

A simple one-pot method was developed to complete the α-diphenyl substitution and cyclization of acetophenone using acetophenone and substituted benzene as substrates, and a series of benzofuran derivatives was synthesized efficiently. It had the advantages of medium to excellent yield and easily obtained substrate. Compared with other methods, the method avoids the use of precious metals and cumbersome operations.

Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors.

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC50=0.065μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC50 values of 2.90±0.32, 5.85±0.35, 2.06±0.27, 5.74±1.03 and 6.15±0.49μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust invivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.

Synthesis, anticancer and antimicrobial evaluation of new benzofuran based derivatives: PI3K inhibition, quorum sensing and molecular modeling study

A new series of benzofuran derivatives has been designed and synthesized. The structures of the synthesized compounds have been confirmed by the use of 1H NMR, 13C NMR, 2D 1H–1H NOESY NMR, and IR. Anticancer activity is evaluated against Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), Epitheliod carcinoma cervix cancer (Hela) and human prostate cancer (PC3). Compounds 8, 9, and 11 showed the highest activity towards the four cell lines with an IC50 range of 8.49–16.72 µM, 6.55–13.14 µM and 4–8.99 µM respectively in comparison to DOX (4.17–8.87 µM). Phosphatidylinositol-3-kinases (PI3K) inhibition was evaluated against the most active anticancer compounds 8, 9 and 11. Compounds 8, 9 and 11 showed good inhibitory activity against PI3Kα with IC50 values 4.1, 7.8, and 20.5 µM, respectively in comparison to 6.18 µM for the reference compound LY294002. In addition, activity of compounds 8 and 9 on cell cycle arrest and induction of apoptosis in different phases of MCF-7 cells were assessed and detected pre-G1 apoptosis and cell growth arrest at G2/M. Also, both extrinsic and intrinsic apoptosis in MCF-7 cells induced by compounds 8 and 9. Molecular docking, binding affinity surface mapping, and contact preference of the synthesized compounds 8, 9 and 11 against PI3K were estimated and studied computationally using molecular operating environment software (MOE) and showed good interaction with essential residues for inhibition Val851. In addition, antimicrobial activity was evaluated against gram positive isolates as Staphylococcus aureus and Bacillus cereus, gram negative isolate as Escherichia coli, Pseudomonas aeruginosa and antifungal potential against Candida albicans. Compound 17 showed outstanding anti Gram-positive activity with MIC values 8 and 256 µg/mL in Staphylococcus aureus and Bacillus cereus respectively. Also, compounds 15, 17, 18 and 21 showed good anti Gram-negative activity with MIC value 512 µg/mL for all compounds. In addition, the state-of-art quorum sensing (QS) inhibiting effects were detected using Chromobacterium violaceum and compounds 7, 9, 10, 11, and 12 showed good QS inhibition (3, 3, 5, 2, and 7 mm).

Design, synthesis, and biological activity of a novel series of benzofuran derivatives against oestrogen receptor-dependent breast cancer cell lines

A docking study of a novel series of benzofuran derivatives with ERα was conducted. In this study, we report the synthesis of a novel series of benzofuran derivatives and evaluation of their anticancer activity in vitro against MCF-7 human breast cancer cells, as well as their potential toxicity to ER-independent MDA-MB-231 breast cancer cells, human renal epithelial HEK-293 cells, and human immortal keratinocytes (HaCaT cells) by using the MTT colorimetric assay. The screening results indicated that the target compounds exhibited anti-breast cancer activity. The target compound 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy]benzofuran hydrochloride (4e) exhibited excellent activity against anti-oestrogen receptor-dependent breast cancer cells and low toxicity. The preliminary structure-activity relationships of the target benzofuran derivatives have been summarised. In conclusion, the novel benzofuran scaffold may be a promising lead for the development of potential oestrogen receptor inhibitors.

Synthesis and Evaluation of Novel Benzofuran Derivatives as Selective SIRT2 Inhibitors.

A series of benzofuran derivatives were designed and synthesized, and their inhibitory activites were measured against the SIRT1–3. The enzymatic assay showed that all the compounds showed certain anti-SIRT2 activity and selective over SIRT1 and SIRT3 with IC50 (half maximal inhibitory concentration) values at the micromolar level. The preliminary structure–activity relationships were analyzed and the binding features of compound 7e (IC50 3.81 µM) was predicted using the CDOCKER program. The results of this research could provide informative guidance for further optimizing benzofuran derivatives as potent SIRT2 inhibitors.

Utility of 2‐Acetyl Benzofuran for the Synthesis of New Heterocycles as Potential Anticancer Agents

A novel series of benzofuran derivatives containing thiazole, thiadiazine, and pyridotriazolopyrimidine were synthesized starting from 1‐(benzofuran‐2‐yl)‐3‐(1H–indol‐3‐yl)prop‐2‐en‐1‐one. Also, triazolopyrimidine derivatives were prepared from the reaction of 2‐acetylbenzofuran and pyrazole‐4‐carbaldehyde with 2‐thiobarbutyric acid and reaction of the product with hydrazonoyl halides. The structures of the newly synthesized compounds were elucidated on the basis of elemental analyses, spectral data, and alternative synthetic routes whenever possible. Anticancer activity against 60 different human tumor cell lines representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney was validated by the U.S. National Cancer Institute using a two‐stage process. The results revealed that pyrazoline‐1‐thiocarbohydrazide 4b, triazolopyrimidine 20d, and pyrimidine thione 25 have promising antitumor activity against most cell lines.

Synthesis and biological evaluation of 2-acylbenzofuranes as novel α-glucosidase inhibitors with hypoglycemic activity.

A series of benzofuran derivatives was synthesized as analogues of known natural α-glucosidase inhibitors. Their activity was evaluated in enzymatic assay and in rat model of diabetes mellitus. Newly identified inhibitors demonstrate significant potency with IC50 values ranging from 6.50 to 722.2μm, as well as hypoglycemic activity exceeding the reference drug acarbose. Docking simulations provided insight into structure-activity relationships to direct further development of these novel hypoglycemic agents.

Spectroscopic and molecular modeling studies on the interactions of some benzofuran derivatives with BSA

In this study, the interactions of a series of benzofuran derivatives with bovine serum albumin (BSA) were investigated using UV–Vis and fluorescence spectroscopy and molecular modeling. The intrinsic fluorescence of BSA was found to be quenched by the benzofuran derivatives. The binding constants between the benzofuran derivatives and BSA calculated from fluorescence quenching were found to be (1.80 ± 0.04) × 104, (1.88 ± 0.06) × 104, and (2.02 ± 0.07) × 104 dm3 mol−1, respectively. According to the fluorescence resonance energy transfer, the average binding distances between the benzofuran derivatives and BSA were calculated to be 3.22, 3.29, and 3.02 nm, respectively. The binding of the benzofuran derivatives and BSA was modeled by molecular docking and molecular dynamic (MD) simulation methods. Principal component analysis was performed on 2001 snapshots of the MD trajectories at the equilibrium state. Based on the different regions in the PC space, about 15 conformations were selected, and the average of these was used to determine the interactions between the benzofuran derivatives and BSA. The results revealed that the benzofuran derivatives preferred the binding pocket of domain II of BSA.

Discovery of Benzofuran Derivatives that Collaborate with Insulin-Like Growth Factor 1 (IGF-1) to Promote Neuroprotection.

A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure-activity relationship study identified compound 8 as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and 8 individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity.

Kidney CLC-K chloride channels inhibitors: structure-based studies and efficacy in hypertension and associated CLC-K polymorphisms.

Alterations in the handling of renal salt reabsorption may contribute to interindividual differences in blood pressure regulation and susceptibility to hypertension. CLC-K chloride channels and their accessory subunit barttin play a pivotal role in kidney by controlling chloride and water absorption. Compounds selective for CLC-Ks, such as the benzofuran derivative MT-189, may have a significant therapeutic potential. Here, we assessed the feasibility of using CLC-K blockers in hypertension and aimed at enhancing drug inhibitory affinity. We demonstrated that acute in-vivo administration of MT-189 to spontaneously hypertensive rats (SHR) caused a reduction of blood pressure and defined the CLC-K/barttin gene expression pattern in kidney of SHR in comparison with normotensive Wistar-Kyoto rats. Based on MT-189, we designed and tested a new series of benzofuran derivatives on CLC-K chloride channels heterologously expressed in HEK293 cells. These studies enabled us to elucidate the causative molecular relationship for obtaining the most potent and selective inhibitor (SRA-36) described so far, with an IC50 of 6.6 ± 1 μmol/l. The biophysical and pharmacological characterization of A447T CLC-Ka and Y315F CLC-Ka, both polymorphisms associated with hypertension, showed that SRA-36 is an efficacious inhibitor of the chloride currents sustained by these polymorphisms. Molecular docking studies allowed hypothesizing an inhibition mechanism for the considered ligands, laying the foundations for the rational design of new and more effective CLC-K inhibitors. The SRA-36 molecule represents a new potential therapeutic option for hypertension.

Synthesis of benzofuran derivatives as selective inhibitors of tissue-nonspecific alkaline phosphatase: effects on cell toxicity and osteoblast-induced mineralization.

Tissue-nonspecific alkaline phosphatase (TNAP) by hydrolyzing pyrophosphate, an inhibitor of apatite formation, promotes extracellular matrix calcification during bone formation and growth, as well as during ectopic calcification under pathological conditions. TNAP is a target for the treatment of soft tissue pathological ossification. We synthesized a series of benzofuran derivatives. Among these, SMA14, displayed TNAP activity better than levamisole. SMA14 was found to be not toxic at doses of up to 40μM in osteoblast-like Saos-2 cells and primary osteoblasts. As probed by Alizarin Red staining, this compound inhibited mineral formation in murine primary osteoblast and in osteoblast-like Saos-2 cells.

Kidney CLC-K Chloride Channels Inhibitors: Definition of Novel Structural Requirements and Efficacy in CLC-K Polymorphism Associated with Hypertension

The human chloride channels CLC-Ka and CLC-Kb play a pivotal role in kidney by controlling chloride and water absorption. Both channels require barttin as an accessory subunit for full activity. Mutations in CLC-Kb and barttin genes lead to severe renal salt loss while CLC-K gain of function polymorphisms could predispose to hypertension. Thus, compounds that selectively bind to CLC-Ka and/or CLC-Kb channels may have a significant therapeutic potential. Recently, we explored the pharmacological profile of CLC-K/barttin expressed in mammalian HEK-293 cells and demonstrated that HEK cells represent a valid biological system to screen CLC-K high affinity blockers (Imbrici et al., Biochim Biophys Acta, 2014). Here, by using molecular modeling and patch-clamp technique, we developed a new series of benzofuran derivatives and evaluated their efficacy on CLC-K channels expressed in HEK 293 cells. Chemical modifications regarding the hydrophobic group at C-5 and C-3 position of the benzofuran nucleus of the lead compounds RT-93 and JBL-44 (IC50 within 10-30 μM range), allowed us to define the structural requirements to ensure an efficacious CLC-Ka block, finally identifying SRA-36 the most potent compound so far described, with an IC50 of 2.6 ± 1 μM. Interestingly, besides capable of inhibiting CLC-Kb and CLC-K1 isoforms, this compound was also efficacious in blocking A447T CLC-Ka, a polymorphism associated with hypertension. Thus, the SRA-36 molecule could represent a useful probe for exploring CLC-K molecular mechanisms of gating as well as a new potential therapeutic option for hypertensive patients carrying CLC-K gene polymorphisms (Telethon GGP14096).

Synthesis, antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives

The synthesis of novel series of benzofuran derivatives, containing barbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl) methylidene]pyrimidin-2,4,6(1H,3H,5H)-trione (4a–i) and thiobarbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl)methylidene]-2-thioxodihydropyrimidin-4,6(1H, 5H)-dione (5a–i) have been reported. The target compounds (4a–i) and (5a–i) were synthesized by the Knoevenagel condensation of (5-substituted-1-benzofuran-2-yl)(2/4-substitutedphenyl) methanone (3a–i) with barbituric acid and thiobarbituric acid, respectively, in acid medium. These compounds were screened for the antimicrobial and antioxidant activities. From antimicrobial activity results it was found that compounds 4a, 5a, 4c, and 5c displayed good antibacterial and antifungal activity against all tested strains. Further, the synthesized compounds were studied for docking on the enzyme, Glucosamine-6-phosphate synthase and the compounds 4c and 5c have emerged has an active antimicrobial agent with least binding energy (−5.27 and −4.85 kJ mol−1). Compounds 4e, 4f, 5e, and 5f showed promising free radical scavenging activity and compounds 5a and 5b showed good chelating ability with Fe2+ ions.

Facile microwave-assisted synthesis of substituted benzofuran derivatives

A series of benzofuran derivatives have been synthesized by use of a microwave-assisted process. Substituted or unsubstituted ο-hydroxyacetophenone and salicylaldehyde reacted with ethyl bromoacetate, ω-bromoacetophenone, or chloroacetone under the action of potassium carbonate in DMF to yield substituted benzofuran derivatives. Compared with conventional heating, this microwave-assisted synthetic process has the advantages of more convenient operation, shorter reaction time, and higher yield.

Synthetic studies on selective adenosine A2A receptor antagonists. Part II: Synthesis and structure–activity relationships of novel benzofuran derivatives

Based on the previously reported lead compound, a series of benzofuran derivatives were prepared to study their antagonistic activities to A2A receptor. The replacement of the phenyl group at the 4-position with a heterocyclic ring improved the PK profile and aqueous solubility. From these studies, we discovered a potent new A2A antagonist, 12a, which has both a good oral bioavailability and in vivo efficacy on motor disability in MPTP-treated common marmosets.

Synthetic studies on selective adenosine A 2A receptor antagonists: Synthesis and structure–activity relationships of novel benzofuran derivatives

A series of benzofuran derivatives were prepared to study their antagonistic activities to the A 2A receptor. Replacement of the ester group of the lead compound 1 with phenyl ring improved the PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds 13c, 13f, and 24a showed good potency in vitro and were identified as novel A 2A receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.

Synthesis, discovery and preliminary SAR study of benzofuran derivatives as angiogenesis inhibitors

A series of benzofuran derivatives were synthesized and evaluated against HUVEC proliferation. Among these compounds, compound 32 exhibited good inhibitory activity and remarkable selectivity to HUVEC. Our current data suggested that array order of methyl, acrylate and carboxylate groups in benzofuran scaffold is the basic requirement for inhibitory activity against HUVEC proliferation. These results demonstrated that benzofuran scaffold represents a promising structural core to discover a new class of active and selective angiogenesis inhibitors.

Synthesis and pharmacological activity of benzofurylhydroxyureas and benzofurylhydroxamic acids

A series of benzofuran derivatives of hydroxyurea and hydroxamic acid has been obtained. Hydroxyureas have been O-alkylated with 3-bromomethyl-4-methylfuroxane. The antiinflammatory and antiulcer properties of these compounds have been investigated.