Benzofuran Derivative Research Articles

Safety of Amiodarone in Ventricular Arrhythmia in Patients Admitted in Bangabandhu Sheikh Mujib Medical University

Background: Amiodarone is the most effective antiarrhythmic medications available today for the treatment of both atrial and ventricular arrhythmias. It is an iodinated benzofuran derivative with demonstrated efficacy against a range of cardiac arrhythmias, including atrial fibrillation, paroxysmal supraventricular tachycardias, and life-threatening ventricular arrhythmias. Objective: To evaluation the status of amiodarone with therapeutic dose in Bangladeshi population. Materials and Methods: The quasi experimental study was conducted in the Department of Cardiology in Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbagh, Dhaka during April, 2019 to March, 2020 Patients got admitted in the Department of Cardiology, BSMMU, consecutive patients who had been treated with amiodarone for arrhythmia were included in this study. Patients without an amiodarone prescription were assumed and patients who will not give informed written consent were excluded in this study. Results: The most common adverse event was bradycardia or conduction disturbance (9.0%) followed by 4(2.2%) thyroid toxicity, 3(1.7%) hepatic toxicity, 2(1.1%) eye toxicity and 1(0.6%) pulmonary toxicity. In multi variable logistic regression, bradycardia or conduction disturbance, amiodarone daily dose (≥300 mg) and duration of amiodarone (>4 month) was found to be significantly (p<0.05) associated with adverse effects of amiodarone. Conclusion: The most common adverse event was bradycardia or conduction disturbance followed by thyroid toxicity, hepatic toxicity, eye toxicity and pulmonary toxicity. Bradycardia or conduction disturbance, amiodarone daily dose (≥300 mg) and duration of amiodarone (>4 month) was found to be significantly associated with adverse effects of amiodarone.
 University Heart Journal Vol. 17, No. 2, Jul 2021; 118-121

Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions.

Amiodarone is a benzofuran derivative used to treat arrhythmias, but its use is limited by adverse reactions. There is evidence that some of the severe adverse reactions such as liver injury and interstitial lung disease are immune-mediated; however, details of the mechanism have not been elucidated. We tested the ability of amiodarone to induce the release of danger-associated molecular patterns (DAMPs) that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for drug bioactivation, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Amiodarone is known to be oxidized to reactive quinone metabolites. The supernatant from the incubation of amiodarone with FLC-4 cells for 7 days increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with amiodarone, the heat shock protein (HSP) 40 was significantly increased. Addition of a cytochrome P450 inhibitor to the FLC-4 cells prevented the release of HSP40 from the FLC-4 cells and activation of THP-1 inflammasomes by the FLC-4 supernatant. These results suggested that the reactive quinone metabolites of amiodarone can cause the release of DAMPs from hepatocytes which can activate inflammasomes. Dronedarone, a safer analog of amiodarone, did not activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by amiodarone, which in some patients, can cause immune-related adverse events. In addition, our data suggest that drugs that block the effects or the formation of IL-1β would provide better treatment of amiodarone-induced immune-related adverse reactions.

New secondary metabolites with immunosuppressive and BChE inhibitory activities from an endophytic fungus Daldinia sp. TJ403-LS1

Five new acetylenic phenol derivatives (1–4 and 7), one new benzofuran derivative (8), one new naphthol derivative (9), and two known analogues (5 and 6), were isolated and identified from an endophytic fungus Daldinia sp. TJ403-LS1 that was isolated from the medicinally valuable plant Anoectochilus roxburghii. Their structures were elucidated by means of extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. In addition, compound 1 exhibited remarkable immunosuppressive activity against LPS and anti-CD3/anti-CD28 mAbs activated murine splenocytes proliferation with the same IC50 values of 0.06 μM and BChE inhibitory activity with an IC50 value of 6.93 ± 0.71 μM, and compounds 6, 8 and 9 showed excellent BChE inhibitory activity with IC50 values of 16.00 ± 0.30, 23.33 ± 0.55, and 15.53 ± 0.39 μM, respectively (positive drug neostigmine, IC50 = 49.60 ± 6.10 μM), highlighting the promising potentials to be designed and developed as immunosuppressive and BChE inhibitory agents.

Nervione, a new benzofuran derivative from Nervilia concolor

A new benzofuran derivative, nervione (1), was isolated from Nervilia concolor (Blume) Schltr. (Orchidaceae). Eight previously reported compounds were also isolated: 5,7-dimethoxyflavone (2), 3,5,7-trimethoxyflavone (3), 7-methoxyflavone (4), 3,7-dimethoxy-5-hydroxyflavone (5), tetramethylscutellarein (4',5,6,7-tetramethoxyflavone) (6), 5,7-dimethoxy-4'-hydroxyflavone (7), rhamnetin (8), and 5,7-dihydroxy-3’,4’-dimethoxyflavone (9). The structures were elucidated by 1D, 2D NMR, and HRESIMS spectroscopy in addition to the literature. The relative configuration of 1 was defined using DP4+ probability while its absolute configuration was defined by comparison of the ECD spectrum of 1 with those of previously reported compounds. All isolated compounds were evaluated for alpha-glucosidase inhibition, revealing weak or no activity.

Susceptibility of Sesbagrandiflorain B against Chlorination: A DFT Study

Sesbagrandiflorain B is a novel aryl benzofuran derivative isolated from Sesbania grandiflora. Due to its novelty, there is almost no study on the reactivity and properties on this compound. In this study, we perform calculation to determine the reactivity of sesbagrandiflorain B against chlorination reaction based on fukui indices and energy calculation of reactant, intermediate, and product structures. The properties of the system are calculated using DFT B3LYP/6-311++g(d), and to simulate the effect of solvent we employ polarizable continuum model (PCM) on GAMESS-US 2018 package software. From the structure of sesbagrandiflorain B, there are five possible positions that susceptible to chlorination. The energy of reaction in those positions are significantly different from each other with energy of the intermediate formations are 446.48 kJ, 428.06 kJ, 428.63 kJ, 364.08 kJ, and 388.86 kJ, indicating that the selectivity of sesbagrandiflorain B against chlorination reaction. The intermediate formation of sesbagrandiflorain B chlorination that is simulated without solvent tend to be endothermic while the implementation of PCM to the system significantly reduce the intermediate energy, suggesting that the solvent promote the reaction to be thermodynamically driven. For some position, the solvent also stabilizes the product of chlorination reaction.

Bioactive sesquiterpenoids from the flower buds of Tussilago farfara

Eleven new compounds including five bisabolane (1–5) and three oplopane (6–8) sesquiterpenoids, a pair of benzopyran enantiomers (9 &10) and a benzofuran derivative (11), along with six known sesquiterpenoid co-metabolites (12–17), have been obtained from the flower buds of Tussilago farfara. Their structures were elucidated by comprehensive spectroscopic analyses and comparison with structurally related known analogues. The absolute configurations of all the compounds except 11 were unequivocally assigned by various techniques, including Mosher’s method and time-dependent density functional theory (TD-DFT) based calculations of 13C NMR and electronic circular dichroism (ECD) data. The C-8 absolute configuration on the sidechain of this group of bisabolane sesquiterpenoids was assigned for the first time. Our bioassays have established that compounds 3, 4, 13 and 14 showed significant α-glucosidase inhibitory activities, while 6, 8 and 14 displayed moderate antiproliferative effects against two human tumor cell lines A549 and MDA-MB-231. Further flow cytometric analysis revealed that 14 effectively induced cell apoptosis and arrested cell cycle at the S/G2 phases in A549 cells, in a dose-dependent manner.

Novel positive allosteric modulators of A2B adenosine receptor acting as bone mineralisation promoters

Small-molecules acting as positive allosteric modulators (PAMs) of the A2B adenosine receptor (A2B AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (4-13) exhibiting different degrees of chemical similarity with three indole derivatives (1-3), which have been recently identified by us as PAMs of the A2B AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of 4-13 in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents. Further biological characterisation of one of the most performing compounds, the benzofurane derivative 9, confirmed that such a molecule behaves as PAM of the A2B AR.

Orally Administered Benzofuran Derivative Disaggregated Aβ Plaques and Oligomers in the Brain of 5XFAD Alzheimer Transgenic Mouse.

Amyloid-β (Aβ) aggregated forms are highly associated with the onset of Alzheimer's disease (AD). Aβ abnormally accumulates in the brain and induces neuronal damages and symptoms of AD such as cognitive impairment and memory loss. Since an antibody drug, aducanumab, reduces Aβ aggregates and delays clinical decline, clearance of accumulated Aβ in the brain is accounted as a therapeutic approach to treat AD. In this study, we synthesized 17 benzofuran derivatives that may disaggregate Aβ oligomers and plaques into inert monomers. By a series of Aβ aggregation inhibition and aggregates' disaggregation assays utilizing thioflavin T assays and gel electrophoresis, YB-9, 2-((5-methoxy-3-(4-methoxyphenyl)benzofuran-6-yl)oxy)acetic acid, was selected as the final Aβ-disaggregator candidate. When it was orally administered to the 8-month-old male transgenic mouse model with five familial AD mutations (5XFAD) via drinking water daily for two months, Aβ oligomers and plaques in hippocampus were reduced. Consequently, decreased astrogliosis and rescued synaptic dysfunction were observed in the hippocampus of YB-9-treated 5XFAD mice compared with the untreated transgenic control group.

Therapeutic Path to Double Knockout: Investigating the Selective Dual-Inhibitory Mechanisms of Adenosine Receptors A1 and A2 by a Novel Methoxy-Substituted Benzofuran Derivative in the Treatment of Parkinson's Disease.

The dual inhibition of adenosine receptors A1 (A1 AR) and A2 (A2A AR) has been considered as an efficient strategy in the treatment of Parkinson's disease (PD). This led to the recent development of a series of methoxy-substituted benzofuran derivatives among which compound 3j exhibited dual-inhibitory potencies in the micromolar range. Therefore, in this study, we seek to resolve the mechanisms by which this novel compound elicits its selective dual targeting against A1 AR and A2A AR. Unique to the binding of 3j in both proteins, from our findings, is the ring-ring interaction elicited by A1Phe275 (→ A2Phe170) with the benzofuran ring of the compound. As observed, this π-stacking interaction contributes notably to the stability of 3j at the active sites of A1 and A2A AR. Besides, conserved active site residues in the proteins such as A1Ala170 (→ A2Ala65), A1Ile173 (→ A2Ile68), A1Val191 (→ A2Val86), A1Leu192 (→ A2Leu87), A1Ala195 (→ A2Ala90), A1Met284 (→ A2Met179), A1Tyr375 (→ A2Tyr369), A1Ile378 (→ A2Ile372), and A1His382 (→ A2His376) were commonly involved with other ring substituents which further complement the dual binding and stability of 3j. This reflects a similar interaction mechanism that involved aromatic (π) interactions. Consequentially, vdW energies contributed immensely to the dual binding of the compound, which culminated in high ΔGbinds that were homogenous in both proteins. Furthermore, 3j commonly disrupted the stable and compact conformation of A1 and A2A AR, coupled with their active sites where Cα deviations were relatively high. Ligand mobility analysis also revealed that both compounds exhibited a similar motion pattern at the active site of the proteins relative to their optimal dual binding. We believe that findings from this study with significantly aid the structure-based design of highly selective dual-inhibitors of A1 and A2A AR.

Novel radiogallium-labeled pyridyl benzofuran derivative for detection of amylin aggregates in pancreas

IntroductionThe deposition of islet amyloid composed of amylin aggregates is related to β-cell mass dysfunction in type 2 diabetes mellitus (T2DM), and it may be involved in the development and progression of T2DM. In this study, we newly designed, synthesized, and evaluated a radiogallium-labeled pyridyl benzofuran derivative ([67/68Ga]GPBF) as an amylin imaging probe. MethodsAn in vitro competitive inhibition assay was performed to determine the binding affinity for amylin aggregates. An in vitro autoradiographic study was carried out using pancreatic sections from a T2DM patient. A biodistribution of [67Ga]GPBF in normal mice was evaluated. Finally, we carried out ex vivo autoradiography using mouse transplanted with amylin aggregates. ResultsGPBF exhibited binding affinity for amylin aggregates in vitro. In addition, [67Ga]GPBF clearly labeled islet amyloids in in vitro autoradiography of a T2DM pancreatic section. In a biodistribution study using normal mice, [67Ga]GPBF showed initial uptake into the pancreas, but non-specific accumulation in the liver, spleen, and pancreas was also observed. Furthermore, an ex vivo autoradiogram demonstrated that [67Ga]GPBF bound to amylin aggregates in the pancreas of the amylin aggregate-transplanted mice. ConclusionsThese results provide useful insights into the development of radiogallium labeled probes that target amylin aggregates in the T2DM pancreas.

Ultrasound Assisted Synthesis of 2-Substituted Benzofurans via One-Pot and Sequential Method: Their In Vitro Evaluation.

The 2-substituted benzofuran framework has attracted enormous attention due to its presence in a range of bioactive compounds and natural products. While various methods for the synthesis of 2- substituted benzofuran derivatives are known, several of them suffer from certain drawbacks. The main objective of this work was to explore a series of 2-(het)aryl substituted benzofurans derivatives for their cytotoxic properties against cancer cell lines in vitro. In our efforts, we have developed a one-pot synthesis of this class of compounds via sequential C-C coupling followed by C-Si bond cleavage and subsequent tandem C-C/C-O bond-forming reaction under ultrasound irradiation. The methodology involved coupling of (trimethylsilyl)acetylene with iodoarenes in the presence of 10% Pd/C-CuI-PPh3-Et3N in MeOH followed by treating the reaction mixture with K2CO3 in aqueous MeOH and finally coupling with 2-iodophenol. A variety of 2-substituted benzofurans were synthesized using this methodology in good yield. All the synthesized compounds were tested in vitro against two cancer cell lines, e.g. MDAMB-231 and MCF-7 cell lines subsequently against SIRT1. The benzofuran derivative 3m showed encouraging growth inhibition of both MDAMB-231 and MCF- 7 cell lines and significant inhibition of SIRT1. The compound 3m also showed a concentration-dependent increase in the acetylation of p53. Our efforts not only accomplished a one-pot and direct access to 2-(het)aryl substituted benzofurans but also revealed that the benzofuran framework presented here could be a potential template for the identification of potent inhibitors of SIRT1.

Synthesis of Polysubstituted 2H‐Pyran‐2‐ones or Phenols via One‐Pot Reaction of (E)‐β‐Chlorovinyl Ketones and Electron‐Withdrawing Group Substituted Acetates or β‐Diketones

This paper describes a facile one‐pot synthesis of highly functionalized 2H‐pyran‐2‐ones and phenols through a base‐promoted annulation of readily available β‐chlorovinyl ketones with various active methylene compounds. Conjugate addition of electron‐withdrawing group substituted acetates to allenone intermediates and direct conjugate addition of β‐diketones to β‐chlorovinyl ketones reveal versatile electrophilic pathways of β‐chlorovinyl ketones under different reaction conditions. In particular, cyclocondensation is regiospecific for 3,5‐disubstituted phenols. Moreover, the utility of [3+3] cyclocondensation is further illustrated by the concise synthesis of benzofuran derivative and penta‐ or hexa‐substituted phenol construction.

Benzofuran and coumarin derivatives from the root of Angelica dahurica and their PPAR-γ ligand-binding activity

A phytochemical investigation of the root of Angelica dahurica led to the isolation of benzofuran and coumarin derivatives. This is the first report of the isolation and identification of three furanocoumarin sulfates from A. dahurica root. The structures of a total of twelve undescribed compounds were determined by extensive spectroscopic analysis, including 2D NMR data, hydrolysis, and solvolysis, followed by either physicochemical and spectroscopic data or X-ray crystallographic analysis. The isolated compounds were evaluated for their PPAR-γ ligand-binding activity, and six compounds showed significant PPAR-γ ligand-binding activity. In particular, the undescribed benzofuran derivative, 3-[6,7-furano-9-hydroxy-4-(2″,3″-dihydroxy-3″-methylbutyloxy)]-phenyl propionic acid, exhibited the most potent PPAR-γ ligand-binding activity and accumulated intracellular lipid in 3T3-L1 cells.

Preclinical evaluation of Amphihevir, a first-in-class clinical Hepatitis C virus NS4B inhibitor.

Amphihevir, a benzofuran derivative, is the first reported NS4B inhibitor that has advanced to clinical trials (currently in Phase Ib). Here, we report the results of a preclinical study of its potency, toxicity, selectivity, DMPK, and safety profiles. Amphihevir displayed good antiviral activities against genotype 1a (EC50=0.34 nM) and genotype 1b (EC50=1.97 nM) replicons and evident cytotoxicity in twelve strains of cell lines derived from animals and humans. Amphihevir was found to be inactive against other viruses, human kinases, and GPCRs, which implies its good selectivity. A 9-day long-term treatment of genotype 1b replicon with Amphihevir resulted in a 3.8 Log10 decline of the hepatitis C viral RNA at a concentration of 25×EC90 Drug resistance screening showed that mutations occurred at H94, F98, and V105 of NS4B, which mediated the resistance to Amphihevir. This result suggests that NS4B is the main target of Amphihevir. There was no cross-resistances between Amphihevir and NS5A, NS3/4A, and NS5B inhibitors, suggesting that Amphihevir on combination of other anti- hepatitis C virus drugs could treat hepatitis C, as proven by studies of Amphihevir and other hepatitis C virus inhibitors. Pharmacokinetic studies demonstrated that Amphihevir has good oral bioavailability and appropriate T1/2 in rats and dogs, thereby supporting its use once per day. Finally, Amphihevir showed good safety profiles in rats and dogs. The results shed light on the use of Amphihevir as a potential treatment option for chronic hepatitis C patients.

One‐Pot Two‐Step Chemoenzymatic Cascade for the Synthesis of a Bis‐benzofuran Derivative

Chemoenzymatic cascades enable reactions with the high productivity of chemocatalysts and high selectivity of enzymes. Nevertheless, the combination of these different fields of catalysis is prone to mutual deactivation of metal‐ and biocatalysts. In this study, a one‐pot sequential two‐step catalytic cascade reaction was successfully implemented for the synthesis of a methylene‐bridged bis(2‐substituted benzofuran). In the first step, a palladium‐free Sonogashira reaction is used for the synthesis of a benzofuran derivative. In the subsequent step, the formed 2‐substituted benzofuran is hydroxylated by the monooxygenase P450 BM3 variant (A74S‐F87V‐L188Q) and undergoes further elimination reactions. The study proofs that combination of Cu scorpionate catalyzed Sonogashira cross‐coupling and P450 mediated oxidation is possible and results in up to 84 % yield of the final product. The oxidation reaction is boosted by capturing inhibiting reaction components.

Quantum Tunneling Mediated Interfacial Synthesis of a Benzofuran Derivative.

Reaction pathways involving quantum tunneling of protons are fundamental to chemistry and biology. They are responsible for essential aspects of interstellar synthesis, the degradation and isomerization of compounds, enzymatic activity, and protein dynamics. On-surface conditions have been demonstrated to open alternative routes for organic synthesis, often with intricate transformations not accessible in solution. Here, we investigate a hydroalkoxylation reaction of a molecular species adsorbed on a Ag(111) surface by scanning tunneling microscopy complemented by X-ray electron spectroscopy and density functional theory. The closure of the furan ring proceeds at low temperature (down to 150 K) and without detectable side reactions. We unravel a proton-tunneling-mediated pathway theoretically and confirm experimentally its dominant contribution through the kinetic isotope effect with the deuterated derivative.

Quantum Tunneling Mediated Interfacial Synthesis of a Benzofuran Derivative

AbstractReaction pathways involving quantum tunneling of protons are fundamental to chemistry and biology. They are responsible for essential aspects of interstellar synthesis, the degradation and isomerization of compounds, enzymatic activity, and protein dynamics. On‐surface conditions have been demonstrated to open alternative routes for organic synthesis, often with intricate transformations not accessible in solution. Here, we investigate a hydroalkoxylation reaction of a molecular species adsorbed on a Ag(111) surface by scanning tunneling microscopy complemented by X‐ray electron spectroscopy and density functional theory. The closure of the furan ring proceeds at low temperature (down to 150 K) and without detectable side reactions. We unravel a proton‐tunneling‐mediated pathway theoretically and confirm experimentally its dominant contribution through the kinetic isotope effect with the deuterated derivative.

A New Meroterpene, A New Benzofuran Derivative and Other Constituents from Cultures of the Marine Sponge-Associated Fungus Acremonium persicinum KUFA 1007 and Their Anticholinesterase Activities.

Previously unreported meroterpene, acremine S (1), and benzopyran derivative, acremine T (2), were isolated, together with lumichrome (3), ergosterol (4) and ergosterol 5,8-endoperoxide, from cultures of the marine sponge-associated fungus Acremonium persicinum KUF1007. The structure of the previously unreported compounds was established based on an extensive analysis of 1D and 2D NMR spectra as well as HRMS data. The absolute configurations of the stereogenic centers of 1 were established, unambiguously, based on NOESY correlations and comparison of calculated and experimental electronic circular dichroism (ECD) spectra. Compounds 1–3 were tested for their in vitro acetylcholinesterase and butyrylcholinesterase inhibitory activities.

Synthesis, photophysical, DFT and solvent effect studies on biologically active benzofuran derivative: (5-methyl-benzofuran-3-yl)-acetic acid hydrazide

Abstract The synthesis, photophysical, DFT and solvent effect studies on novel benzofuran derivative namely, (5-methyl-benzofuran-3-yl)-acetic acid hydrazide [5MLBH] are reported. The probe is characterized by 1H NMR, 13C NMR, IR and mass spectral methods. Absorption and fluorescence maxima of 5MLBH are determined for different solvents of varying polarity and solvatochromic behavior and dipole moments are investigated. Results indicate that, excited state dipole moment (μe) values are higher than ground state dipole moment (μg) values and suggest that, probe molecule 5MLBH is more polar in excited state than ground state. Energy band gap is determined from HOMO-LUMO and absorption threshold wavelengths. Using HOMO-LUMO energies, chemical hardness of probe molecule is estimated. From DFT molecular electrostatic potential (MESP) plots, electrophilic site and nucleophilic site were identified. Using Catalan parameters, solute-solvent interactions were analyzed. Preliminary investigations suggest, probe 5MLBH may be considered as potential candidate for luminescence materials, fluorescent probes and for designing non-linear optical materials in future.

Antiproliferative effect of a benzofuran derivate based on the structure of amiodarone on Leishmania donovani affecting mitochondria, acidocalcisomes and intracellular Ca2+ homeostasis

Leishmaniasis is a parasitic disease representing an important problem of public health. Visceral leishmaniasis, resulting from infection with Leishmania donovani, causes considerable mortality and morbidity in the poorest region of the word. At present there is no current effective treatment, since the approved, drugs are expensive and are not free of undesirable side effects. Therefore, there is a need for the identification of new drugs. In this context, the parasite Ca2+ regulatory mechanisms in which mitochondria and acidocalcisomes are involved have been postulated as important targets for several trypanocidal drugs. Thus, amiodarone and dronedarone, common human antiarrythmics, exert its known action on these parasites through the disruption of the intracellular Ca2+ homeostasis. AMIODER is a benzofuran derivate based on the structure of amiodarone that recently demonstrates a significant effect on Trypanosoma cruzi. We now report the effect of AMIODER on Leishmania donovani demonstrating that it inhibit the growth of promastigotes and also of amastigotes inside macrophages, the clinically relevant stage of the parasite, obtaining IC50 values significantly lower than those reported for T. cruzi. We also show that this compound disrupted Ca2+ homeostasis in L. donovani, through its action on two organelles involved in the intracellular Ca2+ regulation and on the bioenergetics of the parasite. AMIODER totally collapsed the electrochemical membrane potential of the unique giant mitochondrion and simultaneously induced the alkalinization of acidocalcisomes, driving together to a large increase in the intracellular Ca2+ concentration of the parasite as the main mechanism of action of this benzofurane derivative.