Benzofuran Derivative Research Articles

Crystalline Calcium Oxalate in Pandanus Odoratissimus

Pandanus odoratissimus (P. odoratissimus) belongs to the Pandanus genus from Pandanaceae. The research involving this coastal species was reviewed and compiled. From the literature, the pharmacognostical and phytochemical investigations including chromatographic analysis were carried out on the leaves extract. Two phenolic compounds, four lignan type compounds plus a benzofuran derivative were published as the constituents of this plant. In addition, the biological work was also conducted. This included the investigation of antioxidative, antimicrobial, anti-inflammatory and free radical scavenging activities of the fractions. In this paper, the microscopical study utilising Confocal Laser Scanning Microscopy (CLSM) and Scanning Electron Microscopy (SEM) is presented. From the photomicrographs, both fruits and leaves of P. odoratissimus contained singly scattered and bundles of calcium oxalate raphides, observed as acicular crystals, having the shape of narrow, long and pointed needles. In addition, another morphological type of calcium oxalate was also observed. The styloids were detected as rectangular crystals having extensions around their four edges. Previously, the styloids were found in a different Pandanus species, P. gasicus and Freycinetia, another genus of Pandanaceae. In summary, this is the second report of the simultaneous occurrences of two crystalline shapes from a Pandanus.

Ultrastructural Changes in Rat’s Atrial Cardiomyocytes After Short Term Administration of Amiodarone and Possible Protective Role of Vitamin E

BackgroundAmiodarone chlorhydrate is a diiodated benzofuran derivative used to treat a variety of cardiac rhythm abnormalities. The use of amiodarone is associated with ultrastructural changes affecting body tissues, but its effect on the ultrastructure of the heart has not yet been fully elucidated.MethodsThe aim of this study is to test the adverse effects of amiodarone administration on cardiomyocytes and to study the possible protective role of vitamin E co-administration. A total of 18 adult male albino rats were used in this study. The rats were divided randomly into three groups of 6 rats each as follows: group I was considered the control group and was given vegetable oil; group II received 54 mg/kg of oral amiodarone; and group III received a single dose of combined vitamin E (50 mg/kg) and amiodarone (54 mg/kg). After 2 weeks, the rats were sacrificed, and the atrial tissues were harvested and processed for electron microscopic study.ResultsAdministration of amiodarone alone modified the atrial architecture, which was demonstrated by the following: mitochondrial enlargement and cristae lysis; marked heterogeneity of myofibril patterns with partial necrosis and disintegration of myofilaments; and irregularities of the sarcomere and less concentration of atrionatriuretic factor (ANF) granules, which localised in closed proximity to the nucleus with disrupted chromatin contents. Concomitant administration of vitamin E with amiodarone showed a considerable preservation of the atrial architecture.ConclusionsOral administration of amiodarone in rats resulted in ultrastructural changes in atria, which can be attenuated by vitamin E co-administration.

Acute hepatitis secondary to parenteral amiodarone does not preclude subsequent oral therapy

Amiodarone chlorhydrate is a diiodated benzofuran derivative used to treat cardiac rhythm abnormalities. Hepatotoxicity is a relatively uncommon side effect of amiodarone and symptomatic hepatic dysfunction occurs in less than 1% to 3% of patients taking amiodarone. We report here on an unusual case of amiodarone-induced hepatotoxicity. A 29 year old woman with normal liver function was given amiodarone intravenously to treat her atrial fibrillation. She developed acute toxic hepatitis after 24 h. The intravenous form of amiodarone was immediately avoided and replaced by the oral form, using conventional loading doses as soon as the deranged liver function tests had normalized, without recurrence of the hepatitis. These observations show that the occurrence of acute hepatic impairment with intravenous amiodarone does not necessarily preclude the use of this drug by mouth and the necessity of monitoring the hepatic function of patients treated with amiodarone.

AlCl3 induced C-arylation/cyclization in a single pot: a new route to benzofuran fused N-heterocycles of pharmacological interest

A new and one-pot synthesis of benzofuran fused N-heterocycles has been accomplished via AlCl3-mediated C–C followed by C–O bond formation between 2,3-dichloropyrazine or its derivatives and phenols. The methodology provided novel compounds as potential inhibitors of PDE4B. The single crystal X-ray data of a synthesized benzofuran derivative are presented. Scope of the methodology, in vitro pharmacological data of some of the synthesized compounds, along with docking study of an active compound are described.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

ChemInform Abstract: Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)

AbstractReview: 140 refs.

Translational Research From the Tropical Forest: Silvestrol, a Natural Product From the Plant Aglaia Foveolata inhibits the Expression of Tyrosine Kinases and Shows a Significant In Vivo Activity in Acute Myeloid Leukemia (AML)

Abstract 2616Despite the progress made in the diagnosis, classification, prognostication and treatment of AML, the majority of patients still fail to achieve long-term survival and die of their disease. Several cytogenetic and molecular markers including gene mutations and aberrant expression have been shown to impact the outcome of AML patients and some of these are also potential therapeutic targets. Receptor tyrosine kinases (RTKs) regulate cell survival, proliferation and differentiation in normal hematopoiesis. Gain-of-function mutations of genes encoding RTKs, such as internal tandem duplication of FLT3 (FLT3-ITD) and mutations of KIT, result in constitutive tyrosine kinase activity and have been associated with poor outcome in distinct cytogenetic (i.e., normal karyotype and core binding factor, respectively) subsets of AML. In addition, overexpression of FLT3 and wild type (wt) KIT was also found to negatively impact outcome. Tyrosine kinase (TK) inhibitors (Is) (e.g., imatinib, dasatinib or PKC412) have been shown to suppress the aberrant activity of these mutants, but their activities as single agents have been limited by their relatively elevated IC50 values for myeloid blasts and early onset of resistance. Indeed, even in combination with chemotherapy, TKIs have not yet been shown to impact favorably on AML patient outcome. This supports the need for development of novel strategies that effectively interfere with aberrant TK activity in leukemia blasts. Silvestrol, a cyclopenta[b]benzofuran derivative isolated from Aglaia foveolata, a plant that grows in the tropical rain forests of Southeast Asia, has been shown to exhibit potent inhibitory activity against a panel of human cancer cell lines and shows in vitro and in vivo efficacy in B-cell malignancies. The mechanism of action has been thought to involve inhibition of translation initiation, which in turn results in selective depletion of actively translated, short half-lives proteins. We hypothesized that silvestrol-mediated inhibition of the translation of mutated and/or overexpressed RTKs results in a significant antileukemic activity in AML cells that rely on the aberrant TK activity of these proteins. Silvestrol showed antiproliferative and proapoptotic activities in representative AML cell lines harboring activated TK proteins: FLT3-ITD-positive MV4-11, FLT3-overexpressing THP-1 KIT-mutated Kasumi-1 and also BCR-ABL-positive K562, an erythroblastic cell line notoriously resistant to chemotherapy. Importantly, silvestrol treatment reduced the expression levels of FLT3 in MV4-11 (92 %) and THP-1 (84 %), KIT in Kasumi-1 (46 %), and BCR-ABL in K562 (64 %), compared to the respective vehicle-treated controls. The silvestrol IC50 at 48 hr was less than 10nM for all cell lines (MTS assay). Silvestrol also showed antiproliferative activity in FLT3-ITD-positive AML patient blasts (IC50 24 nM at 48 hr). To evaluate in vivo activity, NOD-SCID Gamma (NSG) mice were engrafted with FLT3-ITD-positive MV4-11 cells. Twenty-one days post-engraftment, mice were treated intraperitoneally with vehicle or silvestrol (1.5 mg/kg every 48 hr for 3 weeks). After 3 doses (day 6 of treatment), spleens were obtained from three mice from each group. Spleens from silvestrol treated mice were 60% decreased in size (P=0.016) and showed 80% FLT3 protein downregulation (P=0.002) compared to vehicle-treated controls. Silvestrol treated leukemic mice (n=10) survived significantly longer than vehicle treated control (n=6) (median survival: 55.5 days vs. 29 days from engraftment day respectively; P<0.0001). All vehicle-treated mice died by day 31 from engraftment (day 11 from treatment start), while 50% of silvestrol-treated mice are still alive on day 60 from engraftment (day 40 from treatment start; updated survival curves will be provided). We conclude that silvestrol has a potent in vitro and in vivo antileukemic activity in AML through downregulation of the expression and activity of FLT3 and other TKs driving leukemia. Given the excellent antileukemic activity of silvestrol via a novel mechanism of TK inhibition that is potentially complementary to that of TKIs (i.e., silvestrol-induced suppression of TK protein expression vs. TKI-induced protein enzymatic inhibition), a rapid translation of this natural product to the clinic as a single agent or in combination with other TKIs ± chemotherapy seems warranted. Disclosures:No relevant conflicts of interest to declare.

DNA binding, antiviral activities and cytotoxicity of new furochromone and benzofuran derivatives

Bromination of visnagin (1) afforded 9-bromovisnagin (2) which on its alkaline hydrolysis afforded the 3-acetyl benzofuran derivative (3). The condensation of (3) with hydrazine hydrate, phenylhydrazine and/or hydroxylamine hydrochloride afforded the corresponding pyrazole derivatives (4a, b) and isoxazole derivative (4c). On the other hand, when compound 3 was condensed with some aromatic aldehydes, this yielded corresponding α, β-unsaturated keto derivatives (5a-e). Furthermore, when 1 was subjected to chlorosulfonation, the visnaginsulfonylchloride derivative 6 was afforded, which on amidation using morpholine, a sulonamido derivative (7) was obtained. Alkaline hydrolysis of the latter compound yielded 7-N-morpholinosulsamidobenzofuran (8) which was condensed with some aromatic aldehydes to yield the corresponding chalcone compounds (9a-e). Demethylation of visnagin afforded norvisnagin (10). The reaction of 10 with ethylbromoacetate in dry acetone yielded the ester benzopyran derivative (11) which reacted with hydrazine hydrate to afford the corresponding hydrazide derivative (12) and this was condensed with 3,4,5-trimethoxybenzaldehyde to give the corresponding hydrazone (13). A thaizolidinone derivative (14) was obtained by condensation of (13) with thioglycolic acid. Chloromethylation of norvisnagin afforded a 4-chloromethyl derivative (15) which reacted with different primary and secondary amines to yield the corresponding ethylamino derivative (16a, b). Moreover, mannich bases (16a, b) and (17a-c) were obtained by reacting norvisnagin with different primary and secondary amines in the presence of formalin but benzoylation of (16a, b) and (17a-c) afforded 4-oxybenzoyl derivative (18a-e). The prepared compounds were tested for their interaction with DNA; bromovisnagin 2 showed the highest affinity and compounds 6, 15, 8a, > 14, > 16b, 17a, and 16a showed moderate activity in decreasing potency. Moreover, compound 2 also was the most active as antiviral agent toward HS-I virus and compounds 6, 7, 15, 14, 16a, and 18a were found to be moderately active. CD(50) of the active compounds were also measured.

Thyroxine monotherapy without amiodarone enhances atrial fibrillation recurrences in amiodarone-induced hypothyroidism

Atrial fibrillation (AF) is the most sustained cardiac arrhythmia requiring medical care. Amiodarone is a di-iodinated benzofuran derivative widely used for preventing the recurrences of AF [1]. Although amiodarone is the most effective agent in rhythm control of AF [2], the adverse effects of amiodarone frequently result in treatment discontinuations. Hypothyroidism caused by the iodine in amiodarone is one of the most frequent and important adverse effects. The incidence of amiodarone-induced hypothyroidism varies from 1 to 32% [3–7].

Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

Thrombin is a key enzyme targeted by the majority of current anticoagulants that are direct inhibitors. Allosteric inhibition of thrombin may offer a major advantage of finely tuned regulation. We present here sulfated benzofurans as the first examples of potent, small allosteric inhibitors of thrombin. A sulfated benzofuran library of 15 sulfated monomers and 13 sulfated dimers with different charged, polar, and hydrophobic substituents was studied in this work. Synthesis of the sulfated benzofurans was achieved through a multiple step, highly branched strategy, which culminated with microwave-assisted chemical sulfation. Of the 28 potential inhibitors, 11 exhibited reasonable inhibition of human α-thrombin at pH 7.4. Structure-activity relationship analysis indicated that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. A tert-butyl 5-sulfated benzofuran derivative was found to be the most potent thrombin inhibitor with an IC(50) of 7.3 μM under physiologically relevant conditions. Michaelis-Menten studies showed an allosteric inhibition phenomenon. Plasma clotting assays indicate that the sulfated benzofurans prolong both the activated partial thromboplastin time and prothrombin time. Overall, this work puts forward sulfated benzofurans as the first small, synthetic molecules as powerful lead compounds for the design of a new class of allosteric inhibitors of thrombin.

Dronedarone for atrial fibrillation therapy

Dronedarone is a new benzofuran derivative that has been developed as an antiarrhythmic agent on the basis of the amiodarone molecular structure with the intent of maintaining the same pharmacological effects while reducing thyroid and pulmonary toxicity. The drug is a multichannel blocker with antiadrenergic properties: it reduces heart rate and prolongs the action potential duration. Dronedarone is primarily metabolized by cytochrome P450; its half-life is much shorter than that of amiodarone because of a lower lipophilicity. As a consequence, only 7 days are needed to reach steady-state plasma levels. It has been tested in clinical trials both for rate and rhythm control and, even if its antiarrhythmic efficacy seems to be somehow lower than that of amiodarone, dronedarone is less often discontinued due to adverse reactions or organic toxicity. For these reasons, dronedarone can be very useful in long-term treatment of atrial fibrillation, by reducing hospitalizations and mortality.

A new bioactive compound from the roots of Petasites hybridus

A new benzofuran derivative ( 1) was isolated from the roots of Petasites hybridus and its structure was determined as 1-(6-hydroxy-2-isopropenyl-1-benzofuran-5-yl)-1-ethanone by spectroscopic data and X-ray crystallographic analysis. The compound 1 showed moderate inhibitory activity on human breast cancer MCF-7 cells proliferation in vitro with an IC50 value of 48 μmol/L. The interaction of bovine serum albumin (BSA) and DNA with compound 1 were studied in an aqueous solution under physiological conditions by UV–vis spectroscopy.

Progress in the total synthesis of rocaglamide.

The first cyclopenta[b]benzofuran derivative, rocaglamide, from Aglaia elliptifolia, was found to exhibit considerable insecticidal activities and excellent potential as a therapeutic agent candidate in cancer chemotherapy; the genus Aglaia has been subjected to further investigation. Both the structural complexity of rocaglamide and its significant activity make it an attractive synthetic target. Stereoselective synthesis of the dense substitution pattern of these targets is a formidable synthetic challenge: the molecules bear five contiguous stereocenters and cis aryl groups on adjacent carbons. In past years of effort, only a handful of completed total syntheses have been reported, evidence of the difficulties associated with the synthesis of rocaglate natural products. The advance on total synthesis of rocaglamide was mainly reviewed from intramolecular cyclization and biomimetic cycloaddition approach.

Dronedarone for the management of atrial fibrillation

Atrial fibrillation is a common arrhythmia associated with increased cardiovascular mortality and morbidity including stroke, heart failure and hospitalisations. Major studies on atrial fibrillation have shown no significant difference between rhythm and rate control in terms of mortality. However, rate control treatment may be insufficient to prevent morbidity in a number of patients. Amiodarone is generally considered the agent with the best efficacy for maintaining normal sinus rhythm. Despite amiodarone's efficacy, its use is often limited by its side effect profile and it is not currently recommended as the first choice antiarrhythmic agent, except in patients with heart failure or congenital heart disease. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been recently approved by Swissmedic for management of patients with atrial fibrillation or atrial flutter. Structural modification of dronedarone was introduced to decrease lipophilicity, shorten the half-life and minimise non-cardiovascular toxicity as compared to amiodarone. This article reviews the pharmacology, adverse effects and clinical evidence available to date on the use of dronedarone in the management of atrial fibrillation.

Phytotoxic activities of (2R)-6-hydroxytremetone.

Benzofurans are bioactive compounds isolated from the Asteraceae family. Benzofuran derivatives have been extensively studied because of their toxic effects on humans and animals. The phytotoxic activity of the benzofuran derivative (2R)-6-hydroxytremetone was studied on germination, seedling development, and cytotoxic and genotoxic effects on monocotyledoneous (onion and wheat) and dicotyledoneous (lettuce and tomato) species. Results of these assays demonstrated that (2R)-6-hydroxytremetone is a potent germination inhibitor of onion, lettuce, and tomato seeds. Germination reductions of approximately 80% were measured when seeds were exposed to 100 mg l(-1) of the compound, and showed considerably effects on the posterior development of the sprouts, including rootlets and hypocotyl elongations. Moreover, this benzofuran derivative also significantly reduced the root length and mitotic division of Allium cepa bulbs, although DNA damages were not observed. Our findings suggest that a mechanism of mitosis inhibition may play a role in the phytotoxic effects of plants producing these compounds.

ChemInform Abstract: A Novel 18F‐Labeled Pyridyl Benzofuran Derivative for Imaging of β‐Amyloid Plaques in Alzheimer′s Brains.

AbstractThe novel pyridyl benzofuran derivative (I) and the corresponding 18F‐labeled compound are prepared and used for imaging of β‐amyloid plaques in Alzheimer′s disease brains.

Chemistry and biology of rocaglamides (= flavaglines) and related derivatives from aglaia species (meliaceae).

Rocaglamide (1) is the parent cyclopenta[b]benzofuran derivative which was first identified as an antileukemic agent from the dried roots and stems of Aglaia elliptifolia Merr. (family Meliaceae) in 1982. Based on these findings, phytochemical interest in this genus increased sharply and up to date, more than 100 rocaglamide-type (= flavagline) compounds and structurally related derivatives have been identified from over 30 Aglaia species. Rocaglamide-type compounds show pronounced pharmacological activities including primarily (but not exclusively) antiproliferative and anti-inflammatory activity. The molecular mechanisms underlying these activities have been elucidated in recent years and established rocaglamide and several of its derivatives as interesting candidates for drug development especially in the field of anti-cancer research. Due to their unique structural features and promising pharmacological activities, several strategies leading to total synthesis of enantiomeric rocaglamide derivatives were developed and optimized. This chapter reviews the chemistry and biology of the rocaglamide-type derivatives and related compounds, with emphasis on their structural diversity, biosynthesis, pharmacological significance and total synthesis.

Sinus Rhythm Restoration and Treatment Success: Insight From Recent Clinical Trials

Atrial fibrillation (AF) is a common supraventricular tachyarrhythmia with substantial morbidity and mortality. This review briefly describes the mechanisms of AF development and progression, including electrical, structural, and contractile remodeling. In addition, the potential benefits of achieving and maintaining sinus rhythm are discussed. For example, rhythm control has been associated with improvements in left ventricular function, AF symptoms, exercise tolerance, the ability to perform activities of daily living, and quality of life. More recently, dronedarone, a noniodinated benzofuran derivative approved for use in the treatment of AF, was shown to significantly improve clinical outcomes including cardiovascular hospitalizations and death from any cause in A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA). The review concludes with an examination of AF treatment options and expectations. Evidence suggests that the complete absence of AF recurrence is not always achievable; however, complete restoration of sinus rhythm may not be necessary for patients to achieve clinically meaningful benefits. Copyright © 2011 Wiley Periodicals, Inc. The editorial assistance provided for this manuscript was funded by Sanofi-Aventis. The authors were fully responsible for all content and editorial decision, and received no financial support or other form of compensation related to the development of the paper. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Monitoring Amiodarone Therapy In Cardiac Arrthythmias In The Intensive Care Unit Of A Teaching Hospital In Ghana

Amiodarone hydrochloride, an iodinated benzofuran derivative, is recognized for its antiarrhythmic properties in treating both ventricular and supraventricular arrhythmias, and for converting atrial fibrillation to sinus rhythm and maintaining sinus rhythm. Amiodarone has unusual and complicated pharmacokinetics: it is incompletely absorbed from the gastrointestinal tract and bioavailability is very variable, around 20-80%. Its major metabolite is desethylamiodarone which is pharmacologically active. Amiodarone is one of the most widely used antiarrhymic medications but in spite of its usefulness amiodarone may have numerous and sometimes lethal side effects and the patient should be counseled on both the minor and serious adverse effects that are possible when taking this antiarrhythmic drug. The properties of amiodarone differ in a significant manner electrophysiological, pharmacokinetically and structurally from those of conventional as well as other investigational antiarrthytmic agents. The unique mechanism of action and the pharmacokinetics of amiodarone and how these factors impact adverse reactions and adhering to the recommended monitoring procedures and thereby providing effective patients counseling form the objectives of this article.

Effects of neferine on the pharmacokinetics of amiodarone in rats

Amiodarone, an iodinated benzofuran derivative with predominantly class III anti-arrhythmic effects, is used to treat supraventricular and ventricular arrhythmias. The purpose of this study was to assess the potential of neferine, an effective anti-pulmonary fibrosis drug isolated from the embryo of Nelumbo nucifera Gaertner's seeds, to alter the pharmacokinetic profile of amiodarone. Experimental Sprague-Dawley rats were randomly divided into two groups. In groups 1 and 2, amiodarone was given to rats by intragastric and intravenous administration, respectively, while neferine was co-administratered by intragastric administration. Blood samples were collected from the orbital venous plexus at indicated time points and were analyzed for amiodarone concentration using RP-HPLC. The geometric mean ratio for C(max) and AUC(0-96) was calculated. There were no significant differences between the pharmacokinetics parameters of amiodarone administered intravenously or intragastrically and the control (without neferine) group (with ratios of 0.7-1.4 in all experimental groups), suggesting that neferine had no effect on amiodarone plasma pharmacokinetics. The dosage regimen of amiodarone does not need to be taken into consideration when combined with neferine.