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Benzofuran : SAR And Pharmacological activity scaffold


About Authors:
Ali K. Akhtar, Waquar A. Khan,Lubna azmi
Faculty of Pharmacy,
Integral University Lucknow,
India

Abstact:
The broad and potent activity of benzofuran has established it as one of the biological importent scaffold. This article is covered the methods of synthesis of benzofuran and its derivatives, structural activity relationship and pharmacological activities so it is an effort to highlight the importance of the benzofuran in the present context and promise they hold for the future.

Reference Id: PHARMATUTOR-ART-1185

INTRODUCTION
The Benzofuran containing structures have been found among naturally occurring furocoumarins, such as psoralen and methoxalen isolated from the seed of Ammi majus L. and used for the treatment of psoriasis and other dermal diseases[1, 2] The (Benzofuran-2-yl) carbinols exhibit various biological activities. Such derivatives were investigated as antibacterial3] or antifungal agents[3, 4]. Moreover, optically active 2-(2-tert-butylamino-1-hydroxyethyl)benzofurans were investigated as β-blockers[5] 2-Substituted benzofurans can inhibit the HIV-1 reverse transcriptase[6]or act as antiaging compounds[7].  A previous literature survey described a variety of 2- substituted benzofuran derivatives that received a great deal of attention for their anti-HIV-1[8,9,10,11], anticancer[11,12,13,14,15], and antimicrobial[11,16,17,18], activities.The derivatives of  keto benzofuran are useful as medicines, such as amiodarone and benziodarone, particulary for the treatment of athological syndromes of the cardiovascular system, such as arrhythmia[19]. Several aminobenzofuran derivatives likewise exhibited a marked antiarrhythmic activity[20]. Moreover, benzofuranyl methanols have been reported as hypolipidemic agents[21].  For example, 1-[(benzofuran-2-yl)phenylmethyl]imidazoles  had a potent, reversible, non-selective aromatase-inhibitory effect[15], 2-{4-[(benzofuran-2- yl)carbonyl]piprazin-1-yl}-3-propylpyridine  exhibited good anti-HIV activity[10] and 2-(benzimidazol- 2-yl-carbonyl) benzofuran derivative had a strong inhibitory activity against Candida albicans Nmyristoyl-transferase[18].

CHEMISTRY OF BENZOFURAN:
The benzene ring is fused with five member heterocyclic ring i.e. furan and formed bicyclic ring benzofuran. It also called as Coumarone and obtained from salicylaldehyde by conversion into the aryloxyacetic acid by reaction with sodium chloroacetate in the presence of alkali followed by cyclisation with a mixture of acetic anhydride, acetic acid and sodium acetate. The reactions proceed by an internal Perkin’s reaction followed by decarboxylative dehydration[22].

EXPERIMENTAL PROCEDURE

o-Formylphenoxyacetic acid.A solution of 80.0 g. (2 moles) of sodium hydroxide pellets in 200 ml. of distilled water is added to a mixture of 106 ml. (122 g., 1 mole) of salicylaldehyde (Note 1), 94.5 g. (1 mole) of chloroacetic acid and 800 ml. of water. The mixture is stirred slowly and heated to boiling. The resulting black solution is heated under reflux for 3 hours. The solution is acidified with 190 ml. of concentrated hydrochloric acid (sp. Gr. 1.19) and is steam-distilled to remove unchanged salicylaldehyde (40.0–40.5 g.). The residual acidic mixture is cooled to 20°, and the precipitated product is collected on a Büchner funnel and rinsed with water. The light tan solid when dry weighs 99–100 g. (82–83% based on recovered salicylaldehyde), m.p. 130.5–133.0°C [22-24].

B. Coumarone. A mixture of 90.0 g. (0.5 mole) of crude, dry o-formylphenoxyacetic acid, 180 g. of anhydrous, powdered sodium acetate, 450 ml. of acetic anhydride, and 450 ml. of glacial acetic acid in a 2-l. flask is heated under gentle reflux with stirring for 8 hours. The hot black solution (total volume ca. 1.2 l.) is poured into 2.5 l. of ice water and extracted with one 600- ml. portion of ether. The ether layer is washed with one 600-ml. portion of water and then with several portions of cold dilute 5% sodium hydroxide solution until the aqueous layer is basic. The ether layer is washed successively with water and saturated sodium chloride solution and is partially dried over anhydrous granular sodium sulfate. The ether is removed at water-bath temperature and the product is distilled, b.p. 166.5–168.0° (735 mm.) or 97.5–99.0° (80 mm.). The water-white benzofuran weighs 37.5–40.0 g. (63.5–67.8%, 52–56% overall from salicylaldehyde), n20D 1.5672; λmax 245 (log ε 4.08), 275 (3.45), and 282 mμ (3.48)[22-24].

SYNTHESIS OF BENZOFURAN DERIVATIVES

A.    3-ETHOXYCARBONYL BENZOFURANS

We can use various substituted aromatic aldehyde viz. 5- chlorosalicylaldehyde, 3, 5- Dichloro-salicylaldehyde, 3- methoxysalicylaldehyde, etc.and form mono or di-substituted 3-ethoxy-carbonyl benzofuran derivatives[25].

B.    3- METHYL BENZOFURAN DERIVATIVES

The Methyl benzofuran synthesized by four step reaction from ethyl α-chloroacetoacetate and sodium phenolate  and its yield is 84 – 88 % [26].

C. BENZOFURAN-3 ACETIC ACID DERIVATIVES

The phenol is treated with ethyl 4-chloroacetate in presence of H2SO4 acid and formed 4-chloromethylcoumarin, and which is reflux with NaOH and benzofuran 3-acetic acid[27].

D.    3-METHYL, 5-HYDROXYBENZOFURAN DERIVATIVES

The Benzofuran scaffold was constructed by Michael addition of quinone with activated propanal and then cyclization. It seemed that piperidine is the best amine to the preparation of such compound[28-29].         

E.    3-ETHYLCARBOXYLATE BENZOFURAN DERIVATIVES

The Benzofuran scaffold was constructed by Michael addition of quinone with ethyl acetyl acetate and then cyclization.Such types of derivatives are prepared by the catalysis of anhydrous zinc chloride[29-30].

F.    A STRAIGHTFORWARD SYNTHESIS OF BENZOFURAN DERIVATIVES

The reported synthesis starting from 1-trimethylsilyl-1,3- butadiyne A [31] and protected 2-iodophenol B, we have realized the synthesis of several ortho-substituted aryl diynes C,which produce various benzofuran derivatives.

The reaction of compound C with Cu (OAc)2.H2O and directly obtained the bis-benzofuran derivatives D with the two ring linked to the position 2,2’by two triple bonds[35].The Compound C with a fluoride source, TBAF[32-33] in at 55 ?C, led to the heterocyclic product, 2-ethynyl-benzofuran E[34-35].

G.
1.SYNTHESIS OF 2-(4-METHOXYPHENYL)-5-METHYLBENZOFURAN

To a  solution of 2-((4-methoxyphenyl)ethynyl)-4-methylphenyl acetate in methanol was added potassium carbonate . The reaction mixture was heated to 60 _C overnight, then being left to cool. The reactionwas poured onto EtOAc,washed with brine, and dried over anhydrous sodium sulfate. Purification was performed by flash chromatography, and an amorphous solid was obtained. Yield 90%;

2.GENERAL PROCEDURE FOR (3,5-DIMETHOXYPHENYL)(2-(4-METHOXYPHENYL)-

5-methylbenzofuran-3-yl)methanone

SnCl4 (1.2 eq.) was added dropwise to a mixture of 5 (50 mg,0.21 mmol) and the 3,5-dimethoxybenzoyl chloride (1.2 eq.) in drydichloromethane and the resulting solution was stirred at roomtemperature overnight. The reaction was quenched with ice andstirred for 1 h. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate. Purificationwas performed by flash chromatography, and the yellowoil was obtained[67]

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