World Journal of Pharmaceutical Research Ajit Et Al

World Journal of Pharmaceutical Research Ajit et al. World Journal of Pharmaceutical SJIF ImpactResearch Factor 5.990

Volume 4, Issue 7, 1734-1746. Review Article ISSN 2277– 7105

APPLICATION OF THE BENZOFURAN RING SYSTEM IN CHEMICAL STRUCTURE OF DIFFERENT PHARMACEUTICALS DRUG

Ajit.K.Nangare1* and Amit.N.Chavan2

1*Asst Prof Department of Pharmaceutical Chemistry, Padmashri Dr.Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111. 2 Padmashri Dr.Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111

Article Received on ABSTRACT 05 May 2015, Benzofuran being an hetrocylic compound find its use in research as

Revised on 30 May 2015, starting material for synthesis of larger usually bioactive structure. Accepted on 24 June 2015 Literature indicates that compounds having Benzofuran nucleus have

wide range of therapeutic uses that include antibacterial, antifungal, *Correspondence for

Author anti-inflammatory, analgesic, antidepressant, anticonvulsant, Ajit.K.Nangare antitumor, imaging, Anti-HIV, antidiabetic, antitubercular, antioxidant Asst Prof Department of and miscellaneous activity. The purpose of this review is to provide an Pharmaceutical overview of different property of Benzofuran and some of its Chemistry, Padmashri application in synthesis of pharmacologically active drug. Dr.Vithalrao Vikhe Patil Foundation’s College of KEYWORDS: Benzofuran, antifungal, anticancer, antimicrobial, Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, Anticonvulsant, Antagonistic and Inhibitory Activity. 414111. INTRODUCTION Benzofuran is a hetrocylic compound consisting of fused benzene and a furan ring. This

colourless solid is component of coal tar. Benzofuran is “parent”of many related compound with more complex structures. For example Psoralen is a benzofuran derivative that occur in sevral plants and use in treatment of psoriasis and other dermal diseases. The (Benzofuran-2- yl) carbinols exhibit various biological activities. Such derivatives were investigated as antibacterial or antifungal agents. Moreover, optically active 2-(2-tert-butylamino-1- hydroxyethyl)benzofurans were investigated as β-blockers. 2-Substituted benzofurans can

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inhibit the HIV-1 reverse transcriptase or act as antiaging compounds. A previous literature survey described a variety of 2- substituted benzofuran derivatives that received a great deal of attention for their anti-HIV-1, anticancer and antimicrobial 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. Several aminobenzofuran derivatives likewise exhibited a marked antiarrhythmic activity. Moreover, benzofuranyl methanols have been reported as hypolipidemic agents.

Genral physical and chemical properties of Benzofuran The aromaticity of benzofuran is weaker than in indole and this ring is easily cleaved by reduction and oxidation. Electrophilic reagents tends to react with benzofuran at C-2 position in preference to C-3 , reflecting the reduced ability of hetro atom to stablise the intermediate for 3-substitution. Attack in hetrocycle is often accompanied by substitution in benzoid ring. Nitration with nitric acid in acetic acid gives mainly 2-nitrobenzofuran., plus the 4-,6-,7- isomers . when the reagent is N2O4 in benzene maintained at 10°C , both 3- and 2- nitrofurans are formed in the ratio of 4:1 . under vilsmeier reaction condition , benzofuran gives 2- formylbenzofuran in 40% yield . Chlorine or Bromine add across the C=C bond of the furan ring giving 2-,3-dihydrobenzo furans. Base promoted ehydrohalogenation of the dihalides offord mixture of the corresponding 2- and 3- halobenzofuran.

Reactions Of Benzofurans Synthesis of Benzofuran www.wjpr.net Vol 4, Issue 07, 2015. 1735

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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.

LABORATORY SYNTHESIS OF BENZOFURAN Step1: Synthesis of o-formylphenoxyacetic acid A solution of 80.0g of sodium hydroxide pellets in 200 ml of distilled water is added to a mixture of 106 ml (122 g) of salicylaldehyde , 94.5g 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 and is steam-distilled to remove unchanged salicylaldehyde. The residual acidic mixture is cooled to 20°, and the precipitated product is collected on a Buchner funnel and rinsed with water. The light tan solid when dry weighs 99–100 g. (82–83% based on recovered salicylaldehyde), MP- 130.5–133.0°C .

Step2: Synthesis of Benzofuran A mixture of 90.0 g. 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 flask is heated under gentle reflux with stirring for 8 hours. Then the hot black solution is poured into 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 www.wjpr.net Vol 4, Issue 07, 2015. 1736

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anhydrous granular sodium sulfate. The ether is removed at water-bath temperature and the product is distilled, b.p. 166.5–168.0°. The water-white benzofuran weighs 37.5–40.0 g. (63.5–67.8%, 52–56% overall from salicylaldehyde) λmax 245 nm.

Application of the Benzofuran ring system in Drug synthesis Antimicrobial Activity Swarup jyoti Chattarjee and Co-workers,[1] synthesized series of Thiazolidine-4-one substituted 1, 2, 4- triazole and incorporating 3-methoxy benzofuran moiety derivatives and then check the antibacterial activity against Gram positive and negative microorganism. From the 11 derivatives the 2 have the broad- spectrum activity then other. Other derivatives show the moderate activities. Compounds VIIIe and VIIIf compounds showed significant inhibition against all the strains tested when compared to reference drug .

OMe

N N

O SH N

N S O HO CompoundVIIIe

OMe

N N O N

N S O OMe CompoundVIIIf

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Vidyashri S. Kamble and Co-workers,[2] synthesized the two series of 4-(1- BENZOFURAN-2-YL)-1,3-OXAZOLE-2-AMINE derivatives and to then check the antibacterial activity against Escherichia coli and Staphylococcus aureus. Both the derivatives (a) and (b) showed significant inhibition against all the strains tested, when compared to reference drug s. Amoxicillin was used as reference drugs. Both the compound show the good activity against the Escherichia coli then the Staphylococcus aureus.

O N N

Compound IIIa

O N N

+ O N - O Compound IIIb

Riddhi Madhu and Co-workers,[3] Synthesized the series of 5CHLORO BENZOFURAN compound derivatives and to check the Anti‐bacterial activity against using specific type of gram positive and gram negative bacteria like Escherichia coli and Staphylococcus aureus. The screening showed that derivatives 5Chloro Benzofuran VI (a‐d) had significant activity comparable to that of standard. The ciprofloxacin and ampicillin used as a reference drug.

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Compound no. R R1 via Cl 2‐hydroxy1‐naphthaldehyde vib Cl 3,4,5 trimethoxy benzaldehyde vic Cl 2‐methoxy benzaldehyde vid Cl 4‐hydroxy3‐ethoxybenzaldehyde vie Cl pyridine1‐carboxyaldehyde

V. B. Panchabhai and Co-workers,[4] synthesized the series of 5-Nitrobenzofuran-2- carboxyhydrazide derivatives and check the Antimicrobial Activity and Anti-inflammatory Activity. All the derivatives were tested in-vitro test for their antimicrobial activity Against type of gram positive and gram negative bacteria. The two type of microorganisms Escherichia coli and Staphylococcus aureus has been use. The only 5-a and 5-b derivative showed significant zone of inhibition against gram positive bacteria only as compared to that of reference drug , with respect to other synthesized compounds and reference drug Ampicillin. The derivatives 5-a and 5-b showed significant the anti-inflammatory activity when they possess P value <0.01, when compared with control group.

Alejandro Urzúa and Co-workers,[5] they synthesized the series of 3 H-Spiro [1- benzofuran-2,1’-cyclohexane derivatives and check the antimicrobial activity. The derivatives Compounds 1-5 were evaluated for the antimicrobial activity against Gram positive and Gram negative bacteria. They where activity against Gram positive microorganisms and inactivity against Gram negative bacteria, The reference drug chloramphenicol, ampicillin or tetracycline was use. The compound 2 was inactivity in the test against all the bacteria but other derivatives where activity in increases order 1<3<4< 5.

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Compound 1-5 Madappa B. HALLI and Co-workers.[8] they synthesized the series of (E)-N_ - ((thiophen- 2-yl)methylene)benzofuran-2-carbohydrazide and its metal(II) complexes and check the antimicrobial activity. The synthesized and characterize Co(II), Ni(II), Cu(II), Zn(II), Cd(II), and Hg(II) metal complexes with newly synthesized Schiff base derived from benzofuran-2- carbohydrazide and thiophene-2-aldehyde. the antimicrobial activity against a bacteria like, Escherichia coli, Staphylococcus aureus, and Salmonella typhi bacteria and Aspergillus niger, Aspergillus flavus, and Cladosporium spp. The metal complexes exhibited higher antimicrobial activity than the free ligand. The Fluconazole was use as reference drug.

H H N O N S O

M. B. HALLI and Co-workers.[9] they synthesized the (E)- N'(1phenylethylidene)benzofuran-2- carbohydrazide (BCACP) and its metal(II) complexes and check the antimicrobial activity. Antibacterial activity was screening against one Gram positive and one Gram negative bacteria like, Staphylococcus aureus and Escherichia coli using Gentamycine as reference drug . Antifungal activity was screened against two fungal strain, Candida albicans and Aspergilus fumigatus using Amphotericin as reference drug . The metal complexs Cu(II), Co(II) and Zn(II) show moderate activity against bacteria Escherichia coli but Hg(II) complex show high activity against it. The Ni(II), Co(II) and Zn(II)complexes show moderate activity but only two show Hg(II) and Cu(II) complexes show high activity against bacteria S. aureus. In the case of fungicidal activity most of

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complexes and igand show in activity against fungi A. niger and C. albicans, but in the case of Hg(II) and Cu(II) complexes show high activity against fungi C. albicans and A. niger.

H CH3 N O N O Asrondkar AL and Co-workers.[10] Synthesized the series of Pyrazolene-Benzofuran derivatives and Antimicrobial Activity of it. Antimicrobial activity was screening against one Gram positive and one Gram negative bacteria like, Staphylococcus aureus and Salmonella typhi using the Ampicillin reference drug drug against gram positive Staphylococcus aureus and Trimethoprim reference drug drug against gram negative Salmonella typhi. All the synthesized derivatives showed moderate activity, from which 4-Hydroxy and 2, 4- dimethoxy (Sr.No 4 & 5)against Staphylococcus aureus and 4-fluoro derivative (Sr. No 3) exhibited activity ,The other remaining compounds exhibited activity against Salmonella typhi.

Sr.No Substituent’s R R’ 1 3-Chloro 4-Chloro 2 4-Chloro 4-Chloro 3 4-Chloro 3-Fluoro 4 4-Chloro 4-Hydroxy 5 4-Chloro 2,4-Dimethoxy

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Fatma M. Edressand Co-workers.[12] synthesis series of 5-Benzimidazolylbenzofuran derivatives and check the antimicrobial activity of the derivative. Antimicrobial activity was Gram negative bacteria Escherichia coli. The derivative 3b shows Active growth and the derivative 3a and 4b shows 66 % Percentage of death microbs and derivative 3f shows 33%.percentage of death of microbs.

H3CO N O

N HO R

RNH

Anti-tumor / Anti-cancer Activity MAGDY I. EL-ZAHAR and Co-workers.[7] Synthesized and evaluated antitumor activity of Novel benzofuran-2-yl pyrazole pyrimidine derivatives. The five of the derivatives where selected for the test (9, 14, 18, 21, 25b). The taken Benzofuran pyrazole moiety was attached to the 2-hydrazinyloxopyrimidine, triazolopyrimidine and thiosemicarbazide pyrimidine moieties.

The antitumor activity that was seen by the newly synthesized moieties attached to Benzofuran pyrazolo pyrimidine moiety are more affective and especially thiazolidinone ring of compound 9.

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Antagonistic Activity Sanmati K. Jain and Co-workers,[6] The aryl Benzofuran derivatives (29 molecules) has been use to check the human H3- receptor antagonists activity. Some of the 29 derivative show the significant antagonists activity. The 9 compound where use for the testing (Compounds no.1,4,11,16,18,22,24,26,27). The attributes T_3_N_5 (compound 12,13,15,16) ,T_C_C_7 (compound 9,17,18) and T_2_3_5 contributing 33%, 27% and 15 % respectively were they are the important determinants for H3-receptor antagonistic activity. Descriptors T_C_N_1 and SsBrE-index are contributing 11% and 13% in biological activity

Sr. Ar substituent Sr. Ar substituent Sr. Ar substituent no No no 1 2-nitrophenyl 4 3-cyanophenyl 9 Pyrimidin-5-yl 11 Pyrimidin-2-yl 12 5-nitrothiazol-2-yl 13 3-nitropyridin-2-yl 15 2,6-dicyanopyridin-4- 16 3-cyanopyridin-2-yl 17 5-cyanopyridin-2-yl yl 18 5-nitropyridin-2-yl 22 5-ethyl-pyrimidin-2- 24 Pyrimidin-5-yl yl 26 5-nitropyridin-2-yl 27 3-nitropyridin-2-yl 29 5-trifluoromethyl- pyridin-2-yl

Anticonvulsant Activity Mehnaz Kamal and Co-workers,[11] Synthesized a series of N-(2-benzoylbenzofuran-3-yl)- 4-(substituted)butanamides (IIIa-f) and evaluated for anticonvulsant activity . The compound (IIIb) N-(2-benzoylbenzofuran-3-yl)-4-(4-pyridin-2-yl)piperazin-1-yl)butanamide, (IIIc) N(2 benzoyl benzofuran-3-yl )-4-(dipropylamino)butanamide,(IIId) N-(2-benzoylbenzofuran-3- yl)-4 (cyclohexyl (methyl)amino)butanamide,(IIIf) N-(2-benzoylbenzofuran-3-yl)-4- (dicyclohexylamino) butanamide showed the activity in MES test and where other drug show the less activity in the test. www.wjpr.net Vol 4, Issue 07, 2015. 1743

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NH O

Inhibitory Activity Ling-Yi Kong and Co-workers,[13] They Synthesis series of Benzofuran Derivatives via Rearrangement and check the Inhibitory Activity on Acetylcholinesterase (anti-AChE).The Benzofuran derivatives A1-A5 Equally inhibition activities toward the cholinesterase. Among all the derivatives ,The compound no. A4 (4-(p-tolylpiperazin-1-yl)(5-methyl-3 morpholino benzo furan-2-yl) methanone showed the very good AChE inhibitory activity with the IC50 value of 11 μmol/L.

H3C O

O N

Compounds R

A1 H A2 o-CH3 A3 p-Cl A4 p-CH3 A5 p-OCH3

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CONCLUSIONS This review gives an overview of the broad spectrum of pharmacological activities displayed by Benzofuran. The pharmacological activities of Benzofuran derivatives have attracted considerable attention giving to the use full of this moiety in the field of medicinal chemistry. Further development can be carried out by making slight change leading to severe changes to yield better drug .The Benzofuran importance of moiety can be seen by carrying out further studies on its possible substitution. Thus this paper proves to be significant for further research work on the bioactive Benzofuran ring and biological profiles of these new generations of Benzofuran would represent a successful matrix for further circumstances of better medicinal agents.

REFERENCES 1. Swarup jyoti Chattarjee*, Syed Azhar Nizami1, M. Gurumurthy1, Debashisha Panda (Evaluation of Antimicrobial Potency of Some Synthesized Thiazolidin-4-one substituted 1, 2, 4-triazoles) Journal of Advanced Pharmaceutical Research., 2010; 1; 26-35. 2. Vidyashri S. Kamble1*, Bhalchandra M. Habade , Geeta K. Patil and Y. Agasimundin. (Synthesis And Evaluation Of 4-(1- Benzofuran-2-YL)-1,3-Oxazole-2-Amine And Its Derivatives) International Journal Of Research In Pharmacy And Chemisitry. 2012; 2(1): 32-36. 3. Riddhi Madhu*, M. D. Karvekar (Evalution and Synthesis of 5-Chloro Benzofuran Derivatives for Antibacterial Activity) International Journal of Pharmacy and Pharmaceutical Sciences;, 2010; 2(3): 64-66. 4. V. B. Panchabhai1*, S. N. Budhwani , N. V. Kalyane , Y.B. Zambare , S. S. Jagtap (Synthesis and biological Evaluation of Some Novel Benzofuran Containing Carbamate Derivatives) International Journal of Universal Pharmacy And Life Sciences., 2011; 1(2): 127-134. 5. Alejandro Urzúa *, Javier Echeverría, Marcos C. Rezende and Marcela Wilkens (Antibacterial Properties of 3 H-Spiro [1-benzofuran-2, 1’- cyclohexane] Derivatives from Heliotropium filifolium) Molecules, 2008; 13: 2385-2393. 6. Sanmati K. Jain* and Priyanka Sinha (Quantitative Structure Activity Relationship (QSAR) Analysis on Arylbenzofuran Derivatives as Histamine H3 Antagonists) Der Pharma Chemica, 2011; 3(1): 572-579. 7. Magdyi. EL-Zahar*, Somaia S. Abd EL-Karim, Mogedda E. Haiba and Mohammed A. Khedr (Synthesis , Antitumor Activity and Molecular Docking Study of Novel www.wjpr.net Vol 4, Issue 07, 2015. 1745

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Benzofuran-2-YL Pyrazole Pyrimidine Derivatives) Acta Poloniae Pharmaceutica Drug Research, 2011; 68(3): 357-373. 8. Madappa B. HALLI∗, Vijayalaxmi B. PATIL and Sumathi R. BEVINAMARADA (Synthesis, characterization, and biological activity studies of (E)-N_ -((thiophen-2- yl)methylene) benzofuran-2-carbohydrazide and its metal(II)complexes) Turk J Chem , 2011; 35: 393 – 404. 9. M. B. Halli, Ravindra. S. Malipatil and R. B. Sumathi (Synthesis, Characterization and Antimicrobial Screening of Metal (II) Complexs Derived from Benzofuran-2- Carbohaydrazide and Acetophenone Schiff Base) International Journal of Pharma and Bio Sciences, 2012; 3(4): 547 – 557. 10. Asrondkar A.L, Jadhav YP, Patil V.N, Dawane K.H, Bobade AS and Chowdhary A.S (Pyrazolene-Benzofuran Derivatives: Synthesis and Biological Evaluation) International Journal of Research in Pharmaceutical and Biomedical Sciences, Jan – Mar, 2012; 3(1): 382-384. 11. Mehnaz Kamal * and Ashok K Shakya (Synthesis and Anticonvulsant Screening of Some Novel Derivatives of Substituted Benzofuran) International Journal of Biomedical and Advance Research, 2012; 3(04): 233-237. 12. Fatma AbdAleem A.ElHag, Reem A.K. ElHarbi, Fatma M. Edress and Hoda I. El Diwani (Synthesis of 5-BenzimidazolylBenzofuran Derivatives of Expected Biologocal Activity) 1st Annual International Interdisciplinary Conference, 2013: 24-26. 13. Xiang Zhou, Miao Li 2, Xiao-Bing Wang, Tao Wang and Ling-Yi Kong* (Synthesis of Benzofuran Derivatives via Rearrangement and Their Inhibitory Activity on Acetylcholinesterase) Molecules, 2010; 15: 8593-8601.