Chemistry and Therapeutic Aspect of Furan: A Short Review

 

Biplab De¹, Sandip Sen^2*, T.S. Easwari²

¹Regional Institute of Pharmaceutical Science and Technology, Abhoynagar, Agartal-799005

²IIMT College of Medical Sciences, Department of Pharmaceutical Sciences, Meerut-250001

*Corresponding Author E-mail: sandipsen2010@gmail.com

Furan is a five member aromatic heterocyclic compound. The current review involved recent advance in the synthesis of furan derivative by different researcher. The study also focused on reactivity and therapeutic aspect of furan derivatives.

 

 

 

INTRODUCTION:

The five membered aromatic heterocyclic compounds were considered as important chemical entities due to various biochemical process¹. One of the heterocyclic compound furfural as a derivative of furan was first isolated in 1832 by the German chemist Johann Wolfgang Dobereiner as a byproduct during formic acid synthesis². In 1901 the German chemist Carl Harries deduced furfural's structure. The nucleus of furfural (Furan) can be prepared from tetra hydrophenol³. They are important structural fragment for many active pharmaceutical ingredient and pharmacologically active compounds⁴. Furan was considered as common structural motifs available in many natural products⁵. Its derivatives obtained from synthetic and natural resources have wide range of pharmaceutical interest because of biological activities. The furan derivatives showed interesting biological activity such as nematocidal⁶, insecticidal⁷, antibacterial⁸, antifungal⁹, antiviral¹⁰, antioxidant¹¹, anti inflammatory^12-13and antinociceptive ^14-15 property.

 

Synthesis of furan derivatives:

Furan was obtained from pine-wood⁵. It may be prepared by the dry distillation of mucic acid. Which upon heating obtained furoic acid, at its boiling point. Furic acid then converted to furan by decarboxylation.

 

 

 

 

 

 

 

 

 

Furan can also be obtained from furfural by oxide catalyst.

 

A general method of preparing furan derivative is to dehydrate 1, 4-di ketones or dialdehydes with phosphorous pentoxide, sulphuric acid.

 

 

Alternatively, furan derivatives may be prepared from ethylacetoacetate in the presence of iodine.

 

When diacetosuccinic ester was heated with dilute sulphuric acid 2, 5-dimethylfuran-3, 4-dicarbo xylic acid is formed.

 

Furan derivatives may also be prepared by the Feist Benary synthesis (1902, 1911) where α-chloro ketone is condensed with a β-keto ester in the presence of pyridine⁵.

 

 Au (I)-catalyzed hydroamination¹⁷ or hydration of 1, 3-diynes allows formation of 2, 5-diamidofurans. This method can also be expanded to 2, 5-disubstituted furans.

 

2, 5-Disubstituted 3-iodofurans¹⁸ can be prepared in presence of palladium or copper as catalyst. The cross coupling reaction is taken place between beta bromo enol acetate and terminal alkynes followed by iodocyclization.

 

An efficient substitution reaction¹⁹ of propargylic acetates in enoxysilanes under mild conditions in the presence of FeCl₃ as catalyst affords γ-alkynyl ketone. The intermediate ketone in the presence of TsOH as catalyst forms tri or tetra substituted furan.

 

Synthesis of furan²⁰ can also be obtained by reaction between propargyl alcohols and terminal alkynes, which yields formation of 1, 4-diynes, poly substituted furan and water as by product.

 

Chemistry of furan:

Being a five membered aromatic compound, furan's behavior is quite dissimilar to that of the more typical heterocyclic ethers such as tetrahydrofuran.

 

It is considerably more reactive toward electrophillic substitution⁵.

 

It also undergoes cycloaddition reaction preferably endo isomer²¹ are more favoured.

 

Therapeutic aspects of Furan:

Furan derivatives as antimicrobial agent:

Nilo Zanatta et al. reported²² antimicrobial affect against yeast, filamentous fungi, bacteria, and algae of furan-3-carboxamide derivatives (1). The derivatives were prepared by aromatization and nucleophlilic displacement in 4-trichloroacetyl-2, 3-dihydro furan.

 

Structure-1

 

 

Similarly Fatma Karipcin et al. reported²³ antimicrobial activity of 1-benzoyl-3-furan-2-ylmeth yl-thiourea (2).

 

 

Structure-2

 

 

R.R. Zaky et al. also reported²⁴ antimicrobial effect for (E)-3-(2-(furan-ylmethylene) hydrazinyl)-3-oxo-N-(thiazol-2yl) propanamide (3).

 

 

Structure-3

 

 

Craig A. Obafemi et al. reported²⁵ synthesis of 2, 3a, 8b-trihydroxy-3-(thiophen-2-ylcarbonyl)-2-(trifluoromethyl)-2, 3, 3a, 8b-tetrahydro-4H-indeno [1, 2-b] furan-4-one (4). The compounds showed broad spectrum activity against different strains of gram positive and gram negative bacteria.

 

 

Structure-4

 

A series of novel²⁶ analogues of [5-(furan-2-yl)-3-[2-(alkoxy)-phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide were synthesized by Mamta Rani et al. Alkoxy-[5-(furan-2-yl)-2-(benzyloxy)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide (5) and 5-(furan-2-yl)-1-[2-(naphthalen-2-yl methoxy)-phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide (6) shown better activity compared to standard against A. hydrophila, Y. enterocolitica, L.monocytogenes  and S. aureus.

 

 

Furan derivatives as anticancer agent:

K.S. Rangappa reported²⁷ anticancer activity of 2-[5-(5-(4-chloro- phenyl) furan-2-yl)methyl ene)-4-oxo-2-thioxothiazolidin-3-yl] acetic acid (7 and 8) derivatives.

 

 

 

 

Maurice Hofnung et al.  reported²⁸ in vivo mutagenic properties of a 5-nitrofuran. The 7-metho xy-2-nitro naphtha [2, 1-b] furan (9) was evaluated in transgenic mice (Big Blue).

 

Structure-9

 

Arvind S. Negi et al. reported²⁹ anticancer activity of 1-(3′, 4′, 5′-tri methoxy) phenyl naphtha [2, 1-b] furan (10) by in vitro MTT assay.

 

Structure-10

Andrey E. Shchekotikhin et al.³⁰ reported cytotoxic properties of novel 4, 11-bis [(2-aminoethyl) amino] anthrax [2, 3-b] furan-5, 10-diones (11). The selected compound potently killed mamm alian tumor cell lines, including drug resistant variants.

 

Structure-11

 

 

Yong Mei Li et al. reported³¹ racemic mixture of furan lignans. The optical isomers (12) were obtained through a selective hydrolization. The isomers and the racemates were able to shown anticancer activity against QGY-7701 and HeLa cell lines.

Structure-12

 

 

Girolamo Cirrincione et al. reported³² 2, 5-bis (3′-indolyl) furans and 3, 5-bis (3′-indolyl) iso xazoles (13) as antitumor agents. The antiproliferative activity was also evaluated invitro toward diverse human tumor cell lines.

Structure-13

 

Furan derivatives as analgesic and anti-inflammatory agent:

E.S.Lee reported³³ 1-furan-2-yl-3-pyridin-2-yl-propenone (14), as dual inhibitor of COX/5-LOX. The results suggest that FPP-3 may have a benefit in combating inflammation and pain by dual inhibition of COX and LOX.

 

Structure-14

5-aryl-3-[(2-chloroquinolin-3-yl)methylene] furan-2(3H)-ones  were³⁴ synthesized by M.M. Alam. Compounds 15, 16 and 17 were showing potent antiinflammatory activity.

 

 

Structure-15                 

 

Cherng Chyi Tzeng et al. reported³⁵ anti-inflammatory activity of 2-(furan-2-yl)-4-phenoxy quinolines. Among the reported compounds,   4-{4-[(2-furan-2-yl)-quinolin-4-yloxy]-phenyl}-but-3-en-2-one (18) was most potent compound.  While (E)-1-{3-[(2-Furan-2-yl)-quinolin-4-yl-oxy]-phenyl}-ethanone oxime (19) and 1-{3-[(2-furan-2-yl)-quinolin-4-yloxy]-phenyl}-ethanone (20) was moderately potent than genistein.

 

 

Structure-18

 

 

 

Anticonvulsant, neurotoxic and antinociceptive property for dihydro furan-2(3H)-one (21) was reported³⁶ by Barbara Malawska et al.

 

Structure-21

 

 

The synthesis and pharmacological evaluation³⁷ of novel furan derivative acted as voltage gated sodium channel blockers were reported by Irene Drizin et al. The compounds (5-(4-chloro phenyl)-furan-2-yl)-(piperazin-1-yl)-methanone (22), (5-(4-tert-butylphenyl)-furan-2-yl)-(4-cyclohexylpiperazin-1-yl)-methanone  (23) showed more potent activity.

 

 

Structure-22

Structure-23

 

 

Structure-24

 

Gilson Zeni et al. reported³⁸ anti-inflammatory activity of acetylenic furan derivatives (25); which were synthesized via Pd-catalyzed coupling reactions of 2-(alkyltelluro) furan with several terminal alkynes.

Structure-25

 

Furan derivatives as CNS active agent:

Pratibha Mehta Luthra et al. reported³⁹ 8-(furan-2-yl)-3-substituted thiazolo [5,4-e][1,2,4] triazo lo[1,5-c] pyrimidine-2(3H)-thione derivatives (26) as potential adenosine A2A receptor antagonists.

Structure-26

Peter Stjernlof et al. reported⁴⁰ (Dipropylamino)-tetrahydro naphtha furans (27) as centrally acting serotonin agonists and dopaminergic receptor blocker.

 

Structure-27

 

Sang Yoon Choi et al. synthesized⁴¹ 3-[2-(3, 5-Dimethoxy-phenyl)-vinyl]-furan (28) as synthetic resveratrol derivative. In addition, DPVF also inhibited ATP depletion following oxygen and glucose deprivation in the adult hippocampal slice.

Structure-28

Furan derivatives as antioxidant:

Stefano Manfredini et al. tested radical scavenging activities⁴² of 2, 3-dihydroxy-2, 3-enono-1, 4-lactones. The 3,4-dihydroxy-5R-2(R,S)-(6-hydroxy-2,5,7,8-tetramethylchroman-2(R,S)yl-methyl) -1,3]dioxolan-4S-yl]-5H-furan-2-one (29)  was able to show potent activity.

 

Structure-29

 

Furan derivatives as cytoprotective agent:

Yoshiro Saito et al. examined⁴³ radical scavenging activity and cytoprotective effects of novel furan compounds (30 and 31), which have potent inhibitory activity against oxygenases such as COX-1, COX-2 and 5-LOX.

Structure-30

Structure-31

 

Furan derivatives as miscellaneous therapeutic agents:

M.K. Unnikrishnan et al. reported⁴⁴ antioxidant, 5-lipoxygenase inhibitory, anti-inflammatory and peripheral analgesic activities of 6b, 11b-Dihydroxy-6b,11b-dihydro-7H-indeno-[1,2-b]-naphtho-[2,1-d] furan-7-one (32). It also had promising non-ulcerogenic effect for immune pathogenic chronic inflammatory conditions.

 

Structure-32

 

Daud A. Israf et al. observed⁴⁵ that 3-(2-hydroxyphenyl)-1-(5-methyl-furan-2-y-l)propenone (33), was suppressing various proinflammatory mediators. HMP also selectively inhibited the p38/ATF-2 and AP-1 signaling pathways in the NO synthesis by the macrophage RAW 264.7.

 

Structure-33

 

 

CONCLUSION:

From the above discussion it can be concluded that It is more reactive toward elctrophillic and dielsalder reaction. It have wide range of pharmacological  activity like antimicrobial, anticancer, analgesic, anti-inflammatory, CNS acive agent and antioxidant activity etc.

 

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Received on 21.05.2015         Modified on 17.06.2015

Accepted on 23.06.2015         © AJRC All right reserved