European Journal of Medicinal Chemistry 97 (2015) 561e581

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Biological and medicinal significance of benzofuran

Reshma J. Nevagi a, Santosh N. Dighe b, Satish N. Dighe c, *
a
Department of Pharmaceutical Chemistry, SMBT College of Pharmacy, Nandi Hills, Dhamangaon, Igatpuri, Nashik 422403, Maharashtra, India
b
Department of Chemistry, Sir Parshurambhau College, Pune 30, Maharashtra, India
c
Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Vadgaon (BK), Pune, Maharashtra, India

a r t i c l e i n f o a b s t r a c t

Article history: This article emphasizes on the importance of benzofuran as a biologically relevant heterocycle. It covers
Received 31 August 2014 most of the physiologically as well as medicinally important compounds containing benzofuran rings.
Received in revised form This article also covers clinically approved drugs containing benzofuran scaffold.
15 October 2014
© 2014 Elsevier Masson SAS. All rights reserved.
Accepted 31 October 2014
Available online 7 November 2014

Keywords:
Benzofuran
Enzyme
Inhibition
Biological significance

1. Introduction activity and results, widespread pharmacological activity and

structureeactivity relationship (SAR) in some areas.
Benzofuran 1 is considered as an important class of heterocyclic
compounds. It is present in numerous bioactive natural products as 2. Biological significance of benzofuran
well as pharmaceuticals and polymers [1]. Several derivatives of
benzofuran have been recognized as biologically and pharmaco- 2.1. Benzofuran as antimicrobial agents
logically relevant molecules [2e4].
Several pyridyl-benzofuran derivatives were synthesized and
evaluated for an inhibition of N-Myristoyltransferase enzyme, an
enzyme involved in fungal infection. All the compounds were
synthesized from a known antifungal agent 2 (RO-09-4609) by
structural modification at C-2 position. Compounds 3 (enzyme in-
hibition IC50 ¼ 0.0075 mM; antifungal activity IC50 ¼ 0.03 mM) and 4
(enzyme inhibition IC50 ¼ 0.0057 mM; antifungal activity
It is considered as one of the important heterocyclic rings
IC50 ¼ 0.035 mM) were found to be most active among synthesized
because of its diverse biological profile [2]. Medicinal chemists are
compounds. Both the derivatives showed activity in rat systematic
actively involved in the synthesis of benzofuran ring containing
candidiasis model [7].
molecules due to its clinical importance [5]. Many of the clinically
approved drugs are synthetic and naturally occurring substituted
benzofuran derivatives containing mono and fused benzofuran ring
in conjunction with other heterocycles. Table 1 shows a list of the
drugs with their significant pharmacological activity [6].
In this review, we have highlighted the biological and phar-
macological significance of both synthetic and natural benzofuran
derivatives. This report is focused on the providing details of

* Corresponding author. Current address: The University of Queensland, School of

Pharmacy, Brisbane, QLD 4072, Australia.
E-mail addresses: s.dighe@uq.edu.au, sdighe2008@gmail.com (S.N. Dighe).

http://dx.doi.org/10.1016/j.ejmech.2014.10.085
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.
562 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Table 1
Clinically approved drugs containing benzofuran ring.

Sr. No Name of the drug Structure Approved activity

1. Dronedarone Antiarrhythmic agent

2. Methoxsalen To treat psoriasis, Eczema, Vitiligo, Cutaneous lymphomas

3. Trioxsalen photosensitizer used to increase skin tolerance to sunlight

and enhance pigmentation

4. Naloxone Opioid antagonist

5. Nalbuphine Mixed agonisteantagonists analgesic

6. Amiodarone Antiarrhythmic agent

7. Ethylmorphine Opiate narcotic analgesic

8. Darifenacin To treat urinary incontinence

9. Galantamine Treatment of mild to moderate Alzheimer's disease

10. Fluorescein Diagnostic aid

 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581 563

Table 1 (continued )

Sr. No Name of the drug Structure Approved activity

11. Naltrexone Opioid antagonist

12. Methylnaltrexone m-Opioid antagonists

13. Heroin Opioid analgesic

14. Oxycodone Narcotic analgesic

15. Hydrocodone Antitussive agent

16. Dihydrocodeine Used in severe dyspnea, and an antitussive agent

17. Buprenorphine Mixed agonisteantagonists analgesic

18. Oxymorphone Opioid analgesic

19. Morphine Opioid analgesic

(continued on next page)

564 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Table 1 (continued )

Sr. No Name of the drug Structure Approved activity

20. Hydromorphone Centrally acting analgesic drug

21. Codeine analgesic, antitussive, antidiarrheal, antihypertensive,

anxiolytic, antidepressant, sedative and hypnotic

22. Rifapentine Antitubercular drug

23. Rifaximin Treatment of traveler's diarrhea and hepatic encephalopathy

24. Rifabutin Antitubercular drug

25. Rifampicin Antitubercular drug

26. Griseofulvin Antifungal drug

27. Saprisartan Used in the treatment of hypertension and heart failure.

 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581 565

Table 1 (continued )

Sr. No Name of the drug Structure Approved activity

28. Vilazodone Antidepressant

29. Tasimelteon Used in the treatment of non-24-h sleepewake

disorder (N24HSWD)

30. Ramelteon Used in the treatment of delayed sleep phase syndrome.

31. 6-(2-Aminopropyl)ben-zofuran (6-APB) Psychoactive drugs

32. Benzbromarone Used in the treatment of gout

33. Psoralen Used in the treatment for psoriasis, eczema, vitiligo,

and cutaneous T-cell lymphoma

34. Citalopram Antidepressant

antifungal screening, the compounds showed MIC at 25 mg/ml and

100 mg/ml against Aspergillus fumigatus and Penicillium wortmanni
respectively [8].

Antibacterial and antifungal activity of nine 2-

Seven fused benzofuran derivatives 5 containing coumarin and
pyridine rings were synthesized and evaluated for their antibac-
terial and antifungal activity. In antibacterial screening, all the
compounds showed MIC at 25 ug/ml against Pseudomonas chinchori
but they were ineffective against Micrococcus aureus whereas in
bisaminomethylatedaurone derivatives was evaluated on five bac-
terial and five fungal species. Among nine derivatives, compound 6,
7 and 8 exhibited promising activity [Minimum inhibitory con-
centration (MIC); 6, 7, 8 ¼ 25 mg/ml], and these compounds can be
considered as a useful lead for the further development of the
antimicrobial agents [9].
566 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581

such as Penicillin, Chloramphenicol, Tetracycline, Ampicillin,

Gentamicin and Ketoconazole [12].

Nine derivatives of b-amino carbonyl compounds possessing

benzofuran ring were evaluated for antimicrobial activity against E.
coli (NCTC 12923), S. aureus (NCTC10788), Pseudomonas aeruginosa
(ATCC 27853), Aspergillus flavus, Chrysosporium keratinophilum,
Candida albicans (NCPF 3179). Among nine compounds, compound
13 was found to be most active analogue and showed MIC ranging
between 0.040 and 0.100 mg/ml [13].

Eighteen benzofuropyrimidine derivatives 9 and 10 were eval-

uated against 4 bacterial and 2 fungal strains. Some of the com-
pounds showed considerable activity against tested species [10].
Phytochemical investigation of Root of Ligularia veitchiana (food
supplement in china) was done. From the species, three new
compounds were isolated along with 13 known compounds and
some are evaluated for antibacterial activity. Compound 14 was
found to be active against S. aureus among all the tested compounds
(MIC ¼ 62.5 mg/ml) [14].

Five thiazolyl-benzofuran derivatives were synthesized and

tested against 4 bacterial and 4 fungal strains. All the compounds
Eight pyrazolyl-benzofuran derivatives 11 were synthesized and showed good antimicrobial activity. Compound 15 represents the
tested against two bacterial species Escherichia coli, Staphylococcus general structure for the series of the compound [15].
aureus and one fungal species Aspergillus niger. All the compounds
were found to be active at high concentration against bacterial
species while were active at low concentration against fungal
species [11].

Antibacterial activity of four synthesized derivatives of

Compound 12 was evaluated for antimicrobial activity against Oxadiazolyl-benzofuran 16 was tested against S. aureus and E. coli.
five gram positive, two gram negative bacterial species and one Activity of all the compounds was found to be comparable with
fungal species and it showed better results than known antibiotics standard drug Ampicillin [16].
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581 567

and C. albicans. Among tested compounds, benzofuran ketoxime 20

was most active against S. aureus (MIC ¼ 0.039 mg/ml) while other
benzofuran ketoxime derivatives showed good activity against C.
albicans (MIC ¼ 0.625e2.5 mg/ml) [19].

Ten derivatives of benzofuran derivatives 17 possessing sul-

phonamide and phenyl carbamate moieties were synthesized and
evaluated for their antibacterial screening against four species of
bacteria i.e. S. aureus, Staphylococcus pyogenes, E. coli and P. aeru-
ginosa. Among these series, sulphonamide chain bearing thiophene
derivatives showed comparable activity against standard drug
Ciprofloxacin [17].

A series of compounds containing benzofuran ring with oxa-

diazoles and pyrazoles were synthesized and tested against five
bacterial (E. coli, K. pneumonia, P. aeruginosa, S. aureus, Streptococcus
faecalis) and five fungal strains (A. flavus, A. fumigatus, C. albicans,
Penicillium notatum, Rhizopus). In this series, compound 21 showed
very potent activity against all microbial species (relative %
Microwave assisted synthesis (MWI) tool was used to synthesize inhibition ¼ 80e93.3%) [20].
pyrazolyl-benzofuran derivatives that were then investigated for
their antimicrobial activity against 7 bacterial species. Among
tested compounds, compounds 18 and 19 were found to be most
active analogues and showed activity below 10 mg/ml and 15 mg/ml
respectively against E. coli, Salmonella typhi, Streptococcus pneu-
moniae and S. aureus [18].

2.2. Benzofuran as enzyme inhibitors

6-substituted-(E)-2-(benzofuran-3(2H)-ylidene)-N-alkylaceta-
mide skeleton was used to develop selective monoamine oxidase
(MAO) inhibitors. 6-Sulfonyloxy derivatives showed prominent
affinity and selectivity to MAO-A, more than standard drug
(Moclobemide) while 6-benzyloxyderivatives showed potent
MAO-B inhibitory activity and selectivity. Among 24 compounds,
22 and 23 showed outstanding MAO-A inhibitory potency (IC50 for
22 ¼ 9.1 nM and 23 ¼ 11 nM) and MAO-A over MAO-B selectivity.
Compound 24 was discovered as a new class of MAO-B inhibitor
(IC50 ¼ 36 nM) [21].

Sixteen derivatives of benzofuran ketoxime containing cyclo-

butyl group were synthesized and tested for antimicrobial activity
against S. aureus, Staphylococcus epidermidis, E. coli, Klebsiella
pneumonia, P. aeruginosa, S. typhi, Shigella flexneri, Proteus mirabilis
568 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Benzofuranisoxazoline derivatives were synthesized and
investigated for protein tyrosine phosphatases 1B (PTP 1B) inhibi-
tory activity. PTP 1B enzyme is responsible for selective dephos-
phorylation of tyrosine residues. Inhibition of this enzyme is
considered as an important target in the treatment of type-2 dia-
betes. Among nine compounds, 25 and 26 showed good activity
(25; IC50 ¼ 76 mM, 26; IC50 ¼ 81 mM compared to standard drug
(sodium vanadate)) [22].
Various aurone analogues have been synthesized and evaluated
for their tyrosinase enzyme inhibitory activity. Tyrosinase is a
copper-dependent enzyme essential in L-tyrosine to dopaquinone
conversion process. This dopaquinone is an important precursor in
melanin synthesis, a major pigment responsible for color of the
skin. In aurone molecule, authors introduced hydroxyl group on
ring A and different substitution on ring B. Among 15 derivatives,
compound 27 (75% inhibition at 0.1 mM) was found to be most
active analogue compared with a standard agent (kojic acid, 20%
inhibition at 7 mM) [23].
Four benzofuran derivatives containing tumor necrosis factor-a
(TNF-a) converting enzyme (TACE) inhibitors were synthesized and
evaluated for the activity. TACE is a Zn-dependent metalloprotein
important in the synthesis of TNF-a, a cytokine important for an
inflammatory response. TACE is having an important role in rheu-
matoid arthritis drug discovery. Among four derivatives, compound
28 showed an excellent inhibitory activity (IC50 ¼ 1 nM) and was
selective over other matrix metalloproteinases whereas compound
29 was less active (IC50 ¼ 1.8 nM) but more selective than 28 over
other matrix metalloproteinases [24].
1-[(Benzofuran-2-yl) (phenylmethyl)] pyridine, -imidazole, and
-triazole derivatives were designed from third generation nonste-
roidal aromatase inhibitors (letrozole and anastrozole) and evalu-
ated for aromatase (CYP19) inhibition activity. The aromatase
inhibitors are useful drug candidate for breast cancer. 6-Hydroxy or
6-methoxy substituted derivatives showed comparable activity
(IC50 ¼ 0.01e1.46 mM) with standard drug arimidex (IC50 ¼ 0.6 mM).
Among all synthesized compounds, 30 was most promising com-
pound (IC50 ¼ 44 nM; LC50 > 100 mM; LC50/IC50 ¼ >2273) compared
with standard drug (IC50 ¼ 600 nM; LC50 > 200 mM; LC50/
IC50 ¼ >333) [25].
Thrombin is a key enzyme required in blood coagulation pro-
cess. A regulator of coagulation maintain a balance between pro-
coagulation and anticoagulation (with <100% inhibition efficacy),
while an inhibitor may balance to only anticoagulation (with 100%
inhibition efficacy) [26,27].
Twenty-eight benzofuran derivatives were designed, synthe-
sized and evaluated for their thrombin inhibitory activity. In SAR
studies, it was clearly observed that sulfation at 6th position is
necessary for thrombin inhibitory activity. Overall 11 compounds
were found active in inhibitory assay and compound 31 was most
active analogue within this series (IC50 ¼ 7.3 mM) [26].
In the next study, same author reported benzofuran analogues
as a regulator of coagulation. In this study, they have synthesized
monosulfated benzofuran trimeric and tetrameric homologues of
31 as allosteric regulators of thrombin. Total 8 trimers and 2 tet-
ramers were tested for inhibition of human thrombin. Among both
the series, trimer 32 was found to be nearly 10-fold more potent
than 31. A trimer 32 inhibits thrombin with an efficacy of approx-
imately 80% (IC50 ¼ 0.67 mM) which alludes to the possibility of
allosteric regulation, compared to first generation molecule 31 [27].
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Inhibitors of SIRT1 are important in the treatment of cancer,
diabetes and age-related diseases. 21 derivatives of benzofuran-3-
yl(phenyl)methanones were synthesized and evaluated for their
inhibitory activity on SIRT1. Compound 33 was found be more
active derivative among this series (IC50 ¼ 2.8 mM) [28].
Mitogen-activated protein kinase phosphatase-1 (MKP-1)
enzyme is highly expressed in prostate, breast, gastric and renal
cancers and is considered as a good target for these cancers. NSC
357756 (34) is a well-known MKP-1 enzyme inhibitor which con-
sists of benzofuran moiety. 7 analogues of NSC 357756 (34) were
synthesized and evaluated for their inhibitory activity. Compound
35 was found to be more active analogue against human MKP-1
enzyme (IC50 ¼ 28.8 mM) and less active against MKP-3 enzyme
(IC50 ¼ 400 mM) [29].
The novel anticancer target, protein interaction with NIMA1
(Pin1) specifically catalyzes the conformational change between
cis- and trans-amide bond in pSer-Pro/pThr-Pro motif. This
conformational change process occurs in many protein kinases
participating in the cell cycle. Different scaffolds have been re-
ported in Pin 1 inhibitory activity so far, but benzofuran scaffold
569
was used for the first time, and 11 derivatives containing benzo-
furan scaffold were synthesized. Compound 36 was found to be
more active analogue within the series (IC50 ¼ 5.99 mM) [30].
Protein kinase CK2 is considered as an emerging target for
cancer chemotherapy. Nowadays, radiometric assay is used for
evaluation of CK2 inhibitors. In one report, by using new non-
radiometric technique for CK2 inhibition, different benzofuran
derivatives were investigated as CK2 inhibitors. Among 4 tested
compounds, 37 was found to be most potent compound (%
inhibition ¼ >96; IC50 ¼ 0.2 mM) [31].
Six benzofuran based histone deacetylase (HDAC) inhibitors
were synthesized and evaluated for their activity. Histone deace-
tylase considered as a therapeutic target for cancer treatment and
many drugs are under clinical trials. Compound 38 was found to be
more active analogue within this series (IC50 ¼ 0.221 mM) [32].
It was found that glycogen synthase kinase 3 (GSK-3) plays an
important role in glycogen metabolism but later many reports
published that GSK-3 also plays an important role in cell cycle
progression, proliferation, apoptosis. This enzyme also takes part in
cancer, diabetes and neurodegenerative disorders, and many small
molecules were investigated as GSK-3 inhibitors. Various Indole-
benzofuran linked molecules were synthesized and evaluated for
their GSK-3 inhibitory activity. Some of the compounds showed
very good inhibitory potential against GSK-3 enzyme and com-
pound 39 was found to be most active compound (IC50 ¼ 0.23 nM)
within the series. In the testing for anticancer activity against
pancreatic cancer cell line, compound 40 showed potent activity
(IC50 ¼ 0.6e0.9 mM) [33].
570 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581

2.4. Benzofuran as receptor agonist and antagonist

Two benzofuran carboxylic acid derivatives (44 and 45) were

identified as Endothelin (ET) receptor antagonists from the series of
synthesized thirteen molecules. Affinity and selectivity for ET
binding assay indicated that compound 44 showed a dual ETA/ETB
antagonism activity (ETA ¼ 23 nM, ETB ¼ 930 nM) in nanomolar
concentration and compound 45 was proved to be useful lead
compound in relieving hypoxia-induced pulmonary arterial hy-
pertension [36].

2.3. Benzofuran as enzyme activators

Eight benzofuran derivatives were obtained by phytochemical

investigation of Erythrina abyssinica and evaluated them for AMP-
activated protein kinase (AMPK) activation. AMPK enzyme activa-
tors are considered as anti-obesity and antidiabetic agents. Among
8 compounds, 41 and 42 showed potent activation of AMPK
enzyme at 10 mM [34].

Four butyrophenone analogues containing benzofur-

anoneepiperidine fragments were synthesized and evaluated for
affinity and selectivity as 5-hydroxytryptamine-2A (5-HT2A)e
dopamine-2 (D2) dual ligands. The structureeactivity relationship
(SAR) studies were performed to know the importance of the
chirality and substitution on piperidine and benzofuranone core.
Among all synthesized compounds, compound 46 was found to be
most active analogue in regards to antipsychotic activity. Com-
pound 46 showed moderate-to-high affinities for D2 (pKi ¼ 7.07)
and 5-HT2A (pKi ¼ 8.81) receptors and also possess appropriate
affinity ratio (1.25) for both the receptors. Authors also reported
that chirality of the compounds does not influence their affinity or
selectivity for the studied receptors [37].

Glucokinase activation is considered as a promising target for

the treatment of Type 2 diabetes mellitus. Several substituted 2-
methylbenzofurans were synthesized and evaluated for their
glucokinase activation. Among all the compounds, 43 was consid-
ered as a suitable clinical candidate (EC50 ¼ 188 mM) as it had
optimal combinations of potency, activation profile, metabolic
stability and solubility [35].
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581 571

11 analogues containing indole-arylpiperazine moiety were

synthesized and evaluated for 5-hydroxytryptamine-1A (5-HT1A)
receptor and dopamine-D2 (D2) receptor binding studies. Modifi-
cation of an aryl moiety on the piperazine with 5-benzofuranyl-2-
carboxamide increased 5-HT transporter and 5-HT1A receptor af-
finity but suppressed D2 receptor binding. Piperazine with 5-
benzofuranyl-2-carboxamide with substitution on the indole ring
with a cyano group developed most active analogue 47 within this
series. Compound 47 showed highly selective 5-HT1A receptor
agonist activity in nanomolar range with subnanomolar 5-HT1A
affinity [IC50 ¼ 0.2 nM]. It also showed subnanomolar 5-HT reup-
take inhibition [RUI ¼ 0.5 nM] with an excellent selectivity to
dopamine receptor (IC50 ¼ 666 nM) [38].

Several 2-aminoethylbenzofuran analogues were synthesized

and tested for H3 receptor antagonist activity. All the compounds
showed antagonist activity in nanomolar concentration in human
and rat H3 receptor. Because of their lipophilic nature, most of the
compounds showed good pharmacokinetic profile in the rat model
and achieved high CNS concentrations with large brain/plasma
ratios. All the compounds were also tested for cognition and
attention by using two rodent model and surprisingly 6 compounds
were found to be highly potent at doses ranging from 0.003 to
1 mg/kg. Among all synthesized compounds, compound 48 showed
highly potent H3 receptor antagonist activity and also excellent
pharmacokinetic properties [39].
Compound 54 was used as a basis for the development of new
neurokinin-1 (NK1) tachykinin receptor antagonist. Effect of
different R groups on the neurokinin-1 (NK1) tachykinin receptor
antagonist activity was evaluated. Among the synthesized com-
pounds, four compounds were found to be more active than 54.
Compound 55 was most active compound (IC50 ¼ 0.46 nM) among
this series and exhibited selectivity over the tachykinin NK2 and
NK3 receptors [41].

Bioisosteric replacement of indole ring of the melatonin 49 with

benzofuran was done to develop melatonin (MT) receptor agonists.
2-(4-phenyl butyl) benzofuran nucleus was used to produce three
different series of compounds 50, 51, and 52 and tested them as
melatonin receptor agonists. Compound 53 was most active
analogue within three series and was found to be a good orally
bioavailable agonist at MT1 (Ki ¼ 2.6 nM) and MT2 (Ki ¼ 10 nM)
melatonin receptors [40].
572 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Compound 56 was synthesized and evaluated as selective
Integrin avb3/avb5 dual inhibitor (avb3; IC50 ¼ 0.033 mM and
avb5 ¼ 0.42 mM). It was found that it did not show good activity as
compared to its indole bioisostere, due to its small volume of dis-
tribution and high clearance [42].
Oxytocin antagonists are important agents that will help in
delaying preterm birth. 15 benzofuran derivatives were synthesized
and evaluated oxytocin receptor antagonistic activity and their
pharmacokinetic parameters in rat and dog. The antagonist activity
was studied by measuring kinetics of displacement of oxytocins
receptor by the test compound. All compounds showed good ki-
netics. Compound 57 was found to be most active analogue
(pKi ¼ 9.3) within the series but showed weak pharmacokinetic
parameters in rat and dog while compound 58 (pKi ¼ 8.6) showed
good pharmacokinetic parameters in the in dog [43].
Selective adenosine A2A receptor antagonists are useful in the
treatment of Parkinson's disease. 16 benzofuran derivatives were
synthesized and evaluated for their antagonistic activity and oral
bioavailability. Within this series, compound 59 showed good
antagonist activity (73% inhibition) with good bioavailability [44].
2.5. Benzofuran as anti-inflammatory agents
Benzofuran carboxylic acid esters were synthesized and evalu-
ated for their anti-inflammatory activity by using rat carrageenan
induced foot paw edema model. Among nine compounds, 60 and
61 showed good activity in the rat model compared to the control
group (38.7%). Both compounds after 1.5 h, decreased percentage of
paw edema growth to 20.4% and 12.3% respectively and were found
to be more active than standard drug (Nimesulide, 23.4%). Com-
pounds 60 and 61 also showed potent cyclooxygenase-2 (COX-2)
enzyme inhibitory activity [45].
2,2-Bisaminomethylated aurone analogues were screened
against the pro-inflammatory cytokines [TNF-a; Interleukin-6(IL-
6)]. The compounds 62, 63 and 6 showed the high percentage of
inhibition (76e100%) against both the cytokines at 10 mM concen-
tration [9].
Microwave assisted synthesis (MWI) was carried out to obtain
20 Benzofuran-2-carboxamide derivatives. All the compounds
were evaluated for anti-inflammatory activity by using rat
carrageenan-induced rat paw edema method. Some of the com-
pounds showed good activity comparable with standard drug
(Diclofenac). Compound 64 was found to be most active analogue
within the series of the compounds (66% after 4 h) [46].
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Celecoxib analogues containing benzofuran ring were synthe-
sized and evaluated for their cyclooxygenase (COX-1 and COX-2)
inhibitory activity. Five compounds showed selective COX-2
inhibitory activity comparable with Celecoxib. All five compounds
were tested in the animals for anti-inflammatory activity using
formalin-induced rat paw edema method. Among these five com-
pounds, 65 and 66 showed activity equipotent to Celecoxib (100%
after 2 h) [47].
Some benzofuran derivatives were synthesized and evaluated
for their anti-inflammatory activity using carrageenan-induced rat
paw edema method. All compounds (13e25% after 4 h) showed
weaker activity compared with standard drug (Ibuprofen, 67%).
Compound 67 (25% after 4 h) was found to be most active com-
pound within this series [48].
Some benzofuran e heterocycle derivatives were evaluated for
their anti-inflammatory activity using carrageenan-induced rat
paw edema method. All the compounds showed good activity.
Compound 68 (53.54% after 2 h) was most active analogue within
the series [49].
573
2.6. Benzofuran as anticancer agents
Microwave assisted synthesis (MWI) of a series of benzofuran-
2-yl-(4,5-dihydro-3,5-substituted diphenylpyrazol-1-yl) meth-
anones was done and evaluated the compounds for anticancer
activity on A2780 cis cell line (human ovary cancer cell line).
Among 24 compounds, 69 (IC50 ¼ 4.866 mg/ml) and 70
(IC50 ¼ 4.569 mg/ml) were found to be most active analogue among
this series [50].
A series of heterocyclic derivatives of benzofuran-2-carbox-
amides were synthesized and evaluated for anticancer activity on 6
different cell lines (MCF-7, SK-BR-3, SW620, MiaPaCa-2, WI38 and
HeLa) at micromolar concentration. Compound 71 was found to be
active in 5 cell lines (IC50 ¼ 0.4e7.6 mM), except SK-BR-3 cell line
whereas compound 72 was found to be most active compound in
SK-BR-3 cell line (IC50 ¼ 3.83 mM) [51].
A series of Imidazole scaffold-based 2-benzylbenzofuran de-
rivatives were evaluated against a panel of cell lines (HL-60, A549,
SW480, MCF-7, SMMC-7721) for anticancer activity. Among 43
compounds, 73 and 74 were found to be most active in all cell lines
(IC50 ¼ 1.02e3.57 mM) and more potent than standard drug
(Cisplatin; IC50 ¼ 3.10e12.32 mM) [52].
574 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Benzoheterocyclic analogues of netropsin were synthesized and
evaluated for their anticancer properties against murine L1210 and
human K562 leukemia cells. All the compounds showed activity in
a submicromolar range in both cell lines. Compound 75 was the
most active compound (IC50; L1210 ¼ 290 nM, K562 ¼ 315 nM)
[53].
Tubulin polymerization inhibition is considered as challenging
target for cancer chemotherapy. Several inhibitors based on 2-(30 ,
40 , 5'-trimethoxybenzoyl)-benzo[b]furan scaffold were synthesized
and investigated for inhibition of tubulin polymerization and
anticancer properties. In this new series, compound 76 was found
to be most active compound in 5 different cell lines (L1210, FM3A/0,
Molt4/C8, CEM/0, Hela; IC50 ¼ 1.2e6.4 nM) and also inhibit tubulin
polymerization in micromolar concentration (IC50 ¼ 0.43 mM).
Compound 76 was more active than tested standard drug (Com-
bretastatin) [54].
In another study, on same benzofuran skeleton of 76, various
substituted benzenes, aryl alkyne, and aryl alkene were introduced
at 5th position and then evaluated them as tubulin polymerization
inhibitor and for anticancer activity. Total 29 derivatives were
synthesized and evaluated against five different cell lines (ME-180,
A549, ACHN, HT-29, B-16). Compounds 77 and 78 were found most
active analogues among this series and showed potent activity
against A549 cell lines (77, IC50 ¼ 0.08 mM; 78, IC50 ¼ 0.06 mM). Both
compounds also showed potent activity in tubulin polymerization
inhibition studies (77, IC50 ¼ 3.81 mM; 78, IC50 ¼ 1.95 mM) [55].
Five aurone derivatives containing 2-benzylidene-5-
bromobenzofuranone-3(2H)-one were synthesized and evaluated
for anticancer activity against HT-29, K562, and HepG2 cell lines.
Within five compounds, compound 79 showed good activity in
K562 cell lines (IC50 ¼ 0.37 mM) [56].
Benzofuran bioisosteres from previously reported benzothio-
phene inhibitors of tubulin polymerization were synthesized and
evaluated for the activity. In this series, compound 80 was found to
be more potent (IC50 ¼ 0.41 mM) than its benzothiophene analogue
(IC50 ¼ 3.4 mM) and standard drug (combretastatin; IC50 ¼ 2.1 mM).
Same compound was highly active (IC50 ¼ 34 mM) than its benzo-
thiophene analogue (IC50 ¼ 520 mM) in the inhibition of growth of
MCF-7 cell lines [57].
19 dihydrobenzofuranlignans and benzofurans were synthe-
sized and evaluated against 60 human disease-oriented tumor cell
lines. Compound 81 was found to be most active analogue within
this series with GI50 value at 0.3 mM. Also, it showed activity against
three breast cancer cell lines with GI50 value <10 nM. The com-
pound was resolved from racemic mixture and 2R, 3R-enantiomer
was found to be more active in inhibition of tubulin polymerization,
than its 2S, 3S-enantiomer and racemic mixture [58].
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
Three benzofuran analogues from the anticancer compound
(þ)-CC-1065 (82) were synthesized and then evaluated for anti-
cancer activity against U937 leukemia cell lines. All three com-
pounds found to be active in-vitro however compound 83
(IC50 ¼ 0.2 nM) found to be more active in L1210 leukemia in mice
[59].
A series of 2-aroyl-4-phenyl-5hydroxybenzofuran derivatives
were synthesized and evaluated for antiproliferative activity and
tubulin polymerization inhibitory activity. In SAR studies, it was
observed that methoxy group at para position of the 2-benzoyl
moiety showed potent tubulin polymerization inhibitory activity
while at meta position showed the least activity. Within series,
compound 84 was observed as potent derivative against Molt/4,
CEM and HeLa cancer cell lines (IC50 ¼ 0.51e0.88 mM) and also had
some inhibitory effect on tubulin polymerization [60].
575
Moracin O and moracin P analogues (85 and 86) were synthe-
sized and evaluated for their ability to inhibit hypoxia inducible
factor (HIF-1) activation induced by hypoxia. This factor is impor-
tant for adaptation of cancer cells to tumor hypoxia. In this work,
authors highlighted the importance of the aryl benzofuran in the
moracin derivatives O and P and (R)-configuration. Total 30 mole-
cules were synthesized with variation in an aryl group of moracin O
and P. All compounds were tested in racemic mixture form and
compound 87 was found to be more active among this series. (R)-
configuration of 87 (IC50 ¼ 1.0 nm) was found to be more active
than racemic mixture (IC50 ¼ 4.2 nm) [61].
BNC105 88 is a clinical candidate drug which is under clinical
trials for renal cancer (phase I and II), ovarian cancer [(phase I and
II) IC50 ¼ 0.3 and 0.1 nM in A2780 and A2780 cis cell lines
respectively], malignant pleural mesothelioma (phase II), vascular
disruption agent for the treatment of solid tumors (phase I) [62,63].
2.7. Benzofuran as antiviral agents
31 various spiro-benzofuran derivatives were synthesized using
microwave assisted synthesis and further evaluated for their anti-
viral activity against Influenza virus type A [(A/Taiwan/1/86 (H1N1),
A/Hong Kong/8/68 (H3N2)] and type B [B/Panama/45/90, B/Taiwan/
2/62, B/Lee/40, B/Brisbane/60/2008]. Among all these compounds,
EC50 values are ranging from 3.0 to 16.1 mM. Compound 89 was
found to be the most active compound against type B viruses with
and selectivity index value between 30 and 166. The results were
comparable with standard drug Favipiravir. Compound 89 was also
tested for activity against Human immunodeficiency virus (HIV)
and Herpes simplex virus (HSV) viruses and found to be inactive,
576 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581

which showed that the compound possess selectivity against

influenza virus [64].

By using induced-fit docking program (GENIUS), 6 benzofuran

derivatives were designed for hepatitis C virus (HCV) NS3-4A serine
protease and evaluated for their enzyme inhibitory activity. This
enzyme is important for replication of HCV virus and considered as
a major target for HCV virus. Compounds 90 and 91 were found to
be more active amongst 6 derivatives (IC50; 90 ¼ 8.07 mM,
91 ¼ 8.59 mM) [65].

Same research group synthesized another series of the com-

pounds and evaluated for their anti-HIV-1 activity. Among tested
compound, only compound 95 showed weak activity (46.34%
reduction of viral cytopathic effect) and others were inactive in
anti-HIV-1 activity [68].

2.8. Benzofuran as antitubercular agent

6 derivatives benzofuro[3,2-f][1]benzopyrans were synthesized

and evaluated against two Mycobacterium species (Mycobacterium
smegmatis mc2155 and Mycobacterium tuberculosis H37Rv). In
initial screening, compounds 96 and 97 showed comparable ac-
5 Pyranobenzofuran derivatives were synthesized and tested for
tivity with standard drug (Isoniazide). Both the compounds were
Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase
then screened against 7 different species of mycobacteria (H37Rv,
inhibition. Inhibitors of this enzyme are considered as a potential
Beijing, H37Ra, INH resistant, RIF resistant, Mycobacterium bovis
target for the treatment against HCV virus. In SAR studies, it was
BCG, Mycobacterium microti) and both showed activity in a micro-
observed that 5,8-dichloro substitution and presence of n-propyl
molar range (1e10 mM) against all mycobacterial species [69].
group were important for the activity. Increased or decreased in the
chain length of the alkyl group leads to decrease in the activity.
Among 5 analogues, compound 92 was found to be most active
analogue within the series (IC50 ¼ 0.14 mM) [66].

4 benzofuran compounds were synthesized and evaluated for

their HIV-1 inhibitory activity. All compounds showed weak
inhibitory activity. Compounds 93 and 94 represent the structures
of the synthesized compounds [67]
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581 577

Series of benzofuran-pyrazolyl-pyridine 98 and benzofuran-

pyrazolyl-naphthyridin 99 analogues were synthesized, and anti-
tubercular activity was studied against multidrug-resistant
M. tuberculosis stains (in-vitro and in-vivo). In this study, it was
found that o-carboxylic acid substituted analogue of 98
(IC50 ¼ 2.2 mg/ml and 3.2 mg/ml in M. tuberculosis stain H37RV and
Multidrug-resistant M. tuberculosis respectively) and o-nitro
substituted analogue of 99 (IC50 ¼ 1.9 mg/ml and 3.6 mg/ml in
M. tuberculosis stain H37RV and Multidrug-resistant M. tuberculosis
respectively) was more active analogue in in-vitro. In in-vivo assay,
reduction in bacterial count in lung and spleen tissues has been
measured. It was measured in terms of log of colony forming unit
(CFU) [(98; Lungs ¼ 6.24, Spleen ¼ 5.42) (99; Lungs ¼ 5.67,
Spleen ¼ 6.12)] [70].

2.10. Use of benzofuran ring in Alzheimer's disease

Four I-123 labeled benzofuran derivatives (104e107) were used

as diagnostic imaging agents targeting amyloid plaques in Alz-
heimer's disease (AD). All molecules were tested in mice for brain
uptakes. Results suggested that all four molecules displayed high
brain uptakes ranging 0.5e1.5 %. These compounds were slowly
washed out from mice indicating high binding affinity of the mol-
ecules [73].

2.9. Benzofuran as antioxidant

Benzofuran-1,3-thiazolidin-4-one derivatives were synthesized

and evaluated for their antioxidant properties using 1,1-diphenyl-
2-picrylhydrazyl (DPPH) radical scavenging activity. Compound
100 (67.1%) was found to be most active within this series [71].

Some N0 -(Substituted benzylidene)-1-benzofuran-2-
carbohydrazide and 5-(5-Substituted-1-benzofuran-2-yl)-1,3,4-
oxadiazole-2-thiol derivatives were synthesized and evaluated for
their antioxidant activity. Compound 101, 102 and 103 showed
potent antioxidant properties by DPPH radical scavenging activity
(101 ¼ 38.5%; 102 ¼ 35.24%, 103 ¼ 50.6% at 10 mg/ml) [72].
Two benzofuran derivatives (108 and 109) were tested for the b-
amyloid (Ab) aggregation inhibition in terms of critical micelle
concentration (CMC) and IC50. Both the compounds showed IC50
value at low micromolar concentration however formed micelles at
high concentrations (108 ¼ 225 mM; 109 ¼ 220 mM) compared to
IC50 values (108 ¼ 20 mM; 109 ¼ 78 mM) [74].
578 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581

2.11. Benzofuran as complement system inhibitors

Complement system plays an important role in host-defense

response against infection. Controlled activation of this system
leads to the proper response, but improper activation leads to
xenograft rejection, necrosis of infarcted heart tissue and brain
damage. So inhibitors of this system play an important physiolog-
ical role. Natural complement inhibitor K76eCOOH (110) contains
benzofuran ring. Various analogues of 110 (IC50 ¼ 238 mM) were
synthesized to improve activity and compound 111 (IC50 ¼ 70 mM)
was found to be more active analogues within the series [75].

2.13. Benzofuran as ischemic cell death inhibitors

Derivatives of 3-substituted-benzofuran-2-carboxylic esters

were synthesized and evaluated for ischemic cell death inhibitors
in H9c2 cells. Among 17 derivatives, 115 (EC50 ¼ 0.532 mM, cell
death ¼ 6.18%) and 116 (EC50 ¼ 0.557 mM, cell death ¼ 7.02%) were
found to be more potent than standard drug (KR-31378; cell
death ¼ 15.54%) [77].

2.12. Benzofuran as anti-ulcerogenic effect in ulcerative colitis

4 benzofuran derivatives were synthesized and their anti-

ulcerogenic activity was studied by using acetic acid-induced ul-
cerative colitis model in rats. The activity was evaluated by using
different microscopic parameters (Lesion score, ulcer area, ulcer
index and wet weight/Length (W/L) ratio). Compounds 112 (Lesion
score ¼ 2.2, Ulcer area ¼ 2.6 cm2, Ulcer index ¼ 4.8, Wet W/L
Ratio ¼ 84.5), 113 (Lesion score ¼ 2.8, Ulcer area ¼ 3.9 cm2, Ulcer
index ¼ 6.7, Wet W/L Ratio ¼ 95.2) and 114 (Lesion score ¼ 2.2,
Ulcer area ¼ 3.3 cm2, Ulcer index ¼ 5.5, Wet W/L Ratio ¼ 90.0) were
comparable with the standard drug (Sulphasalazine; Lesion
score ¼ 1.6, Ulcer area ¼ 2.1 cm2, Ulcer index ¼ 3.7, Wet W/L
Ratio ¼ 79.0) [76].
 R.J. Nevagi et al. / European Journal of Medicinal Chemistry 97 (2015) 561e581
2.14. Benzofuran as dopamine uptake inhibitor
Compound 117, a benzofuran derivative was investigated for
dopamine uptake inhibitory activity in nanomolar concentration
(Ki uptake ¼ 37.5 nM) but it was less active than its indole analogue
(Ki uptake ¼ 5.5 nM) [78].
3. Conclusion
Benzofuran moiety has received biological and medicinal
importance from researchers and scientists. Many marketed drugs
also possess this heterocyclic moiety. Numerous publications have
been reported on benzofuran derivatives to have antimicrobial,
enzyme inhibition, enzyme activation, receptor agonist and
antagonist, anti-inflammatory, anticancer, antiviral, antitubercular,
antioxidant, anticonvulsant, anti-alzheimer, complement system
inhibitors, anti-ulcerogenic, ischemic cell death inhibitors and
dopamine uptake inhibitor activities. From all these activities, it is
clear that benzofuran moiety has a great value in medicinal
chemistry.
Conflict of interest
There is no conflict of interest.
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