European Journal of Medicinal Chemistry 162 (2019) 266e276

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European Journal of Medicinal Chemistry

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

Mini-review

Benzofuran derivatives and their anti-tubercular, anti-bacterial

activities
Zhi Xu a, *, Shijia Zhao b, Zaosheng Lv b, Lianshun Feng a, Yinling Wang a, Feng Zhang a,
Liuyang Bai a, Jialun Deng c
a
College of Chemistry and Pharmaceutical Engineering, Huanghuai University, Zhumadian, PR China
b
Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, Wuhan University of Science and Technology, Wuhan, PR China
c
Haiso Technology Co., Ltd., Wuhan, PR China

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

Article history: Benzofuran is a fundamental structural unit in a variety of biologically active natural products, and its
Received 9 October 2018 derivatives display various biological properties. Some benzofuran derivatives possess unique anti-
Received in revised form tubercular and anti-bacterial action mechanism, and exhibit excellent in vitro and in vivo activities
3 November 2018
against both drug-sensitive and drug-resistant pathogens. Moreover, several benzofuran derivatives have
Accepted 9 November 2018
Available online 10 November 2018
already used in clinics for the treatment of various diseases. Thus, benzofuran is a useful pharmacophore
to develop new anti-tubercular and anti-bacterial drugs. This review covers the recent advances of
benzofuran derivatives as potential anti-tubercular and anti-bacterial agents, and the structure-activity
Keywords:
Benzofuran
relationship is also discussed to pave the way for the further rational development of this kind of
Hybrid compounds derivatives.
Anti-mycobacterial © 2018 Elsevier Masson SAS. All rights reserved.
Anti-tubercular
Anti-bacterial
Structure-activity relationship

1. Introduction
Gram-positive and Gram-negative pathogens are responsible
for the majority of hospital-acquired and community-acquired in-
fections, resulting in extensive mortality and burden on global
healthcare systems [1]. Antiobics are effective weapons to fight
against bacterial infections, but bacteria have already generated
resistance to almost all antibiotics currently used in clinics [2,3].
The emergence and wide-spread of drug-resistant bacteria
including multi-drug resistant (MDR) and pan-drug resistant
pathogens creating an urgent need to develop new drugs active
against both drug-sensitive and -resistant Gram-positive and
Gram-negative pathogens.
Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile
bacillus, is a species of pathogenic bacteria in the family Myco-
bacteriaceae, can appear either Gram-negative or Gram-positive [4].
MTB is globally spread, typically living in a variety of environments,
and is the main causative agent of tuberculosis (TB) [5,6]. Around
1.7 billion infected with MTB, and 5e10% will develop TB disease
* Corresponding author.
E-mail address: chemorgchem@126.com (Z. Xu).
during their lifetime [7]. Worldwide, TB is the leading cause from a
single infectious agent, ranking above human immunodeficiency
virus (HIV)/acquired immune deficiency syndrome (AIDS). The
World Health Organization estimated that at least 10 million people
developed TB with 1.3 million deaths in 2017 [7]. There were cases
in all countries and age groups, but overall 90% were adults (aged

15 years), 9% were people living with HIV. Besides TB co-infected
with HIV, drug-resistant TB (DR-TB), including multi-drug resistant
TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally
drug-resistant TB (TDR-TB), and these new virulent MTB forms
which are spread the same way with drug-susceptible MTB have
further aggravated the mortality and spread of this disease [8]. To
control this plague, new anti-TB agents are needed.
Benzofuran (Fig. 1), consisting of fused benzene and furan rings,
is a fundamental structural unit in a variety of biologically active
natural products [9,10]. Benzofuran derivatives possess diverse
pharmacological properties such as anti-cancer [11,12], anti-viral
[13,14], anti-Alzheimer's disease [15,16], anti-parasitic [17,18],
anti-TB [19,20] and anti-bacterial [21,22] activities. Some
benzofuran-based compounds such as benzbromarone and amio-
darone (Fig. 1) have already used in clinics for the treatment of
various diseases, so benzofuran is an important pharmacophore for

https://doi.org/10.1016/j.ejmech.2018.11.025
0223-5234/© 2018 Elsevier Masson SAS. All rights reserved.
 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
Fig. 1. Chemical structures of benzofuran, benzbromarone and amiodarone.
the development of new drugs.
In recent years, numerous of benzofuran derivatives have been
designed, synthesized and screened for their anti-TB and anti-
bacterial activities, and some of them exhibited promising po-
tency. This review covers the recent advances of benzofuran de-
rivatives as well as their anti-TB and anti-bacterial properties. The
structure-activity relationship (SAR) is also discussed to pave the
way for the rationale design of benzofuran derivatives.
2. Anti-tubercular activity
A series of benzofuro[3,2-f][1]benzopyrans were screened for
their in vitro anti-TB, anti-bacterial and anti-fungal activities by
Prado et al. [23]. These compounds seem as promising specific anti-
TB agents, since they exhibited neither significant cytotoxicity
against mammal cells, nor effect on the growth of various bacteria
and fungi. The preliminary results indicated that three derivatives
1a-c (Fig. 2) showed considerable activities against Mycobacterium
smegmatis (M. smegmatis) mc2155 and MTB H37Rv, and the mini-
mum inhibitory concentration (MIC) values were in a range of
1e60 mg/mL. The SAR revealed that compared with compound 1a
(MIC99: 5 and 5 mg/mL), reduction of double-bond (1b, MIC99: 1 and
5 mg/mL) could enhance the activity against M. smegmatis mc2155,
but has no influence on the activity against MTB H37Rv. Oxidization
of double-bond to vicinal diol 1c (MIC99: 30 and 60 mg/mL) resulted
in great loss in activity against both strains. Conversion of diol to
ester or cyclic carbonate led to the absence of activity. The most
active compounds 1a,b were further evaluated for their in vitro
anti-mycobacterial activities against M. bovis, M. microti, MTB
H37Ra, isoniazid(INH)-resistant and rifampicin(RIF)-resistant MTB
Fig. 2. Chemical structures of benzofurobenzopyrans and their derivatives 1e4.
267
strains. Both of them (MIC99: 1e10 mg/mL) displayed great potency
against the above tested 5 strains, and also showed low cytotoxicity
towards macrophage and VERO cells (IC50:
80 mg/mL). Further
study suggested that they could inhibit the biosynthesis of mycolic
acids present in Mycobacteria and Nocardia cell walls. Among them,
compound 1b (MIC99: 1 mg/mL) was 5-fold more active than INH
(MIC99: 5 mg/mL) against INH-resistant MTB strain. Further modi-
fication yielded the derivatives 2 (MIC95: 4->500 mg/mL) [24], 3
(MIC95: 3->500 mg/mL) [25], and 4 (MIC95: 37.5->1712 mg/mL)
[26,27] with various substituents at different positions, but the
anti-mycobacterial activity didn't increase apparently.
The anti-mycobacterial activity of dibenzofuran derivatives 5
(Fig. 3) were screened against MTB H37Rv, and all of them displayed
considerable activities with MIC values ranging from 3.13 to
50.0 mg/mL [28]. The SAR indicated that derivatives with
substituted phenyl ring at Ar position were more potent than the
corresponding thienyl analog 5j (MIC: 50.0 mg/mL) generally. For
derivatives 5a-i with substituted phenyl ring at Ar position, intro-
duction of mono-substitutent or bis-electron-withdrawing sub-
stituent on the phenyl ring couldn't boost up the activity, while bis-
electron-donating substituent 2-methyl-4-methoxyl could
enhance the activity. The relative contribution order of substituents
at phenyl ring was 2-Me-4-OMe > eH ¼ 4-Me > 4-n-hexyl > 3-
Me ¼ 4-n-pentyl > 4-OCF3 ¼ 2,4-diF against MTB H37Rv. In partic-
ular, the most active compound 5c (MIC: 3.13 mg/mL) was compa-
rable to ethambutol (EMB, MIC: 3.13 mg/mL), and was 16-fold more
potent than pyrazinamide (PZA, MIC: 50.0 mg/mL), but was less
active than INH (MIC: 0.1 mg/mL) against MTB H37Rv. In addition,
compound 5c (CC50 > 50 mg/mL) also showed low cytotoxicity
against HEK-293T cells, so it could act as a lead for further
optimization.
All dibenzofuran derivatives 6 (MIC: 3.13e12.5 mg/mL) and 7
(MIC: 1.56e12.5 mg/mL) were more potent than PZA (MIC: 50.0 mg/
mL) against MTB H37Rv, and some of them were comparable to or
better than EMB (MIC: 3.13 mg/mL) [29]. The SAR suggested that the
cyclic compounds 7 were more active than the corresponding de-
rivatives 6 generally. Introduction of halogen atoms eCl and eBr at
the para-position of phenyl ring (R1) was favorable to the activity,
but 3,4,5-trimethoxyl group was detrimental to the activity. For
derivatives 6, substituents at R2 position influenced the activity
greatly, and the contribution order was eNH2 > -Me > -Ph. Com-
pounds 7b,c (MIC: 1.56 mg/mL) were found to be most active against
268 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
Fig. 3. Chemical structures of dibenzofuran derivatives 5e12.
MTB H37Rv, and were 2- and 16-fold more potent than the refer-
ences EMB and PZA, but was less active than INH (MIC: 0.1 mg/mL)
against MTB H37Rv.
Dibenzofuran-isoflavonoid hybrids 8 (MIC: 12.5e50 mg/mL) only
exhibited moderate activities against MTB H37Rv, and were far less
potent than the references INH and RIF (MIC: 0.1 and 0.2 mg/mL,
respectively) [30]. Dibenzofuran derivatives 9 and their epimers 10
with MIC values in a range of 3.13e25.0 mg/mL were less potent
than the first-line anti-TB agents INH and RIF (MIC: 0.1 and 0.2 mg/
mL, respectively) against MTB H37Rv [31]. The SAR showed that
compounds 10 were as potent as or better than the corresponding
epimers 9. In general, compared with unsubstituted analogs 9a and
10a, introduction of either electron-withdrawing or electron-
donating groups at R position could increase the activity, and eF
was optimal. Among them, the most active compounds 9f and 10f
(MIC: 3.13 mg/mL) were comparable to EMB (MIC: 3.13 mg/mL).
The dibenzofuran-triazole hybrid 11 could inhibit both short-
and long-term growth of M. vanbaalenii, similar to INH, and has no
toxic effects on MDCK cells and SH-SY5Y cells [32]. The IC50 of
hybrid 11 was 5.3 mM, which was less than that of INH (IC50: 15 mM)
against M. vanbaalenii. The dibenzofuran-triazole hybrids 12 (MIC:
6.25e25.0 mg/mL) only showed moderate activities against MTB
H37Rv, and were less active than INH and EMB (MIC: 0.05 and
1.56 mg/mL, respectively) [33]. The SAR indicated that substituted
phenyl groups were more favorable than the alkyl groups, and
eCH2OH and eCH2OBn were disfavored. For alkyl groups, the
length has some influence on the activity, and the longer one
preferred. The most active hybrids 12c and 12f-h with MIC of
6.25 mg/mL, were comparable to PZA (MIC: 6.25 mg/mL) against
MTB H37Rv.
Mycobacterium protein tyrosine phosphatase B (mPTPB) is an
essential virulence factor that is secreted by the bacterium into the
cytoplasm of macrophages, where it mediates mycobacterial sur-
vival in the host [34]. Thus, mPTPB is a promising target for novel
anti-TB agents. A library of benzofuran-triazole hybrids 13 (Fig. 4)
were screened as potential mPTPB inhibitors, and I-A09 observed
an IC50 of 1.26 mM in an enzyme panel [34e37]. The study
demonstrated that inhibition of mPTPB with I-A09 in macrophages
reverses the altered host immune responses induced by the bac-
terial phosphatase and prevents MTB growth in host cells. Inter-
estingly, I-A09 was also shown to target PTP1B and TC-PTP (IC50: 19
and 22 mM, respectively) [34]. The multi-target properties make I-
A09 a potential candidate for the treatment of drug-sensitive and
drug-resistant TB, including MDR-TB and XDR-TB. Currently, I-A09
is being under clinical evaluations, and may be used to treat TB
infection in the near future [33].
The thirty-three benzofuran-pyrazole hybrids 14 (Fig. 4) were
screened for their in vitro activities against enoyl-acyl carrier pro-
tein reductase (InhA) and MTB, and all of them showed promising
activities against InhA and MTB with IC50 and MIC90 were
0.002e0.112 mM and 0.05e16.0 mM, respectively [38]. The SAR
indicated that for R1 position, large volumn substituents disfavored,
and eH > -Et > -Ph; for R2 position, eCH2COOMe was optimal; for
R3 position, -Et > -Me; for R4 position, -Et > cyclopropyl. Hybrid 14a
(IC50: 0.003 mM, MIC90: 0.05 mM) was highly active against InhA and
MTB, so it could act as a starting point for further investigation.
Further modification generated benzofuran-pyrazole amide 14b
which also exhibited excellent in vitro activity against InhA and
MTB (IC50: 0.003 mM, MIC90: 0.05 mM) [38]. The bactericidal po-
tential of hybrid 14b was assessed in killing rate experiments, and
the results showed that hybrid 14b was able to reduce >2 Log
colony forming units (cfu) counts after 1 week of incubation, which
was comparable to that of moxifloxacin. In C57BL/6 J mice model,
hybrid 14b (4 mg/kg, intravenous route) exhibited high in vivo
clearance (CL ¼ 85.5 mL/min/kg) and short half-life (t1/2 ¼ 0.5 h).
The oral pharmacokinetic (PK) profile of hybrid 14b was charac-
terized by Cmax value of 1.75 mg/mL at 0.83 h post-dosing and
AUC0∞ of 3.59 mg h/mL corresponding to 36% bioavailability. The
maximal nonlethal dose of hybrid 14b was higher than 1000 mg/kg,
and no adverse clinical events were observed. Subsequently, hybrid
14b was in vivo assessed to determine the therapeutic efficacy in a
murine acute MTB infection model, but no significant reduction of
 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
Fig. 4. Chemical structures of benzofuran-heterocycle hybrids 13e20.
cfu at any dose tested was observed in the lungs of infected mice.
Overall, hybrid 14b possessed good balance between InhA inhibi-
tion, anti-TB potency, and PK profile, but was inactive in vivo in a
murine TB acute infection model. The benzofuran-pyrazole hybrids
15a,b only exhibited weak activity against MTB Inosine 50 -mono-
phosphate dehydrogenase (IMPDH) with 36% and 31% inhibition at
100 mM, still need to be modified [39].
The benzofuran-pyrazoline hybrids 16 and 17 (Fig. 4) were
screened for their in vitro and in vivo anti-TB activities by Manna
et al. [40]. All hybrids (MIC: 1.2e11.5 mg/mL) displayed moderate to
excellent activities against both drug-sensitive MTB H37Rv and
MDR-TB strains, and no cytotoxicity was observed towards VERO
cells (IC50: >85.34 mM). The SAR indicated that hybrids 16 with
naphthyridine ring were more active than the corresponding pyr-
idinylcarbonyl ring derivatives 17 against MDR-TB in vitro, but
compounds 17 showed higher activity against MTB H37Rv generally.
Among them, hybrid 17a (MIC: 1.2 mg/mL) was slightly less active
than the first-line anti-TB agents INH and RIF (MIC: 0.32 and
0.60 mg/mL) against MTB H37Rv, while conjugate 16d (MIC: 3.2 mg/
269
mL) was more potent than INH and RIF (MIC: 4.2 and 8.5 mg/mL,
respectively) against MDR-TB strain. In MTB ATCC 35,801 infected
female CD-1 mice models, four hybrids 16d (Log CFU/Lung: 6.24
and Log CFU/Spleen: 5.42), 17a (Log CFU/Lung: 4.11 and Log CFU/
Spleen: 5.36), 17e (Log CFU/Lung: 2.65 and Log CFU/Spleen: 3.25)
and 17n (Log CFU/Lung: 4.61 and Log CFU/Spleen: 6.32) (at a dose of
25 mg/kg) were found to be promising in reducing of bacterial
count in lung and spleen tissues, which were comparable to or
better than INH (Log CFU/Lung: 4.62 and Log CFU/Spleen: 5.45) and
RIF (Log CFU/Lung: 3.21 and Log CFU/Spleen: 3.98) (at a dose of
25 mg/kg). The benzofuran-pyrazoline-indophenazine hybrids 18
(MIC90: 0.42e15.4 mg/mL) also showed considerable in vitro anti-
mycobacterial activities against MTB H37Rv and MDR-TB strains,
and were more active than gatifloxacin (MIC90: 28.46 mg/mL)
against MDR-TB [41]. Hybrid 18j (MIC90: 0.42 mg/mL) was as potent
as gatifloxacin (MIC90: 0.50 mg/mL) against MTB H37Rv, and was 4.8
folds more active than RIF (MIC90: 2.0 mg/mL). Hybrid 18e (MIC90:
2.0 mg/mL) was 3.6 and 14.23 times more active than gatifloxacin
and RIF (MIC90: 7.37 mg/mL) against MDR-TB. Both 18e and 18j
270 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
contained eNO2 at the phenyl ring, suggesting eNO2 was favorable
to the activity.
All benzofuran-isatin hybrids 19 tethered via triazole with
acceptable cytotoxicity (CC50: 128->1024 mg/mL) in VERO cells
exhibited considerable anti-mycobacterial activities (MIC:
0.25e8 mg/mL) against MTB H37Rv and MDR-TB strains [42]. The
SAR demonstrated that substituents at both C-3 and C-5 position of
isatin moiety have significant influence on their anti-mycobacterial
activities. For C-3 position, hydrogen-bond donors such as
NNHCSNH2 and NOH were favorable to the activity, and the relative
contribution of the substituents to the activity was
NNHCSNH2 > NOH > NOMe > NOEt > O, indicating replacement of
ketone with imine could improve the activity. Electron-donating
-OMe at C-5 position could enhance the activity when compared
with eH and eBr. Hybrid 19h (MIC: 0.25 and 0.5 mg/mL) was found
to be the most active against MTB H37Rv and MDR-TB strains, and
was 128- and >256-fold more effective than the RIF and INH (MIC:
64 and > 128 mg/mL, respectively) against MDR-TB, and 2 times
more active than RIF (MIC: 0.5 mg/mL) against MTB H37Rv. It is
worth mentioning that the resistance index (RI, MIC(MDR-TB)/
MIC(MTB H37Rv)) values for the hybrids were around 1, suggesting
that these hybrids may bear novel mechanism of action against TB.
However, compared with the parent TAM16 (t1/2: >60 min), hybrid
19h showed much lower metabolic stability (t1/2: 28.9 min). Phar-
macokinetic investigation displayed that hybrid 19h was inferior to
TAM16 in term of Cmax (389 ng/mL vs 5064 ng/mL), t1/2 (4.26 h vs
9.88 h), Tmax (1.24 h vs 3.46 h) and AUC0-inf (2564 ngh/mL vs
39,329 ngh/mL). All benzofuran-isatin hybrids 20 only showed
weak activity against MTB H37Rv DNA gyrase with IC50 ranging
form 50 to >200 mM, still need to be optimized [43].
In MTB, polyketide synthase 13 (Pks13) performs the final as-
sembly step of mycolic acid synthesis, so it is the potential target for
novel anti-TB agents [44]. Twenty-four benzofuran derivatives 21
(Fig. 5) were screened for their in vitro activities against Pks13 and
MTB strains [45]. The majority of them showed great potency
against Pks13 C-terminal thioesterase domain and MTB mc27000
with IC50 < 1 mg/mL and MIC<5 mM, respectively. TAM16 (IC50:
Fig. 5. Chemical structures of benzofuran derivatives 21e28.
0.19 mg/mL and MIC: 0.09 mM) was found to be most active against
Pks13 C-terminal thioesterase domain and MTB mc27000, and the
resistant mutants emerged at frequencies was ~100-fold lower than
that of INH [45,46]. TAM16 also highly active against 38 drug-
sensitive strains and clinical isolates including fully susceptible,
SM mono-resistant, RIF mono-resistant, INH mono-resistant, MDR,
XDR and poly-resistant clinical isolates representing a wide range
of mutations covering all known molecular mechanisms, and the
MIC90 values were in a range of 0.050e0.420 mM. The above results
suggested TAM16 has no cross-resistance with the first- and
second-line anti-TB agents, so it may bear a novel action mecha-
nism. TAM16 showed no synergistic activity with INH and EMB, but
the combination of TAM16 with RIF showed highly synergistic
activity which may due to the increment of permeability of the
bacterial cell wall leading to enhanced RIF accumulation. TAM16
has excellent physicochemical, toxicological, and pharmacological
properties, and was well tolerated in BALB/c mice model at up to
300 mg/kg administered orally once daily for 3 days. In acute TB
mouse model, TAM16 (200 mg/kg) showed a significant reduction
in the lung CFU to around 6.8 log10, which was comparable to INH
(10 mg/kg, reduction in the lung CFU to around 6.7 log10). In a
chronic TB infection mice model, TAM16 (300 mg/kg) was also as
effective as INH (25 mg/kg) in reduction of lung and spleen CFU by
0.9 vs. 1.1 and 2.2 vs. 2.5 log10, respectively. Moreover, the combined
application of TAM16 and RIF in the chronic infection model was as
potent as the gold-standard combination of INH and RIF at
reducing the bacterial load, and was more active than RIF alone.
Overall, TAM16 demonstrated excellent in vitro and in vivo anti-TB
activities, and physicochemical, toxicological, and pharmacological
properties, highlighted its potential for further pre-clinical
development.
All TAM16 lactone derivatives 22 (Fig. 5) showed promising
activities against MTB H37Rv with MIC of 0.125e4 mg/mL, and the
SAR revealed that introduction of either electron-donating -OMe
and -Me or electron-withdrawing eF and eBr at the phenyl ring led
to loss of activity [47]. The most active compounds 22a,b (MIC:
0.125e0.25 mg/mL) also showed low cytotoxicity towards MRC-5,
 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
HFL-1, QSG-7701 and HEK-293 cells with IC50
38.8 mg/mL. Further
study confirmed a single nucleotide polymorphism in the pks13
gene responsible for the resistance phenotype, demonstrating the
drug-ability of this target for the development of new anti-TB
agents.
The benzofuran derivatives 23 and their thio analogs 24 (Fig. 5)
displayed moderate activities against MTB with MIC values ranging
from 4.24 to 92.62 mM, and compounds 23 were as effective as 24
generally [48,49]. The most active compound 23f (MIC: 4.24 mM)
was comparable to ofloxacin (MIC: 2.16 mM), but was less active
than INH and RIF (MIC: 0.66 and 0.23 mM). The benzofuran de-
rivatives 25 (MIC>50 mg/mL) were inactive against both replicating
and non-replicating MTB strains, while compound 26 exhibited
some activity against MTB H37Ra [50,51]. The MIC for compound 27
against MTB H37Rv was 6.25 mg/mL, and was comparable to these of
PZA, SM and ciprofloxacin (MIC: 3.125, 6.25 and 3.125 mg/mL,
respectively) [52].
The benzufuran-3-carbohydrazide derivatives 28 displayed
weak to moderate activities against MTB H37Rv, and MIC values
were ranging from 2.0 to 128.0 mg/mL [53]. The SAR indicated that
the introduction of either electron-withdrawing or electron-
donating groups at phenyl ring was detrimental to the activity.
The eCl substituted derivatives 28k-t were as potent as unsub-
stituted analogs 28a-j, and the most active compounds 28a and 28k
(MIC: 2.0 mg/mL) were far more potent than the rest derivatives
(MIC: 32.0e128.0 mg/mL), but were less active than INH (MIC:
0.25 mg/mL). Several other benzofuran derivatives also endowed
with some anti-TB activities, still need to be modified [54,55].
3. Anti-bacterial activity
Due to the emergency and widely spread of bacterial resistance,
development of new antibiotics is very important for public health
globally [56]. Eight benzofuran-pyrazole hybrids 29 (Fig. 6) were
evaluated for their in vitro antimicrobial activities against Gram-
positive Bacillus subtilis (B. subtilis) and Saphylococcus aureus
(S. aureus), as well as Gram-negative Escherichia coli (E. coli) and
Proteus vulgaris (P. vulgaris) pathogens by Ashok et al., and all hy-
brids showed moderate activity with MIC of 1.6e100.0 mg/mL [57].
The SAR indicated that introduction of electron-donating -OMe on
the phenyl ring could enhance the activity, while halogen atoms
eCl and eBr were disfavored. The bis-OMe substituted hybrid 29g
(MIC: 1.6e3.1 mg/mL) was more potent than the corresponding
mono-OMe substituted 29e (MIC: 3.1e6.3 mg/mL), while replace-
ment of -OMe at para-position of phenyl ring by -OEt (29f, MIC:
6.3e25.0 mg/mL) led to loss of activity. Among them, the most
active hybrid 29g was comparable to gentamicin (MIC: 1.6e3.1 mg/
mL) against both Gram-positive and Gram-negative pathogens. The
quinoline-containing benzofuran-pyrazole hybrids 30a,b (inhibi-
tion zone: 12e14 mm at 250 mg/mL) exhibited moderate activities
against the tested S. aureus and E. coli, and were comparable to
chloramphenicol (inhibition zone: 17 mm at 250 mg/mL) against
E. coli, but were less potent than chloramphenicol (inhibition zone:
27 mm at 250 mg/mL) against S. aureus [58].
The SAR for benzofuran-3(2H)-one-pyrazole hybrids 31 (inhi-
bition zone: 3e33 mm at 50 mg/mL) against B. subtilis, S. aureus,
E. coli and Pseudomonas aeruginosa (P. aeruginosa) indicated that
introduction of eCl at C-6 position and -Me at C-7 position
increased the anti-bacterial activity, while incorporation of either
electron-withdrawing halogen atoms eF, eCl eBr or electron-
donating -Me at C-5 position reduced the activity [59]. Hybrid
31h with inhibition zone of 13e33 mm was slightly more potent
than ampicillin (inhibition zone: 10e30 mm) against all tested or-
ganisms. The benzofuran-pyrazole hybrids 32, 33 and benzofuran-
isoxazole hybrids 34 showed potential anti-bacterial activities
271
against B. subtilis, S. aureus, E. coli and P. aeruginosa with inhibition
zone of 9e30 mm at the concentration of 1 mg/mL, and some of
them were comparable to the reference chloramphenicol (inhibi-
tion zone: 21e32 mm) [60,61]. The SAR indicated that for hybrids
32, replacement of methyl ester with hydrazide (33) [61] or intro-
duction of eCN (35) [62] on pyrazole ring resulted in a slightly loss
of activity. Benzofuran-isoxazole hybrids 34 were as potent as the
corresponding benzofuran-pyrazole hybrids 32, and introduction
of formamide into R1 position for hybrids 32 couldn't increase the
activity [60]. In particular, the most active hybrid 32d (inhibition
zone: 19e30 mm) was no inferior to chloramphenicol against all
tested strains. The benzofuran-pyrazole hybrids 36 except 36d
bearing pyrimidine fragment were inactive against E. coli and
P. aeruginosa, and the most active conjugate 36d (inhibition zone:
9e18 mm at 5 mg/mL) was less potent than ciprofloxacin (inhibition
zone: 25e28 mm at 5 mg/mL) [63].
The benzofuran-benzoxazole hybrids 37 (MIC: 15.625e500 mg/
mL) displayed weak to moderate anti-bacterial activities against a
panel of pathogens including 5 clinical isolates, and were far less
active than the references gentamicin, RIF and ofloxacin (MIC:
0.06e1.9 mg/mL) against the majority of organisms [64]. The SAR
showed that the anti-bacterial activity of hybrids with (substituted)
benzyl at benzoxazole motif was equal to that of (substituted)
phenyl analogs, and installation of either electron-withdrawing
halogen atoms eF, eCl, eBr or electron-donating -Me, -Et and t-
Bu at phenyl ring seems has no significantly influence on the
activity.
The benzofuran-imidazothiazole hybrids 38 and 39 (Fig. 6)
exhibited weak to moderate anti-bacterial activities against
S. aureus, Klbesilla pneumona (K. pneumona), P. aeruginosa and
E. coli, and inhibition zone was 6e23 mm at 1 mg/mL [65,66]. The
anti-bacterial activity of hybrids 38 was similar to 39, suggesting
incorporation of the second benzofuran motif couldn't enhance the
activity. The most active conjugate 38b (inhibition zone:
15e20 mm at 1 mg/mL) was slightly less active than the reference
ampicillin (inhibition zone: 20e28 mm at 1 mg/mL). The
benzofuran-imidazolium hybrids 40 [67,68] and benzofuran-
thiazole 41 [69] were inactive against the tested Gram-negative
and the majority of the tested Gram-positive strains, and were far
less potent than the reference ciprofloxacin.
The benzofuran-oxazole hybrids 42 showed great potency
against Gram-positive S. aureus, B. subtilis, and Methicillin-resistant
S. aureus (MRSA), the Gram-negative bacteria E. coli and
P. aeruginosa with MIC of 0.78e6.25 mg/mL [70]. Interestingly, the
hybrids displayed equal activity against S. aureus and MRSA, sug-
gesting their potential for the treatment of infections caused by
drug-resistant pathogens. Hybrids 42b,c (MIC: 0.78e3.12 mg/mL)
were comparable to or better than the references cefradine, cefta-
zidime, cefotaxime and sodium penicillin (MIC: <0.39->200 mg/
mL) against all tested strains, so they could act as starting points for
further investigation.
The SAR of benzofuran-isatin hybrids 43 (Fig. 7) indicated that
compared with unsubstituted hybrid 43a (MIC: 250e500 mg/mL),
hybrids with electron-withdrawing groups eF, eCl, eBr and eNO2,
showed much higher anti-bacterial activities (MIC: 31.25e250 mg/
mL), and substituents at C-7 position were more favorable than at
C-5 position [71]. All hybrids were less potent than ampicillin (MIC:
0.48, 3.90, 3.90 and 3.90 mg/mL) against S. aureus, B. subtilis, E. coli
and P. vulgaris, but conjugates 43o,p (MIC: 31.25 mg/mL) were 2-
fold more active than norfloxacin (MIC: 62.50 mg/mL) against
P. vulgaris. For benzofuran-indole hybrids 44, the hybrids with 4-
BrPh at R2 position were more potent than the corresponding t-
Bu analogs [72]. Introduction of halogen atoms eF, eCl and eBr at
C-5 position was favorable to the anti-bacterial activity, while -Me
at C-6 position disfavored. Hybrid 44d (MIC: 3.125e6.25 mg/mL)
272 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276

Fig. 6. Chemical structures of benzofuran-azole hybrids 29e42.

was comparable to gentamicin (MIC: 1.625e3.125 mg/mL) against
S. aureus, B. subtilis, E. coli and P. vulgaris, worth to be further
investigated. The benzofuran-pyridine hybrids such as 45a,b (in-
hibition zone: 7.4e23.2 mm at 10 mg/mL) also demonstrated po-
tential anti-bacterial activities, but were far less active than the
references [73,74].
All benzofuran-pyrimidine hybrids 46 (Fig. 7) displayed poten-
tial anti-bacterial activities against B. subtilis, E. coli and
P. aeruginosa with MIC ranging from 4.32 to 18.45 mg/mL, and were
more potent than streptomycin (MIC: 17.25e19.37 mg/mL) [75]. The
SAR indicated that eNH2 at pyrimidine fragment (R) preferred, and
eNH2 > eOH > eSH. Introduction of -Me at R1 position or eBr at R2
 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
Fig. 7. Chemical structures of other N-containing and O-containing heterocycle-benzofuran hybrids 43e51.
position could not improve the anti-bacterial activity apparently.
Replacement of pyrimidine motif with barbitone (47) or thio-
barbitone (48) led to loss of activity [76]. The most active conjugate
46j (MIC: 4.32e6.32 mg/mL) was >3-fold more potent than strep-
tomycin against all tested pathogens, so it can serve as a new
building block for synthesis and design of broad spectrum anti-
microbial compounds.
The norfloxacin-benzofuran hybrid 49 with inhibition zone of
8.35e11.16 mm at 50 mg/mL against X. oryzae, X. axonopodis,
E. aroideae, B. subtilis and R. solanacearum was far more potent
than streptomycin (inhibition zone: 0.20e0.81 mm at 50 mg/mL)
against X. oryzae, X. axonopodis and E. aroideae [77]. However, it
was less active than the parent norfloxacin (inhibition zone:
17.74e30.49 mm at 50 mg/mL) against all tested organisms.
The O-containing heterocycle-benzofuran hybrids such as
benzofuran-coumarin hybrids 50 and 51 showed promising anti-
bacterial activities, and some of them were more potent than
the references [78e80]. For benzofuran-coumarin hybrids 51, the
majority of them (MIC: 0.2e1.6 mg/mL) were highly active against
Gram-positive S. aureus and B. subtilis, and were more potent than
ciprofloxacin (MIC: 2 mg/mL) [80]. However, all of them (MIC:
6.25e100 mg/mL) except 51a were less active than ciprofloxacin
(MIC: <4 mg/mL) against Gram-negative bacteria. The most active
compound 51a with MIC of 0.2, 0.4 and 0.2 mg/mL against
S. aureus, B. subtilis and E. coli was
5 folds more potent than
ciprofloxacin.
The benzofuran derivatives 52 (Fig. 8) with inhibition zone of
11e28 mm at 100 mg/mL against S. aureus, S. pyogenes, E. coli and
P. aeruginosa were no inferior to ciprofloxacin (inhibition zone:
21e28 mm at 100 mg/mL) [81]. The SAR indicated that compounds
with sulfamide were more potent than acetamide and benzamide
analogs. For sulfamide-containing derivatives, electron-donating
273
-Me and -OMe groups at phenyl ring were more favorable than
the electron-withdrawing eCl. Derivative with thienyl group was
slightly more active than the corresponding phenyl analog. The
most potent compounds 52b,f (inhibition zone: 19e28 mm at
100 mg/mL) were found to be comparable to ciprofloxacin against
all tested strains. Further modification generated benfuran de-
rivatives 53 and 54, and all of them showed potential anti-
bacterial activities [82,83]. The anti-bacterial activity of 53 (inhi-
bition zone: 21e27 mm at 25 mg/mL) was slightly higher than
norfloxacin (inhibition zone: 19e25 mm at 25 mg/mL) against the
tested S. aureus, S. pyogenes, E. coli and P. aeruginosa organisms
[82]. The SAR of benzofuran-chalcone hybrids 54 revealed that
introduction of fluorine-containing functional groups eF (54l),
eCF3 (54m), and eCF3 (54n) or benzofuran (54o) was favorable to
the anti-bacterial activity [83]. The number of -OMe also has some
influence on the activity, and hybrids with more -OMe displayed
higher activity. Hybrid 54o (inhibition zone: 21e28 mm at 25 mg/
mL) was found to be most active against S. aureus, S. pyogenes,
E. coli and P. aeruginosa, and was more potent than the reference
norfloxacin (inhibition zone: 19e25 mm at 25 mg/mL) against all
tested pathogens.
A new type of benzofuran-derived diapophytoene desaturases
(CrtN) inhibitors based on the naftifine scaffold were screened for
their anti-bacterial activities and the most potent compound 55a
(Fig. 8) could inhibit the pigment production of S. aureus Newman
and three MRSA strains with IC50 values of 0.38e5.45 nM [84].
Notably, compound 55a (1 mM) could significantly sensitize the
tested four strains to immune clearance and could effectively
attenuate the virulence of three strains in vivo. In addition, com-
pound 55a also showed good oral bioavailability (F ¼ 42.2%) and
excellent safety profiles. Further modification indicated that the
compound 55b (IC50: 0.02e10.5 nM) showed promising inhibitory
274 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
Fig. 8. Chemical structures of benzofuran derivatives 52e57.
activity against the pigment production of S. aureus Newman and
thritten-three MRSA strains [85]. The pigment inhibitory activity
of 55b against additional nine MRSA strains was at the same level
to the Newman strain, which demonstrated that 55b had a broad
spectrum bactericidal effect. In the in vivo assay, compound 55b
was proven efficacious in the S. aureus Newman and multi-drug
resistant MRSA (Mu50 and NRS271) model, and treatment with
0.1 mg b.i.d./3.5 d (35 mg/kg in total) in the normal treatment
group was preferred. All compound 55b treatment groups
significantly decreased Mu50 (vancomycin-intermediate
S. aureus/VRSA and MRSA) loads in hearts and kidneys, which was
compared with the efficacy of the positive groups, vancomycin
and linezolid. In NRS271 (linezolid-reisitant S. aureus/LRSA and
MRSA) infected model, 55b strongly decreased the NRS271 loads
in kidneys and hearts (>99% reduction), which was also compa-
rable with the positive control groups. Compound 55b showed no
inhibitory activity on CYP enzymatic, and is characterized by an
acceptable half-life (t1/2: 2.5, 1.3 and 7.6 h for i.v., p.o. and i.p.
respectively), high volume of distribution and low clearance, and
had 16.3% orally bioavailability in rat and 83.8% orally bioavail-
ability in mice. It is worth to notice that compound 55b was not
easy to induce the resistance development, and the frequency of
mutant was <1  105. Overall, compound 55b has the potential
to be developed as therapeutic drugs, especially against intrac-
table MRSA (VISA and LRSA) issues, by blocking virulence, and this
class of antibiotics holds great promise in treatment of infections
by difficult human pathogens.
Some other benzofuran derivatives such as 56 (MIC:
0.78e1.56 mg/mL) and 57 (Fig. 8) also exhibited anti-bacterial po-
tential against Gram-positive and Gram-negative bacteria,
including drug-resistant pathogens such as MRSA [86e101]. The
majority of them were far less active than the references, but the
enriched SAR may pave the way for the further development of
benzofuran derivatives.
4. Conclusion
Benzofuran derivatives possess a broad spectrum of chemo-
therapeutic properties, and some of benzofuran-based compounds
have already used in clinics for the treatment of various diseases, so
benzofuran derivatives occupy an important position in the
development of new drugs.
This review covers the recent advances of benzofuran de-
rivatives as potential anti-TB and anti-bacterial agents. Some
benzofuran derivatives which are exemplified by TAM16 showed
excellent in vitro and in vivo anti-TB activities against both drug-
sensitive and drug-resistant MTB isolates including MDR, XDR
and poly-resistant MTB clinical isolates. TAM16 has no cross-
resistant with the first- and second-line anti-TB agents, and dis-
played excellent physicochemical, toxicological, and pharmaco-
logical properties. Compound 55b exhibited promising in vitro and
in vivo potency against a panel of S. aureus including drug-resistant
clinical isolates, and was not easy to induce the resistance devel-
opment. Thus, both of them could act as ideal starting points for
further investigations.
The SAR is also discussed in this review, and the enriched SAR
may pave the avenue for the further development of benzofuran
derivatives as anti-TB and anti-bacterial agents.
References
[1] Y.Q. Hu, S. Zhang, Z. Xu, Z.S. Lv, M.L. Liu, L.S. Feng, 4-Quinolone hybrids and
their antibacterial activities, Eur. J. Med. Chem. 141 (2017) 335e345.
[2] F. Gao, P. Wang, H. Yang, Q. Miao, L. Ma, G.M. Lu, Recent developments of
quinolone-based derivatives and their activities against Escherichia coli, Eur.
J. Med. Chem. 157 (2018) 1223e1248.
[3] C. Gao, Y.L. Fan, F. Zhao, Q.C. Ren, X. Wu, L. Chang, F. Gao, Quinolone de-
rivatives and their activities against methicillin-resistant Staphylococcus
aureus (MRSA), Eur. J. Med. Chem. 157 (2018) 1081e1095.
[4] M. Dinakaran, P. Senthilkumar, P. Yogeeswari, A. China, V. Nagaraja,
D. Sriram, Antimycobacterial activities of novel 2-(sub)-3-fluoro/nitro-5,12-
 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
dihydro-5-oxobenzothiazolo[3,2-a]quinoline-6-carboxylic acid, Bioorg. Med.
Chem. 16 (2008) 3408e3418.
[5] S. Zhang, Z. Xu, C. Gao, Q.C. Ren, L. Chang, Z.S. Lv, L.S. Feng, Triazole de-
rivatives and their anti-tubercular activity, Eur. J. Med. Chem. 138 (2017)
501e513.
[6] Y.L. Fan, X.H. Jin, Z.P. Huang, H.F. Yu, Z.G. Zeng, T. Gao, L.S. Feng, Recent
advances of imidazole-containing derivatives as anti-tubercular activity, Eur.
J. Med. Chem. 150 (2018) 347e365.
[7] World Health Organization, Global Tuberculosis Report 2018, 2018, pp. 1e4.
[8] Z. Xu, C. Gao, Q.C. Ren, X.F. Song, L.S. Feng, Z.S. Lv, Recent advances of
pyrazole-containing derivatives as anti-tubercular agents, Eur. J. Med. Chem.
139 (2017) 429e440.
[9] A. Radadiya, A. Shah, Bioactive benzofuran derivatives: an insight on lead
developments, radioligans and advances of the last decade, Eur. J. Med.
Chem. 97 (2015) 356e376.
[10] K.M. Dawood, Benzofuran derivatives: a patent review, Expert Opin. Ther.
Pat. 23 (2013) 1133e1156.
[11] I.N. Gaisina, F. Gallier, A.V. Ougolkov, K.H. Kim, T. Kurome, S. Guo, D. Holzle,
D.N. Luchini, S.Y. Blond, D.D. Billadeau, A.P. Kozikowski, From a natural
product lead to the identification of potent and selective benzofuran-3-yl-
(indol-3-yl)maleimides as glycogen synthase kinase 3b inhibitors that sup-
press proliferation and survival of pancreatic cancer cells, J. Med. Chem. 52
(2009) 1853e1863.
[12] R. Naik, D.S. Harmalkar, X.Z. Xu, K. Jang, K. Lee, Bioactive benzofuran de-
rivatives: moracins A-Z in medicinal chemistry, Eur. J. Med. Chem. 97 (2015)
379e393.
[13] M. Zhong, E. Peng, N. Huang, Q. Huang, A. Quq, M. Lau, R. Colonno, L. Li,
Discovery of novel potent HCV NS5B polymerase non-nucleoside inhibitors
bearing a fused benzofuran scaffold, Bioorg. Med. Chem. Lett 28 (2018)
963e968.
[14] S.A. Galal, A.S.A. El-All, M.M. Abdallah, H.I. El-Diwani, Synthesis of potent
antitumor and antiviral benzofuran derivatives, Bioorg. Med. Chem. Lett 19
(2009) 2420e2428.
[15] A. Hiremathad, K. Chand, L. Tolayan, Rajeshwari, R.S. Keri, A.R. Esteves,
S.M. Cardoso, S. Chaves, M.A. Santos, Hydroxypyridinone-benzofuran hybrids
with potential protective roles for Alzheimer's disease therapy, J. Inorg.
Biochem. 179 (2018) 82e96.
[16] G. Deepti, K. Amandeep, G. Bhupesh, Benzofuran and indole: Promising
Scaffolds for drug development in Alzheimer's disease, ChemMedChem 13
(2018) 1275e1299.
[17] T. Marion, T. Sylviane, G. Philippe, D. Joelle, Synthesis of polysubstituted
benzofuran derivatives as novel inhibitors of parasitic growth, Bioorg. Med.
Chem. 21 (2013) 4885e4892.
[18] H. Khanam, S. Uzzaman, Bioactive benzofuran derivatives: a review, Eur. J.
Med. Chem. 97 (2015) 483e504.
[19] B. Sangeeta, R. Deepti, Synthetic routes and biological activities of benzo-
furan and its derivatives: a review, Lett. Org. Chem. 14 (2017) 381e402.
[20] R.J. Nevagi, S.N. Dighe, S.N. Dighe, Biological and medicinal significance of
benzofuran, Eur. J. Med. Chem. 97 (2015) 561e581.
[21] A. Hiremathad, M.R. Patil, K. Chand, M.A. Santos, R.S. Keri, Benzofuran: an
emerging scaffold for antimicrobial agents, RSC Adv. 5 (2015) 96809e96828.
[22] S.O. Simonetti, E.L. Larghi, A.B.J. Bracca, T.S. Kaufman, Angular tricyclic ben-
zofurans and related natural products of fungal origin. Isolation, biological
activity and synthesis, Nat. Prod. Rep. 30 (2013) 941e969.
[23] S. Prado, H. Ledeit, S. Michel, M. Koch, J.C. Darbord, S.T. Cole, F. Tillequin,
P. Brodin, Benzofuro[3,2-f][1]benzopyrans: a new class of antitubercular
agents, Bioorg. Med. Chem. 14 (2006) 5423e5428.
[24] S. Prado, Y.L. Janin, B. Saint-Joanis, P. Brodin, S. Michel, M. Koch, S.T. Cole,
F. Tillequin, P.E. Bost, Synthesis and antimycobacterial evaluation of benzo-
furobenzopyran analogues, Bioorg. Med. Chem. 15 (2007) 2177e2186.
[25] L. Alvey, S. Prado, V. Huteau, B. Saint-Joanis, S. Michel, M. Koch, S.T. Cole,
F. Tillequin, Y.L. Janin, A new synthetic access to fluoro[3,2-f]chromene an-
alogues of an antimycobacterial, Bioorg. Med. Chem. 16 (2008) 8264e8272.
[26] A. Termentzi, I. Khouri, T. Gaslonde, S. Prado, B. Saint-Joanis, F. Bardou,
E.P. Amanatiadou, I.S. Viziranakis, J. Kordulakova, M. Jackson, R. Brosch,
Y.L. Janin, M. Daffe, F. Tillequin, S. Michel, Synthesis, biological activity, and
evaluation of the mode of action of novel antitubercular benzofur-
obenzopyrans substituted on A ring, Eur. J. Med. Chem. 45 (2010)
5833e5847.
[27] S. Prado, V. Toum, B. Saint-Joanis, S. Michel, M. Koch, S.T. Cole, F. Tillequin,
Y.L. Janin, Antimycobacterial benzofuro[3,2-f]chromenes from a 5-
bromochromen-6-ol, Synthesis 10 (2007) 1566e1570.
[28] T. Yempala, J.P. Sridevi, P. Yogeeswari, D. Sriram, S. Kantevari, Design, syn-
thesis and antitubercular evaluation of novel 2-substituted-3H-benzofuro
benzofurans via palladium-copper catalysed Sonagashira coupling reaction,
Bioorg. Med. Chem. Lett 23 (2013) 5393e5396.
[29] S. Kantevari, T. Yempala, P. Yogeeswari, D. Sriram, B. Sridhar, Synthesis and
antitubercular evaluation of amidoalkyl dibenzofuranols and 1H-benzo[2,3]
benzofuro[4,5-e][1,3]oxazin-3(2H)-ones, Bioorg. Med. Chem. Lett 21 (2011)
4316e4319.
[30] T. Yempala, D. Sriram, P. Yogeeswari, S. Kantevari, Molecular hybridization of
bioactives: synthesis and antitubercular evaluation of novel dibenzofuran
embodied homoisoflavonoids via Baylis-Hillman reaction, Bioorg. Med.
Chem. Lett 22 (2012) 7426e7430.
[31] S. Kantevari, T. Yempala, G. Surineni, B. Sridhar, P. Yogeeswari, D. Sriram,
275
Synthesis and antitubercular evaluation of novel dibenzo[b,d]furan and 9-
methyl-9H-carbazole derived hexahydro-2H-pyrano[3,2-c]quinolines via
Povarov reaction, Eur. J. Med. Chem. 46 (2011) 4827e4833.
[32] Y. Izumizono, S. Arevalo, Y. Koseki, M. Kuroki, S. Aoki, Identification of novel
potential antibiotics for tuberculosis by in silico structure-based drug
screening, Eur. J. Med. Chem. 46 (2011) 1849e1856.
[33] S.R. Patpi, L. Pulipati, P. Yogeeswari, D. Sriram, N. Jain, B. Sridhar, R. Murthy,
A. Devi, S.V. Kalivendi, S. Kantevari, Design, Synthesis, and structure-activity
correlations of novel dibenzo[b,d]furan, dibenzo[b,d]thiophene, and N-
methylcarbazole clubbed 1,2,3-triazoles as potent inhibitors of Mycobacte-
rium tuberculosis, J. Med. Chem. 55 (2012) 3911e3922.
[34] B. Zhou, Y. He, X. Zhang, J. Xu, Y. Luo, Y. Wang, S.G. Franzblau, Z. Yang,
R.J. Chan, Y. Liu, J. Zheng, Z.Y. Zhang, Targeting mycobacterium protein
tyrosine phosphatase B for antituberculosis agents, Proc. Natl. Acad. Sci.
U.S.A. 107 (2010) 4573e4578.
[35] Y. Tao, L.F. Zeng, Z.H. Yu, R. He, S. Li, Z.Y. Zhang, Bicyclic benzofuran and
indole-based salicylic acids as protein tyrosine phosphatase inhibitors, Bio-
org. Med. Chem. 20 (2012) 1940e1946.
[36] S. Haftchenary, D.P. Ball, I. Aubry, M. Landry, V.M. Shahani, S. Fletcher,
B.D.G. Page, A.O. Jouk, M.L. Tremblay, P.T. Gunning, Identification of a potent
salicylic acid-based inhibitor of tyrosine phosphatase PTP1B, MedChem-
Comm 4 (2013) 987e992.
[37] P. Kamsri, A. Punkvang, S. Hannongbua, P. Saparpakorn, P. Pungpo, Structural
requirements of benzofuran pyrrolidine 1 pyrazole derivatives as highly
potent anti-tuberculosis agents for good correlation of IC50-MIC based on
integrated results from 3D-QSAR and MD simulations, RSC Adv. 5 (2015)
52926e52937.
[38] L. Encinas, H. O'Keefe, M. Neu, M.J. Remuinan, A.M. Patel, A. Guardia,
C.P. Davie, N. Perez-Macias, H. Yang, M.A. Convery, J.A. Messer, E. Perez-
Herran, P.A. Centrella, D. Alvarez-Gomez, M.A. Clark, S. Huss, G.K. O'Donovan,
F. Ortega-Muro, W. McDowell, P. Castaneda, C.C. Arico-Muendel, S. Pajk,
J. Rullas, I. Angulo-Barturen, E. Alvarez-Ruiz, A. Mendoza-Losana, L.B. Pages,
J. Castro-Pichel, G. Evindar, Encoded library technology as a source of hits for
the discovery and lead optimization of a potent and selective class of
bactericidal direct inhibitors of Mycobacterium tuberculosis InhA, J. Med.
Chem. 57 (2014) 1276e1288.
[39] A. Trapero, A. Pacitto, V. Singh, M. Sabbah, A.G. Coyne, V. Mizrahi,
T.L. Blundell, D.B. Ascher, C. Abell, A fragment-based approach to targeting
inosine-5’-monophosphate dehydrogenase (IMPDH) from mycobacterium
tuberculosis, J. Med. Chem. 61 (2018) 2806e2822.
[40] K. Manna, Y.K. Agrawal, Design, synthesis, and antitubercular evaluation of
novel series of 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-
benzofuran-5-aryl-1- pyrazolylcarbonyl-4-oxo-naphthyridin analogs, Eur. J.
Med. Chem. 45 (2010) 3831e3839.
[41] K. Manna, Y.K. Agrawal, Potent in vitro and in vivo antitubercular activity of
certain newly synthesized indophenazine 1,3,5-trisubstituted pyrazoline
derivatives bearing benzofuran, Med. Chem. Res. 20 (2011) 300e306.
[42] F. Gao, H. Yang, T. Lu, Z. Chen, L. Ma, Z. Xu, P. Schaffer, G. Lu, Design, synthesis
and anti-mycobacterial activity evaluation of benzofuran-isatin hybrids, Eur.
J. Med. Chem. 159 (2018) 277e281.
[43] T. Aboul-Fadl, H.A. Abdel-Aziz, M.K. Abdel-Hamid, T. Elsaman, J. Thanassi,
M.J. Pucci, Schiff bases of indoline-2,3-dione: potential novel inhibitors of
Mycobacterium Tuberculosis (Mtb) DNA gyrase, Molecules 16 (2011)
7864e7879.
[44] D. Portevin, C.D. Sousa-D’Auria, C. Houssin, C. Grimaldi, M. Chami, M. Daffe,
C. Guilhot, A polyketide synthase catalyzes the last condensation step of
mycolic acid biosynthesis in mycobacteria and related organisms, Proc. Natl.
Acad. Sci. U.S.A. 101 (2004) 314e319.
[45] A. Aggarwal, M.K. Parai, N. Shetty, D. Wallis, L. Woolhiser, C. Hastings,
N.K. Dutta, S. Galaviz, R.C. Dhakal, R. Shrestha, S. Wakabayashi, C. Walpole,
D. Matthews, D. Floyd, P. Scullion, J. Riley, O. Epemolu, S. Norval, T. Snavely,
G.T. Robertson, E.J. Rubin, T.R. Loerger, F.A. Sirgel, R. vam der Merwe, P.D. van
Helden, P. Keller, E.C. Bo € ttger, P.C. Karakousis, A.J. Lenaerts, J.C. Sacchettini,
Development of a novel lead that targets M. tuberculosis polyketide synthase
13, Cell 170 (2017) 249e259.
[46] J.N. Cruz, J.F.S. Costa, A.S. Khayat, K. Kuca, C.A.L. Barros, A.M.J.C. Neto, Mo-
lecular dynamics simulation and binding free energy studies of novel leads
belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis
polyketide synthase 13, J. Biomol. Struct. Dyn. 5 (2018) 1e8.
[47] W. Zhang, S. Lun, S.H. Wang, X.W. Jiang, F. Yang, J. Tang, A.L. Manson,
A.M. Earl, H. Gunosewoyo, W.R. Bishai, L.F. Yu, Identification of novel cou-
mestan derivatives as polyketide synthase 13 inhibitors against Mycobacte-
rium tuberculosis, J. Med. Chem. 61 (2018) 791e803.
[48] K.I. Reddy, K. Srihari, J. Renuka, K.S. Sree, A. Chuppala, V.U. Jeankumar,
J.P. Sridevi, K.S. Badu, P. Yogeeswari, D. Sriram, An efficient synthesis and
biological screening of benzofuran and benzo[d]isothiazole derivatives for
Mycobacterium tuberculosis DNA GyrB inhibition, Bioorg. Med. Chem. 22
(2014) 6552e6563.
[49] J. Renuka, K.I. Reddy, K. Srihari, V.U. Jeankumar, M. Shravan, J.P. Sridevi,
P. Yogeeswari, K.S. Babu, D. Sriram, Design, synthesis, biological evaluation of
substituted benzofurans as DNA gyrase B inhibitors of Mycobacterium
tuberculosis, Bioorg. Med. Chem. 22 (2014) 4924e4934.
[50] Z.J. Liu, X.Y. Guo, G. Liu, Modified calanolides incorporated with furan-2-nitro
mimics against Mycobacterium tuberculosis, Bioorg. Med. Chem. Lett 25
(2015) 1297e1300.
276 Z. Xu et al. / European Journal of Medicinal Chemistry 162 (2019) 266e276
[51] X.Y. Lu, J. Tang, Z.Y. Liu, M. Li, T. Zhang, X. Zhang, K. Ding, Discovery of new
chemical entities as potential leads against, Mycobacterium tuberculosis.
Bioorg. Med. Chem. Lett. 26 (2016) 5916e5919.
[52] B.R. Thorat, B. Nazirkar, V.B. Thorat, K. More, R. Jagtap, R. Yamgar, Synthesis,
SAR, molecular docking and antituberculosis study of 3-methyl-1-
benzofuran-2-carbohydrazide, Asian J. Chem. 28 (2016) 2346e2352.
[53] V.N. Telvekar, A. Belubbi, V.K. Bairwa, K. Satardekar, Novel N’-benzylidene
benzofuran-3-carbohydrazide derivatives as antitubercular and antifungal
agents, Bioorg. Med. Chem. Lett 22 (2012) 2343e2346.
[54] Y.T. He, J. Xu, Z.H. Yu, A.M. Gunawan, L. Wu, L. Wang, Z.Y. Zhang, Discovery
and evaluation of novel inhibitors of Mycobacterium protein tyrosine phos-
phatase B from the 6-hydroxy-benzofuran-5-carboxylic acid scaffold, J. Med.
Chem. 56 (2013) 832e842.
[55] D.G. Kokare, V. Kamat, K. Naik, A. Nevrekar, A. Kotian, V.K. Revankar, Eval-
uation of DNA cleavage, antimicrobial and anti-tubercular activities of
potentially active transition metal complexes derived from 2,6-
di(benzofuran-2-carbohydrazono)-4-methylphenol, J. Mol. Struct. 1127
(2017) 289e295.
[56] G. Khodarahmi, P. Asadi, F. Hassanzadeh, E. Khodarahmi, Benzofuran as a
promising scaffold for the synthesis of antimicrobial and antibreast cancer
agents: a review, J. Res. Med. Sci. 20 (2015) 1094e1104.
[57] D. Ashok, K. Rangu, S. Gundu, V.H. Rao, Synthesis of pyrazolylfuro[2,3-f]
chromenes and evaluation of their antimicrobial activity, Chem. Heterocycl.
Comp. 52 (2016) 928e933.
[58] M. Idrees, Y.G. Bodkhe, N.J. Siddiqui, Synthesis and antimicrobial assay of
some novel 4-thiazolidinone derivatives possessing benzofuran, quinoline
and pyrazole moieties, Asian J. Chem. 30 (2018) 2361e2364.
[59] D. Ashok, M. Ziauddin, B.V. Lakshmi, M. Sarasija, Microwave assisted syn-
thesis of substituted (Z)-2-{[1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl]
methylene}benzofuran-3(2H)-ones and their antimicrobial activity1, Russ. J.
Gen. Chem. 86 (2016) 1753e1757.
[60] N.J. Siddiqui, M. Idrees, Condensation-cyclodehydration of 2,4-
dioxobutanoates: synthesis of new esters of pyrazoles and isoxazoles and
their antimicrobial screening, Der Pharma Chem. 6 (2014) 406e410.
[61] N.J. Siddiqui, M. Idrees, N.T. Khati, M.G. Dhonde, Use of transesterified 1,3-
diketoesters in the synthesis of trisubstituted pyrazoles and their biolog-
ical screening, Bull. Chem. Soc. Ethiop. 27 (2013) 85e94.
[62] H.A. Abdel-Aziz, A.A.I. Mekawey, K.M. Dawood, Convenient synthesis and
antimicrobial evaluation of some novel 2-substituted-3-methylbenzofuran
derivatives, Eur. J. Med. Chem. 44 (2009) 3637e3644.
[63] E. Nassar, Y.A.M. El-Badry, H.E. Kazaz, Synthesis, In vivo anti-inflammatory,
and in vitro antimicrobial activity of new 5-benzofuranyl fused pyrimi-
dines, Chem. Pharm. Bull. 64 (2016) 558e563.
[64] S. Alper-Hayta, M. Arisoy, O. Temiz-Arpaci, I. Yildiz, E. Aki, S. Ozkan,
F. Kaynak, Synthesis, antimicrobial activity, pharmacophore analysis of some
new 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzox-
azoles, Eur. J. Med. Chem. 43 (2008) 2568e2578.
[65] S. Shankerrao, Y.D. Bodke, S. Santoshkumar, Synthesis and antimicrobial
activity of some imidazothiazole derivatives of benzofuran, Arab. J. Chem. 10
(2017) S554eS558.
[66] B. Shankar, P. Jalapathi, B. Saikrishna, S. Perugu, V. Manga, Synthesis, anti-
microbial activity, cytotoxicity of some novel substituted (5-(3-(1H-benzo
[d]imidazole-2-yl)-4-hydroxybenzyl)benzofuran-2-yl)(phenyl)methanone
analogs, Chem. Cent. J. 12 (2018) 1e17.
[67] P. Asadi, G. Khodarahmi, A. Jahanian-Najafabadi, L. Saghaie, F. Hassanzadeh,
Synthesis, characterization, molecular docking studies and biological evalu-
ation of some novel hybrids based on quinazolinone, benzofuran and imi-
dazolium moieties as potential cytotoxic and antimicrobial agents, Iran. J.
Basic Med. Sci. 20 (2017) 975e989.
[68] P. Asadi, G. Khodarahmi, A. Jahanian-Najafabadi, L. Saghaie, F. Hassanzadeh,
Biologically active heterocyclic hybrids based on quinazolinone, benzofuran
and imidazolium moieties: synthesis, characterization, cytotoxic and anti-
bacterial evaluation, Chem. Biodivers. 14 (2017), e1600411.
[69] B.F. Abdel-Wahab, H.A. Abdel-Aziz, E.M. Ahmed, Synthesis and antimicrobial
evaluation of 1-(benzofuran-2-yl)-4-nitro-3-arylbutan-1-ones and 3-
(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1H-pyr-
azoles, Eur. J. Med. Chem. 44 (2009) 2632e2635.
[70] J.B. Liu, F.Q. Jiang, X.Z. Jiang, W. Zhang, J.J. Liu, W.L. Liu, L. Fu, Synthesis and
antimicrobial evaluation of 3-methanone-6-substitutedbenzofuran de-
rivatives, Eur. J. Med. Chem. 54 (2012) 879e886.
[71] V. Ugale, H. Patel, B. Patel, S. Bari, Benzofurano-isatins: Search for antimi-
crobial agents, Arab. J. Chem. 10 (2017) S389eS396.
[72] D. Ashok, G. Srinivas, A.V. Kumar, D.M. Gandhi, Microwave-assisted synthesis
and evaluation of indole based benzofuran Scaffolds as antimicrobial and
antioxidant Agents1, Russ. J. Bioorg. Chem. 42 (2016) 560e566.
[73] R.E. Khidre, A.A. Abu-Hashem, M. El-Shazly, Synthesis and anti-microbial
activity of some 1-substituted amino-4,6-dimethyl-2-oxo-pyridine-3-
carbonitrile derivatives, Eur. J. Med. Chem. 46 (2011) 5057e5064.
[74] K. Gorlitzer, C. Kramer, C. Boyle, Synthesis and transformations of ethyl 1,4-
dihydro-4-oxo-[1]benzofuro[3,2-b]pyridine-3-carboxylate, new antibacte-
rial agents, Pharmazie 55 (2000) 651e658.
[75] T. Venkatesh, Y.D. Bodke, M.N. Joy, B.L. Dhananjaya, S. Venkataraman, Syn-
thesis of some benzofuran derivatives containing pyrimidine moiety as
potent antimicrobial agents, Iran. J. Pharm. Res. (IJPR) 17 (2018) 75e86.
[76] R. Kenchappa, Y.D. Bodke, B. Asha, S. Telkar, M.A. Sindhe, Synthesis, anti-
microbial, and antioxidant activity of benzofuran barbitone and benzofuran
thiobarbitone derivatives, Med. Chem. Res. 23 (2014) 3065e3081.
[77] Z. Yu, G. Shi, Q. Sun, H. Jin, Y. Teng, K. Tao, G. Zhou, W. Liu, F. Wen, T. Hou,
Design, synthesis and in vitro antibacterial/antifungal evaluation of novel 1-
ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)quinoline-3-carboxylic
acid derivatives, Eur. J. Med. Chem. 44 (2009) 4726e4733.
[78] S.S. El-Nakkady, H.F. Roaiah, W.S. El-Serwy, A.M. Soliman, S.I.A. El-Moez,
A.A. Abdel-Rahman, Anti-tumor and antimicrobial activities of some hetero
aromatic benzofurans derived from naturally occurring visnagin, Acta Pol.
Pharm-Drug Res. 69 (2012) 645e655.
[79] A.A. Al-Rifai, M.T. Ayoub, A.K. Shakya, K.A.A. Safieh, M.S. Mubarak, Synthesis,
characterization, and antimicrobial activity of some new coumarin de-
rivatives, Med. Chem. Res. 21 (2012) 468e476.
[80] B.M. Chougala, S.L. Shastri, M. Holiyachi, L.A. Shastri, S.S. More, K.V. Ramesh,
Synthesis, anti-microbial and anti-cancer evaluation study of 3-(3-
benzofuranyl)-coumarin derivatives, Med. Chem. Res. 24 (2015) 4128e4136.
[81] T. Venkateshwarlu, A.R. Nath, K.P. Chennapragada, Synthesis and antimi-
crobial activity of novel benzo[b]furan derivatives, Der Pharma Chem. 5
(2013) 229e234.
[82] V.K. Reddy, J.V. Rao, L.B. Reddy, B. Ram, B. Balram, Synthesis and antibacterial
activity of 7-methoxyl-2(2,4,6-trimethoxyphenyl)benzofuran-5-
carbohydrazide and its intermediates, Der Pharma Chem. 5 (2013) 237e342.
[83] V.K. Reddy, J.R. Venkateswara, R.L. Bhaskar, B. Ram, B. Balram, Synthesis of
chalcone derivatives of benzo[b]furan as potential antibacterial agents, In-
dian J. Chem. 54B (2015) 791e797.
[84] Y. Wang, F. Chen, H. Di, Y. Xu, Q. Xiao, X. Wang, H. Wei, Y. Lu, L. Zhang, J. Zhu,
C. Sheng, L. Lan, J. Li, Discovery of potent benzofuran-derived diapophytoene
desaturase (CrtN) inhibitors with enhanced oral bioavailability for the
treatment of methicillin-resistant staphylococcus aureus (MRSA) infections,
J. Med. Chem. 59 (2016) 3215e3230.
[85] B. Li, S.S. Ni, F. Mao, F. Chen, Y. Liu, H. Wei, W. Chen, J. Zhu, L. Lan, J. Li, Novel
terminal bipheny-based diapophytoene desaturases (CrtN) inhibitors as anti-
MRSA/VISR/LRSA agents with reduced hERG activity, J. Med. Chem. 61 (2018)
224e240.
[86] M.W. Khan, M.J. Alam, M.A. Rashid, R. Chowdhury, A new structural alter-
native in benzo[b]furan for antimicrobial activity, Bioorg. Med. Chem. 13
(2005) 4796e4805.
[87] P.T. Cherian, J. Yao, R. Leonardi, M.M. Maddox, V.A. Luna, C.O. Rock, R.E. Lee,
Acyl-sulfamates target the essential glycerol-phosphate acyltransferase
(PlsY) in Gram-positive bacteria, Bioorg. Med. Chem. 20 (2012) 4985e4994.
[88] K.N. Tiwari, J.P. Monserrat, A. Hequet, C. Ganem-Elbaz, T. Cresteil, G. Jaouen,
A. Vessieres, E.A. Hillard, C. Jplinalt, In vitro inhibitory properties of
ferrocene-substituted chalcones and aurones on bacterial and human cell
cultures, Dalton Trans. 41 (2012) 6451e6458.
[89] B. Kumar, B. Kumari, N. Singh, B. Ram, B. Balram, Synthesis, characterization
and antibacterial activity of some new chalcone derivatives, Der Pharma
Chem. 7 (2015) 286e291.
[90] H.A. Abdel-Aziz, A.A.I. Mekawey, Stereoselective synthesis and antimicrobial
activity of benzofuran-based (1E)-1-(piperidin-1-yl)-N2-arylamidrazones,
Eur. J. Med. Chem. 44 (2009) 4985e4997.
[91] B.F. Abdel-Wahab, R.E. Khidre, G.E.A. Awad, Regioselective synthesis and
antimicrobial activities of some novel aryloxyacetic acid derivatives, Eur. J.
Med. Chem. 50 (2012) 55e62.
[92] H. Tanaka, M. Hirata, H. Etoh, M. Sako, M. Sato, J. Murata, H. Murata,
D. Darnaedi, T. Fukai, Four new isoflavonoids and a new 2-arylbenzofuran
from the roots of Erythrina variegate, Heterocycles 60 (2003) 2767e2773.
[93] M. Deepthi, B.V. Harinadha, R.B. Madhava, Synthesis of some modified
aurones as antileukemic and antibacterial agents, Indian J. Chem. 52B (2013)
1455e1461.
[94] R. Kenchappa, Y.D. Bodke, S.K. Peethambar, S. Telkar, V.K. Bhovi, Synthesis of
b-amino carbonyl derivatives of coumarin and benzofuran and evaluation of
their biological activity, Med. Chem. Res. 22 (2013) 4787e4797.
[95] W. He, B. Xu, J. Bao, X. Deng, W. Liu, Y. Zhang, F. Jiang, L. Fu, Synthesis and
antimicrobial evaluation of 3-substituted-imine-6-hydroxybenzofuran de-
rivatives, Med. Chem. Res. 25 (2016) 2485e2497.
[96] P.T.T. Phan, T.T.T. Nguyen, H.N.T. Nguyen, B.K.N. Le, T.T. Vu, D.C. Tran,
T.A.N. Pham, Synthesis and bioactivity evaluation of novel 2-
salicyloylbenzofurans as antibacterial agents, Molecules 22 (2017) 687e699.
[97] F.L. Yan, A.X. Wang, Z.J. Jia, Three new polymeric isopropenyl benzofurans
from Ligularia stenocephala, Pharmazie 60 (2005) 155e159.
[98] C.C.W. Wanjala, B.F. Juma, G. Bojase, B.A. Gashe, R.R.T. Majinda, Erythrinaline
alkaloids and antimicrobial flavonoids from Erythrina latissima, Planta Med.
68 (2002) 640e643.
[99] T. Fukai, Y. Oku, Y. Hano, S. Terada, Hydrophobic 2-arylbenzofurans and an
isoflavone against vancomycin-resistant enterococci and methicillin-resistant
Staphylococcus aureus, Planta Med. 70 (2004) 685e687.
[100] B.J. Reddy, V.P. Reddy, Synthesis and antimicrobial evaluation of substituted
(1,1'-biphenyl)-4-yl(3-methylbenzofuran-2-yl)methanones by Suzuki cross-
coupling reaction1, Russ. J. Gen. Chem. 86 (2016) 2791e2796.
[101] M. Mielczarek, R.V. Thomas, C. Ma, H. Kandemir, X. Yang, M. Bhadbhade,
D.S. Black, R. Griffith, P.J. Lewis, N. Kumar, Synthesis and biological activity of
novel mono-indole and mono-benzofuran inhibitors of bacterial transcrip-
tion initiation complex formation, Bioorg. Med. Chem. 23 (2015) 1763e1775.