Synthesis of arylfuran derivatives as potential antibacterial agents

Article abstract of DOI:10.1007/s00044-021-02711-y

Bacterial infections represent a serious health care problem mainly due to the misuse and overuse of antibiotics, with consequent emergence of multidrug resistant bacterial strains. Then, because the urgent need to find novel and alternative antibacterial agents, the present work focuses on the synthesis of arylfuran derivatives with potential antimicrobial activity. Eighteen arylfuran derivatives were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Among them, seven compounds containing an amino group in their structure showed activity, with compound 24 being the most effective against both Gram-negative (E. coli, MIC = 49 μM) and Gram-positive (S. aureus, MIC = 98 μM) bacteria, besides having exhibited a modest activity against P. aeruginosa (MIC = 770 μM). In addition, based on in silico studies, this is a druglike compound since it does not violate any rules for predicting oral bioavailability. In this context, the significant antibacterial potential and the low similarity with known antibiotics indicate the innovative aspect of compound 24.

Full text of DOI:10.1007/s00044-021-02711-y

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research (2021) 30:1074–1086
https://doi.org/10.1007/s00044-021-02711-y
ORIGINAL RESEARCH
Synthesis of arylfuran derivatives as potential antibacterial agents
Marina M. S. Andrade1 Ícaro F. Protti1 Vinícius G. Maltarollo1 Ygor F. G. da Costa2 Wesley G. de Moraes2
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Nicole F. Moreira2 Giovana G. Garcia2 Gabriel F. Caran3 Flaviano M. Ottoni1 Ricardo J. Alves1
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Carolina P. S. Moreira4 Helen R. Martins3 Maria Silvana Alves2 Renata B. de Oliveira
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Received: 8 September 2020 / Accepted: 30 January 2021 / Published online: 17 February 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021
Abstract
Bacterial infections represent a serious health care problem mainly due to the misuse and overuse of antibiotics, with
consequent emergence of multidrug resistant bacterial strains. Then, because the urgent need to find novel and alternative
antibacterial agents, the present work focuses on the synthesis of arylfuran derivatives with potential antimicrobial activity.
Eighteen arylfuran derivatives were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus,
Escherichia coli and Pseudomonas aeruginosa. Among them, seven compounds containing an amino group in their
structure showed activity, with compound 24 being the most effective against both Gram-negative (E. coli, MIC = 49 µM)
and Gram-positive (S. aureus, MIC = 98 µM) bacteria, besides having exhibited a modest activity against P. aeruginosa
(MIC = 770 µM). In addition, based on in silico studies, this is a druglike compound since it does not violate any rules for
predicting oral bioavailability. In this context, the significant antibacterial potential and the low similarity with known
antibiotics indicate the innovative aspect of compound 24.
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Keywords Arylfuran derivatives Antibacterial agents Oral bioavailability Innovative compound
Introduction
emergence of multidrug resistant (MDR) bacteria limits the
effectiveness of therapeutic options, representing a serious
public health problem [4–6].
Bacteria are present everywhere and can cause a variety of
infections that, if untreated, it can develop into much more
serious consequences [1–3]. Currently, the increasing
Based on this the World Health Organization (WHO)
declared the antimicrobial resistance (AMR), mainly the
antibiotic (antibacterial) resistance (AR), as a major global
public health problem of the 21st century, and requested the
intervention of the scientific community to the research,
discovery, and development of new innovative antibiotics
[7]. In fact, although there has been an increase in the
number of the FDA approved antibacterial agents in
2018–2019, the number and efficacy of these new drugs is
far from sufficient [8].
As example of this worrying scenario related to the
incidence of infections caused by MDR pathogens, it can
mention the quinolones and fluoroquinolones whose use
and rate of resistance have been increasing around the world
[9], and the significant toxicity (nephrotoxicity) of the
polymyxin B and colistin, considered the last-line options
for the treatment of infections caused by MDR Gram-
negative bacteria such as Pseudomonas aeruginosa, Aci-
netobacter baumannii and Klebsiella pneumoniae [10].
Therefore, it is urgent and necessary that new approaches to
treat bacterial infections are found.
Supplementary information The online version contains
supplementary material available at https://doi.org/10.1007/s00044-
021-02711-y.
* Renata B. de Oliveira
renatabo.ufmg@gmail.com
1
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia,
Universidade Federal de Minas Gerais (UFMG), Belo Horizonte,
MG, Brazil
2
Laboratório de Bioatividade Celular e Molecular, Centro de
Pesquisas Farmacêuticas, Faculdade de Farmácia, Universidade
Federal de Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil
3
Laboratório de Doenças Parasitárias, Universidade Federal dos
Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, MG,
Brazil
4
Serviço de Desenvolvimento Tecnológico Farmacêutico, Diretoria
de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias
(FUNED), Belo Horizonte, MG, Brazil

Medicinal Chemistry Research (2021) 30:1074–1086
1075
Fig. 1 Examples of furan
derivatives with biological
activity
urinary tract infections since many MDR microorganisms
preserve their susceptibility to this antibiotic [19].
In general, heterocycles are considered a privileged
scaffold in medicinal chemistry and triazoles are other
representatives of this class. Due to the strong moment
dipole, triazole can be used as an effective amide surrogate
and as a linker in bioactive molecules. These motifs show
bioisosteric relationship with peptide linkage, aromatic ring,
double bonds and an imidazole ring. Triazoles can also be
used to improve the solubility of compounds because of
their ability to form hydrogen bonds [20]. The 1,2,3-triazole
heterocycle has been included as a main moiety of many
pharmaceutical drugs, such as anticancer carboxyamido-
triazole and antibacterials cefatrizine and tazobactam (Fig. 3).
In a recent research, El Malah and collaborators reported a
series of 1,2,3-triazole glucosides as antimicrobial agents,
especially against Staphylococcus aureus, which was found
sensitive to all the tested compounds [21].
Fig. 2 Examples of hydantoin derivatives with biological activity
To overcome these limitations, mainly the AMR, natural
products, combinatorial chemistry and synthetic approaches
have been applied to face these challenges. In this context,
furan derivatives represent an important class of compounds
due to their diversified biological activities and the common
presence of the furan moiety in the structure of several
drugs, e.g., antiulcer ranitidine [11], diuretic furosemide
[12], muscle relaxant dantrolene [13], anti-protozoal dilox-
anide [14] and antibacterial nitrofurazone [15] and nitro-
furantoin [16] (Fig. 1).
Dantrolene and nitrofurantoin are synthetic drugs derived
from furan by the addition of a side chain containing a
hydantoin ring. Clinically approved drugs such as antic-
onvulsant phenytoin and androgen receptor antagonist
nilutamide are also representative of compounds for ther-
apeutic use that present the hydantoin moiety in their
structure (Fig. 2). This other class of heterocycles also plays
an important and significant role in the field of medicinal
chemistry, especially because of its application as key
pharmacophoric moieties or skeletal components. Besides
that, hydantoin provides two hydrogen-bond acceptors and
two hydrogen-bond donors, which are relevant for interac-
tion with molecular targets [17]. The importance of the
hydantoin scaffold in drug discovery has been supported by
several pharmacological and biological activities associated
with this group, mainly in antibiotic agents’ development
due to its low rate of bacterial resistance [18]. The old
nitrofurantoin, for example, has been used to treat resistant
With this context in mind, we decided to synthesize and
evaluate a series of arylfuran derivatives linked, or not, to
other heterocycles (triazole or hydantoin) for their anti-
bacterial property.
Material and methods
Chemistry
All melting points were determined on a Microquímica
MQAPF 301 apparatus. The infrared (IR) spectra were
recorded using a Perkin Elmer Spectrum One IR spectrometer
and absorptions were reported as wave numbers (cm−1). The
nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker AVANCE DRX200 or Bruker AVANCE DRX400
instrument, using tetramethylsilane as the internal standard.
Chemical shifts were given in δ (ppm) scale and J values were
given in Hz. Splitting patterns are designed as s (singlet), d
(doublet), dd (doublet of doublets), t (triplet), q (quartet), qt

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Medicinal Chemistry Research (2021) 30:1074–1086
Fig. 3 Examples of triazole
derivatives with biological
activity
(quintet) or m (multiplet). High resolution mass spectra
(HRMS) analyses were conducted on Agilent 1290 Infinity
LC system and Agilent 6540 UHD Accurate-Mass Q-TOF
mass spectrometer, equipped with an electrospray ion source
in the positive mode. The aldehydes 5-(4-Bromophenyl)
furan-2-carboxaldehyde 1 and 5-(4-chlorophenyl)furan-2-
carboxaldehyde 2 [22], the morpholine derivatives 9 and 10
[23, 24], and the glycosyl derivatives 11 and 12 [25, 26] were
synthesized according to the published procedures.
carbodiimide (1.1 eq.) were put into the reaction mixture. The
reaction was stirred at room temperature for 5 h. In the
sequence, the corresponding amine (1.5 eq) was added and
the reaction continued for more 24 h. The completion of the
reaction was observed by TLC. Posteriorly, the flask contents
were washed with 3 M HCl solution, sodium bicarbonate
10% solution and, finally, distilled water. The organic layers
were dried with Na2SO4, filtered and the solvent was
removed under reduced pressure, obtaining the corresponding
product.
5-(4-bromophenyl)furan-2-carboxylic acid (3) and 5-(4-
chlorophenyl)furan-2-carboxylic acid (4)
5-(4-bromophenyl)-N-(2-hydroxyethyl)furan-2-carboxamide (5)
In a round-bottom flask containing AgNO3 solubilized in
distilled water, 1 M NaOH solution was added, obtaining a
brown solid. After that, the aldehyde 1 or 2 (1 eq.) solu-
bilized in ethanol was added to this suspension. The reac-
tion mixture was refluxed under magnetic stirring for 2 h.
The completion of the reaction was observed by thin
layer chromatography (TLC) and precipitate was filtered
and washed with hot water. Then, the filtered was acid-
ified with 3 M HCl solution and extracted with EtOAc as
solvent. The organic layers were dried with Na2SO4, fil-
tered and the solvent was removed under reduced pres-
sure, obtaining a green solid as the product, 93% yield for
both acids; mp 199.6–200.1 °C (compound 3), lit.:
198.0–200.0 °C [22]; mp 189.0–190.0 °C (compound 4),
lit.: 197.0–198.0 °C [27]; (Compound 3) 1H NMR
(200 MHz, acetone-d6) δ 7.79 (d, 2H, J = 8.6, H-7), 7.66
(d, 2H, J = 8.6, H-8), 7.32 (d, 1H, J = 3.5, H-3), 7.10 (d,
1H, J = 3.5, H-4); 13C NMR (50 MHz, acetone-d6) δ
159.3 (C-10), 156.7 (C-5), 145.3 (C-2), 132.9 (C-8),
129.7 (C-6), 127.2 (C-7), 123.2 (C-9), 120.7 (C-3), 108.8
This compound was prepared from 5-(4-bromophenyl)
furan-2-carboxylic acid 3 (500 mg, 1.9 mmol) in 20 mL of
dichloromethane and obtained from the general procedure
as a yellow solid (497 mg, 86% yield); mp 164.6–165.8 °C;
1
IR (neat, cm−1) 3435, 3335, 1626; H NMR (400 MHz,
DMSO-d6) δ 8.49 (t, J = 5.4, 1H, NH), 7.86 (d, 2H, J =
8.5, H-7), 7.66 (d, 2H, J = 8.5, H-8), 7.15 (d,1H, J = 3.5,
H-4), 7.13 (d, 1H, J = 3.5, H-3), 4.76 (t, 1H, J = 5.2, OH),
3.52 (q, 2H, J = 5.7, H-12), 3.34-3.30 (m, 2H, H-11); 13C
NMR (100 MHz, DMSO-d6) δ 157.6 (C-10), 153.1 (C-5),
147.5 (C-2), 131.8 (C-8), 128.6 (C-6), 126.2 (C-7), 121.5
(C-9), 115.4 (C-4), 108.2 (C-3), 59.7 (C-12), 41.4 (C-11);
HRMS (m/z) [M + H]+ calcd for C13H13BrNO3+ 310.0073,
found 310.0077.
5-(4-bromophenyl)-N-(3-hydroxypropyl)furan-2-
carboxamide (6)
This compound was prepared from 5-(4-bromophenyl)
furan-2-carboxylic acid 3 (200 mg, 0.7 mmol) in 10 mL of
dichloromethane and obtained from the general procedure
as a brown solid (157 mg, 66% yield); mp 109.0–110.0 °C;
1
(C-4). (Compound 4) H NMR (400 MHz, acetone-d6) δ
7.84 (d, 2H, J = 8.6, H-7), 7.50 (d, 2H, J = 8.6, H-8),
7.31 (d, 1H, J = 3.5, H-3), 7.06 (d, 1H, J = 3.5, H-4); 13
C
IR (neat, cm−1) 3396, 3309, 1622; H NMR (200 MHz,
1
NMR (100 MHz, acetone-d6) δ 159.3 (C-10), 156.7 (C-
5), 145.3 (C-2), 135.0 (C-9), 129.9 (C-8), 129.3 (C-6),
126.9 (C-7), 120.7 (C-3), 108.8 (C-4).
DMSO-d6) δ 8.54 (t, NH, J = 5.4), 7.85 (d, 2H, J = 8.5,
H-7), 7.65 (d, 2H, J = 8.5, H-8), 7.14–7.12 (m, 2H, H-3,
H-4), 4.51 (t, 1H, J = 4.9, OH), 3.46 (q, 2H, J = 5.8, H-13),
3.34–3.26 (m, 2H, H-11), 1.67 (qt, 2H, J = 6.5, H-12);
13C NMR (50 MHz, DMSO-d6) δ 157.5 (C-10), 153.1
(C-5), 147.5 (C-2), 131.8 (C-8), 128.6 (C-6), 126.2 (C-7),
121.5 (C-9), 115.3 (C-4), 108.2 (C-3), 58.5 (C-13), 35.9
(C-11), 32.5 (C-12); HRMS (m/z) [M + H]+ calcd for
General procedure for the preparation of amides 5-8
In a round-bottom flask the acid derivative 3 or 4 (1 eq.)
solubilized in dichloromethane was added. Then, N-hydro-
xysuccinimide (1 eq.) and 1-ethyl-3-(3-dimethylaminopropyl)
+
C14H15BrNO3 326.0230, found 326.0220.

Medicinal Chemistry Research (2021) 30:1074–1086
1077
5-(4-bromophenyl)-N-(prop-2-yn-1-yl)furan-2-carboxamide
5-(4-bromophenyl)-N-((1-(2-morpholino-2-oxoethyl)-1H-
(7)
1,2,3-triazol-4-yl)methyl) furan-2-carboxamide (13)
This compound was prepared from 5-(4-bromophenyl)
furan-2-carboxylic acid 3 (200 mg, 0.7 mmol) in 10 mL of
dichloromethane and obtained from the general procedure
as an orange solid (154 mg, 68% yield); mp
129.4–130.4 °C; IR (neat, cm−1) 3250, 2935, 2119, 1632;
1H NMR (400 MHz, DMSO-d6) δ 9.00 (t, NH, J = 5.6),
7.87 (d, 2H, J = 8.6, H-7), 7.67 (d, 2H, J = 8.6, H-8), 7.20
(d, 1H, J = 3.6, H-4), 7.15 (d, 1H, J = 3.6, H-3), 4.6 (dd,
2H, J = 5.6, 2.4, H-11), 3.14 (t, 1H, J = 2.4, H-13); 13C
NMR (100 MHz, DMSO-d6) δ 157.2 (C-10), 153.5 (C-5),
143.8 (C-2), 131.8 (C-8), 128.5 (C-6), 126.3 (C-7), 121.7
(C-9), 116.0 (C-4), 108.3 (C-3), 81.0 (C-12), 72.9 (C-13),
27.7 (C-11); HRMS (m/z) [M + H]+ calcd for
This compound was prepared from alkene 5-(4-bromophe-
nyl)-N-(prop-2-yn-1-yl)furan-2-carboxamide (350 mg,
7
1.15 mmol) in 4 mL of THF and obtained from the general
procedure. A solution of ethanol/water (1:1, v/v) was added
to the obtained residue and the precipitate formed was fil-
tered. The filtrate volume was reduced by ~50% and the
solid formed was isolated by filtration, obtaining a beige
solid as the product (317 mg, 58% yield); mp 94.0–96.0 °C;
IR (neat, cm−1); 3287, 2968, 2859, 1644; 1H NMR
(400 MHz, DMSO-d6) δ 9.16 (broad s, NH), 7.90–7.87 (m,
3H, H-13 and H-7), 7.67 (d, 2H, J = 8.4, H-8), 7.20 (d, 1H,
J = 3.3, H-4), 7.15 (d, 1H, J = 3.3, H-3), 5.43 (s, 2H, H-14),
4.53 (d, 2H, J = 4.6, H-11), 3.65–3.58 (m, 4H, H-17),
3.52–3.44 (m, 4H, H-16); 13C NMR (100 MHz, DMSO-d6)
δ 164.5 (C-15), 157.5 (C-10), 153.4 (C-5), 147.1 (C-2),
131.8 (C-8), 128.6 (C-6), 126.3 (C-7), 124.7 (C-13), 121.6
(C-9), 115.8 (C-3), 108.3 (C-4), 65.9 (C-17), 65.8 (C-17‘),
50.5 (C-14), 44.7 (C-16‘), 41.9 (C-16), 34.1 (C-11); HRMS
+
C14H11BrNO2 305.9968, found 305.9953.
5-(4-chlorophenyl)furan-2-yl)(4-(2-hydroxyethyl)piperazin-
1-yl)methanone (8)
+
This compound was prepared from 5-(4-chlorophenyl)
furan-2-carboxylic acid 4 (50 mg, 0.22 mmol) in 15 mL of
dichloromethane and obtained from the general procedure
as an yellow solid (56 mg, 74% yield); mp 100.0–103.0 °C;
IR (neat, cm−1) 3390, 2924, 2814, 1610; 1H NMR
(400 MHz, acetone-d6) δ 7.81 (d, 2H, J = 8.7, H-7), 7.49
(d, 2H, J = 8.7, H-8), 7.07 (d, 1H, J = 3.6, H-4), 7.03 (d,
1H, J = 3.6, H-3), 3.90–3.70 (m, 4H, H-11, H-13),
3.68–3.63 (m, 2H, H-16), 2.61–2.58 (m, 4H, H-12, H-14),
2.57–2.53 (m, 2H, H-15); 13C NMR (100 MHz, Acetone-
d6) δ 158.2 (C-10), 153.5 (C-5), 147.7 (C-2), 133.5 (C-9),
129.0 (C-8), 128.8 (C-6), 125.8 (C-7), 117.7 (C-4), 107.2
(C-3), 60.1 (C-12, C-14), 58.7 (C-11, C-13), 53.4 (C-15, C-
(m/z) [M + H]+ calcd for C20H21BrN5O4 474.0771, found
474.0777.
5-(4-bromophenyl)-[(1-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-1H-1,2,3-triazol-4-yl)methyl]furan-2-
carboxamide (14)
This compound was prepared from alkene 5-(4-bromophenyl)-
N-(prop-2-yn-1-yl)furan-2-carboxamide 7 (100 mg, 0.3 mmol)
in 4 mL of THF and obtained from the general procedure. The
obtained residue was purified by column chromatography
(Hexane/EtOAc 8:2), obtaining the product as a white solid
(100 mg, 44% yield); mp 135.8–136.6 °C; IR (neat, cm−1);
3348, 2959, 1747, 1651, 1215; 1H NMR (400 MHz, DMSO-
d6) δ 9.15 (t, NH, J = 5.8), 8.29 (s, 1H, H-13), 7.88 (d, 2H,
J = 8.5, H-7), 7.67 (d, 2H, J = 8.5, H-8), 7.20 (d, 1H, J = 3.5,
H-4), 7.15 (d, 1H, J = 3.5, H-3), 6.31 (d, 1H, J = 9.3, H-14),
5.67 (t, 1H, J = 9.3, H-15), 5.52 (t, 1H, J = 9.3, H-16), 5.17 (t,
1H, J = 9.3, H-17), 4.56–4.47 (m, 2H, H-11), 4.36–4.32 (m,
1H, H-18), 4.14–4.05 (m, 2H, H-19), 2.02 (s, 3H, COCH3),
1.98 (s, 3H, COCH3), 1.95 (s, 3H, COCH3), 1.79 (s, 3H,
COCH3); 13C NMR (100 MHz, DMSO-d6) δ 169.9 (COCH3),
169.5 (COCH3), 169.3 (COCH3). 168.4 (COCH3), 157.5 (C-
10), 153.4 (C-5), 147.0 (C-2), 145.7 (C-12), 131.8 (C-8),
128.5 (C-6), 126.2 (C-7), 122.0 (C-13), 121.6 (C-9), 115.9
(C-4), 108.3 (C-3), 83.8 (C-14), 73.2 (C-18), 72.2 (C-16), 70.0
(C-15), 67.5 (C-17), 61.8 (C-19), 33.9 (C-11), 20.4 (COCH3),
20.3 (COCH3), 20.2 (COCH3), 19.8 (COCH3); HRMS (m/z)
+
16); HRMS (m/z) [M + H]+ calcd for C17H20ClN2O3
335.1157, found 335.1149.
General procedure for the preparation of furan triazoles 13
and 14
In a round-bottom flask the alkyne 7 (1 eq.) and the
corresponding azide 10 or 12 (1 eq.) were added and
solubilized in tetrahydrofuran (THF). Then, sodium
ascorbate (0.8 eq.) and a 10% aqueous solution of
CuSO4.5H2O (0.4 eq.) were put into the reaction mixture.
The reaction mixture was maintained under magnetic
stirring at room temperature for about 4 h. After con-
firming the completion of the reaction by TLC, ethanol
was added and the precipitate formed was filtered,
washed with ethanol and the filtrate was evaporated under
reduced pressure.
+
[M + H]+ calcd for C28H30BrN4O11 677.1089, found
677.1089.

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Medicinal Chemistry Research (2021) 30:1074–1086
((5-(4-chlorophenyl)furan-2-yl)methylene)amino)
imidazolidine-2,4-dione (15)
9.65 (s, 2H, NH2+), 7.79 (d, 2H, J = 8.0, H-7), 7.50 (d, 2H,
J = 8.0, H-8), 7.02 (d, 1H, J = 4.0, H-4), 6.78 (d, 1H, J =
4.0, H-3), 4.24 (s, 2H, H-10), 3.29–3.24 (m, 1H, H-11),
1.31 (d, 6H, J = 8.0, H12, H-13); 13C NMR (100 MHz,
DMSO-d6) δ 152.6 (C-5), 146.2 (C-2), 132.2 (C-9), 128.9
(C-8), 128.7 (C-6), 125.4 (C-7), 114.1 (C-4), 107.5 (C-3),
49.1 (C-11), 39.6 (C-10), 18.5 (C-12, C-13); HRMS (m/z)
[M-Cl]+ calcd for C14H17ClNO+ 250.0993, found
250.0991.
In a round-bottom flask, immersed in an ice bath, 1-
aminohydantoin (80.7 mg, 0.5 mmol) solubilized in 5 mL of
0.67 M HCl solution was added. Then, the aldehyde 2
(100 mg, 0.5 mmol) and 2.2 mL of N,N-dimethylformamide
(DMF) were put into the reaction mixture. The reaction was
maintained under magnetic stirring at room temperature for
3 h. After the end of the reaction, the precipitate formed was
filtered and washed with cold water, obtaining a brown
solid as the product (122 mg, 83% yield); mp 257–259 °C;
IR (neat, cm−1); 3287, 1774, 1764, 1726; 1H NMR
(400 MHz, DMSO-d6) δ 11.28 (s, 1H, NH), 7.77 (d, 2H, J
= 8.6, H-7), 7.72 (s, 1H, H-10), 7.51 (d, 2H, J = 8.6, H-8),
7.15 (d, 1H, J = 3.6, H-4), 6.95 (d, 1H, J = 3.6, H-3), 4.34
(s, 2H, H-11); 13C NMR (100 MHz, DMSO-d6) δ 168.9 (C-
12), 153.3 (C-14 or C-5), 153.2 (C-5 or C-14), 149.4 (C-2),
132.9 (C-9), 132.6 (C-8), 129.0 (C-6), 128.4 (C-10), 125.4
(C-7), 115.4 (C-4) 108.9 (C-3) 48.9 (C-11); HRMS (m/z)
N-((5-(4-chlorophenyl)furan-2-yl)methyl)propan-1-amine
(17)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (400 mg, 1.93 mmol) and
propylamine (1.6 mL, 1.14 g, 19.37 mmol) in 20 mL of
chloroform. Compound 17 was obtained from the general
procedure as a brown oil (263 mg, 55% yield); IR (neat, cm−1)
1
2959, 2874, 1572-1481; H NMR (200 MHz, CDCl3) δ 7.57
(d, 2H, J = 8.6, H-7), 7.32 (d, 2H, J = 8.6, H-8), 6.56 (d, 1H,
J = 3.2, H-4), 6.28 (d, 1H, J = 3.2, H-3), 3.85 (s, 2H, H-10),
2.68–2.60 (m, 2H, H-11), 1.55 (qt, 2H, J = 7.3, H-12), 0.93 (t,
3H, J = 7.3, H-13); 13C NMR (50 MHz, CDCl3) δ 153.4 (C-
5), 152.1 (C-2), 132.6 (C-9), 129.3 (C-6), 128.7 (C-8), 124.7
(C-7), 109.4 (C-4), 106.0 (C-3), 50.7 (C-10), 45.9 (C-11), 22.7
(C-12), 11.6 (C-13). HRMS (m/z) [M + H]+ calcd for
C14H17ClNO+ 250.0993, found 250.0980.
+
[M + H]+ calcd for C14H11ClN3O3 304.0483, found
304.0476.
General procedure for the preparation of amines 16-24
In a round-bottom flask the aldehyde 2 (1 eq.) and the
corresponding amine (1-10 eq.) solubilized in chloroform
were added. Then, Na2SO4 (1 eq.) was put into the reaction
and the mixture was maintaining under magnetic stirring at
room temperature overnight. In the sequence, under ice
bath, methanol and NaBH4 (6 eq) were added and the
reaction was maintaining under magnetic stirring at room
temperature for about 3 h. The completion of the reaction
was observed by TLC and then distilled water was added
and the mixture was extract with dichloromethane. After
that, the organic phase was washed with 3 M HCl solution.
The resulting aqueous phase of this last extraction was
alkalized with 4 M NaOH solution and extracted with
dichloromethane (3 × 20 mL). The organic layers were
combined, dried over anhydrous Na2SO4, filtered and the
solvent was removed under reduced pressure, obtaining the
corresponding product.
2-(((5-(4-chlorophenyl)furan-2-yl)methyl)amino)ethanol
(18)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol)
and ethanolamine (0.29 mL, 295.8 mg, 4.84 mmol) in
10 mL of chloroform. Compound 18 was obtained from the
general procedure as a brown oil (73 mg, 60% yield); IR
(neat, cm−1) 3285, 3109, 2924, 2861, 1537-1479; 1H NMR
(400 MHz, CDCl3) δ 7.57 (d, 2H, J = 8.6, H-7), 7.34 (d,
2H, J = 8.6, H-8), 6.57 (d, 1H, J = 3.2, H-4), 6.28 (d, 1H,
J = 3.2, H-3), 3.86 (s, 2H, H-10), 3.69 (t, 2H, J = 5.1, H-
12), 2.84 (t, 2H, J = 5.1, H-11); 13C NMR (100 MHz,
CDCl3) δ 153.4 (C-5), 152.4 (C-2), 132.9 (C-9), 129.3 (C-
6), 128.9 (C-8), 124.8 (C-7), 109.5 (C-4), 106.1 (C-3), 60.8
(C-12), 50.3 (C-10), 45.3 (C-11); HRMS (m/z) [M + H]+
N-((5-(4-chlorophenyl)furan-2-yl)methyl)propan-2-amine
hydrochloride (16)
+
calcd for C13H15ClNO2 252.0786, found 252.0788.
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (200 mg, 0.96 mmol)
and isopropylamine (0.83 mL, 571.7 mg, 9.69 mmol) in
15 mL of chloroform. Compound 16 was obtained from the
general procedure as a hydrochloride salt, white solid
3-(((5-(4-chlorophenyl)furan-2-yl)methyl)amino)propan-1-ol
(19)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol)
and 3-aminopropanol (0.37 mL, 363.4 mg, 4.84 mmol) in
10 mL of chloroform. Compound 19 was obtained from the
(186 mg, 67% yield); mp 215.5–216.7 °C; IR (neat, cm−1
)
1
2948, 2692, 1574-1544; H NMR (400 MHz, DMSO-d6) δ

Medicinal Chemistry Research (2021) 30:1074–1086
1079
general procedure as a brown oil (87 mg, 68% yield); IR
(neat, cm−1) 3298, 2926, 2841, 1542–1481; 1H NMR
(400 MHz, CDCl3) δ 7.57 (d, 2H, J = 8.6, H-7), 7.34 (d,
2H, J = 8.6, H-8), 6.57 (d, 1H, J = 3.2, H-4), 6.31 (d, 1H,
J = 3.2, H-3), 3.88 (s, 2H, H-10), 3.82 (t, 2H, J = 5.2, H-
13), 2.94 (t, 2H, J = 5.2, H-11), 1.79–1.74 (m, 2H, H-12);
13C NMR (100 MHz, CDCl3) δ 153.6 (C-5), 152.2 (C-2),
132.9 (C-9), 129.2 (C-6), 128.9 (C-8), 124.9 (C-7), 109.9
(C-4), 106.1 (C-3), 63.6 (C-13), 48.4 (C-10), 45.8 (C-11),
N-benzyl-1-(5-(4-chlorophenyl)furan-2-yl)methanamine
hydrochloride (22)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol)
and benzylamine (0.15 mL, 154.3 mg, 1.44 mmol) in 10 mL
of chloroform. Compound 22 was obtained from the general
procedure as a hydrochloride, white solid (130 mg, 81%
yield); mp 248.0–250.0 °C; IR (neat, cm−1) 2921, 2727,
+
1
30.6 (C-12); HRMS (m/z) [M + H]+ calcd for C14H17ClNO2
2593, 1575-1438; H NMR (400 MHz, DMSO-d6) δ 10.04
266.0942, found 266.0932.
(broad s, 2H, NH2+), 7.79 (d, 2H, J = 8.6, H-7), 7.62–7.56
(m, 2H, H-14, H-16), 7.52 (d, 2H, J = 8.6, H-8), 7.45–7.40
(m, 3H, H-13, H-15, H-17), 7.04 (d, 1H, J = 3.4, H-4), 6.77
(d, 1H, J = 3.4, H-3), 4.25 (s, 2H, H-10), 4.18 (s, 2H, H-
11); 13C NMR (100 MHz, DMSO-d6) δ 153.2 (C-5), 146.3
(C-2), 132.7 (C-19 or C-12), 132.2 (C-12 or C-9), 130.7 (C-
8), 129.4 (C-13, C-17), 129.1 (C-7), 129.0 (C-14, C-16),
125.9 (C-15), 114.9 (C-4), 108.01 (C-3), 49.9 (C-11), 42.5
(C-10); HRMS (m/z) [M-Cl]+ calcd for C18H17ClNO+
298.0993, found 298.0983.
2-(4-((5-(4-chlorophenyl)furan-2-yl)methyl)piperazin-1-yl)
ethanol (20)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol)
and 1-(2-hydroxyethyl)piperazine (0.1 mL, 124.0 mg,
0.96 mmol) in 10 mL of chloroform. Compound 20 was
obtained from the general procedure as a yellow oil (57 mg,
37% yield); IR (neat, cm−1) 3351, 2938, 2815, 1542-1481;
1H NMR (400 MHz, acetone-d6) δ 7.71 (d, 2H, J = 8.6, H-
7), 7.43 (d, 2H, J = 8.6, H-8), 6.83 (d, 1H, J = 3.3, H-4),
6.37 (d, 1H, J = 3.3, H-3), 3.60–3.55 (m, 4H, H-10 and H-
16), 2.52–2.44 (m, 10H, H-11, H-12, H-13, H-14, H-15);
13C NMR (100 MHz, acetone-d6) δ 152.7 (C-5), 151.9 (C-
2), 132.2 (C-9), 129.8 (C-6), 128.8 (C-8), 124.9 (C-7),
110.8 (C-4), 106.7 (C-3), 60.2 (C-16), 58.5 (C-15), 54.4
(C-10), 53.3 (C12, C-14), 52.7 (C-11, C-13); HRMS (m/z)
1-(5-(4-chlorophenyl)furan-2-yl)-N-(furan-2-ylmethyl)
methanamine (23)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol) and
furfurylamine (0.14 mL, 139.8 mg, 1.44 mmol) in 10 mL of
chloroform. Compound 23 was obtained from the general
procedure as a yellow solid (92 mg, 66% yield); mp
197.0–200.0 °C; IR (neat, cm−1) 2925, 2731, 1580–1439;
1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, 2H, J = 8.6, H-
7), 7.75 (d, 1H, J = 1.2, H-15), 7.51 (d, 2H, J = 8.6,H-8),
7.02 (d, 1H, J = 3.4, H-4), 6.72 (d, 1H, J = 3.4, H-3), 6.65
(d, 1H, J = 3.1, H-13), 6.52–6.51 (m, 1H, H-14), 4.20 (s,
4H, H-10, H-11); 13C NMR (100 MHz, DMSO-d6) δ 153.1
(C-5), 146.9 (C-2 or C-12), 146.8 (C-12 or C-2), 144.4 (C-
15), 132.7 (C-9), 129.4 (C-6), 129.2 (C-8), 125.8 (C-7),
114.5 (C-14), 112.5 (C-13), 111.5 (C-4), 107.9 (C-3), 42.5
(C-10 or C-11), 42.4 (C-11 or C-10). HRMS (m/z) [M + H]+
+
[M + H]+ calcd for C17H22ClN2O2 321.1364, found
321.1356.
N-((5-(4-chlorophenyl)furan-2-yl)methyl)-3-
morpholinopropan-1-amine (21)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol)
and 3-morpholinopropylamine (0.07 mL, 69.2 mg,
0.48 mmol) in 10 mL of chloroform. Compound 21 was
obtained from the general procedure as a yellow oil
(105 mg, 65% yield); IR (neat, cm−1) 3299, 2948, 2812,
+
calcd for C16H15ClNO2 288.0786, found 288.0779.
1
1584-1481; H NMR (400 MHz, acetone-d6) δ 7.68 (d,
N-((5-(4-chlorophenyl)furan-2-yl)methyl)-3-phenylpropan-1-
2H, J = 8.7, H-7), 7.40 (d, 2H, J = 8.7, H-8), 6.79 (d, 1H,
J = 3.3, H-4), 6.32 (d, 1H, J = 3.3, H-3), 3.78 (s, 2H, H-
10), 3.55 (t, 4H, J = 4.6, H-15, H-17), 2.67 (t, 2H, J =
6.8, H-11), 2.31-2.38 (m, 6H, H-13, H-14, H-16), 1.63
(qt, 2H, J = 6.8, H-12); 13C NMR (100 MHz, acetone-d6)
amine hydrochloride (24)
This compound was prepared from aldehyde 5-(4-chlor-
ophenyl)furan-2-carboxaldehyde 2 (100 mg, 0.48 mmol)
and
3-phenyl-1-propylamine
(0.2 mL,
194.7 mg,
δ
155.5 (C-5), 151.4 (C-2), 132.0 (C-9), 129.9
1.44 mmol) in 10 mL of chloroform. Compound 24 was
obtained from the general procedure as a white solid
(80 mg, 46%); mp 203.0–204.0 °C; IR (neat, cm−1) 2927,
(C-6), 128.8 (C-8), 124.8 (C-7), 108.7 (C-4), 106.7 (C-3),
66.6 (C-15, C-17), 57.0 (C-13), 53.8 (C-14, C-16),
47.3 (C-10), 46.0 (C-11), 26.5 (C-12); HRMS (m/z)
1
2752, 1605-1451; H NMR (400 MHz, DMSO-d6) δ 9.69
+
[M + H]+ calcd for C18H24ClN2O2 335.1521, found
(s, 2H, NH2+), 7.76 (d, 2H, J = 8.6, H-7), 7.51 (d, 2H, J =
8.6, H-8), 7.29–7.13 (m, 5H, H-15, H-16, H-17, H-18, H-
335.1516.

1080
Medicinal Chemistry Research (2021) 30:1074–1086
19), 7.01 (d, 1H, J = 3.4, H-4), 6.74 (d, 1H, J = 3.4, H-3),
4.25 (s, 2H, H-10), 2.90 (t, 2H, J = 7.8, H-11), 2.65 (t, 2H,
J = 7.8, H-13), 1.98 (qt, 2H, J = 7.8, H-12); 13C NMR
(100 MHz, DMSO-d6) δ 153.2 (C-5), 146.5 (C-2), 141.1
(C-14), 132.8 (C-9), 129.4 (C-6), 129.2 (C-8), 128.9 (C-16,
C-18), 128.7 (C-15, C-19), 126.5 (C-7), 114.9 (C-4), 107.9
(C-3), 46.1 (C-10), 42.6 (C-11), 32.4 (C-13), 27.4 (C-12);
HRMS (m/z) [M-Cl]+ calcd for C20H21ClNO+ 326.1306,
found 326.1303.
aerobic conditions, 20 μL of 2-(4-iodophenyl)-3-(4-nitro-
phenyl)-5-phenyl-2H-tetrazolium chloride (INT) solution
(1 mg/mL) were added and used as an indicator of bacterial
growth (any color change from purple to pink was recorded
as bacterial growth). Posteriorly, the system was incubated
for further 30 min, and the MIC was determined. When
necessary, other biological indicator such as resazurin was
used and the protocol was properly adjusted. The appro-
priate controls were performed. After determination of MIC
values, MBC was established according to Andrews’
method [30] by spreading of 10 μL of suspensions from
wells that did not received INT and corresponding to the
concentrations that showed no visible bacterial growth on
MHA Petri dishes. After incubation at 35 2 °C for 16–20 h
under aerobic conditions, MBC was determined as the
lowest concentration of dilutions that prevented the visible
bacterial growth after subculture on MHA Petri dishes.
Bacterial growth or absence of bacterial growth on MHA
revealed a bacteriostatic or bactericidal effect, respectively.
In vitro antibacterial activity
Bacterial strains and culture conditions
To carry out the in vitro antibacterial activity assays, three
American Type Culture Collection (ATCC®) strains were
selected according to the WHO priority group [7] and tes-
ted. Staphylococcus aureus subsp. aureus (ATCC® 29213™)
[methicillin sensitive S. aureus (MSSA)], Escherichia coli
(ATCC® 25922™) (fermentative Gram-negative bacteria)
and Pseudomonas aeruginosa (ATCC® 27853™) (non-fer-
mentative Gram-negative bacteria), in the second passage,
were obtained from the Instituto Nacional de Controle de
Qualidade em Saúde, Fundação Oswaldo Cruz, Rio de
Janeiro city, Rio de Janeiro state, Brazil. These strains were
maintained as suspensions in 10% (w/v) skim milk solution
containing 10% (v/v) glycerol at −20 °C. Before use, these
cultures were transferred to Müller-Hinton agar (MHA)
(Difco Laboratories, Detroit, MI, USA) at 35 2 °C for
18–24 h under aerobic conditions.
Computational studies
Semi-empirical calculations employing PM3 method
[31, 32] implemented on MOPAC [33] interface imple-
mented on Sybyl X 2.1 platform [34] were carried out in
order to minimize the structure of selected compounds and
calculate their molecular properties. Electrostatic potential
surfaces were generated using MOLCAD module of Sybyl
X 2.1. In addition, 30 lowest energy conformers of com-
pounds 5 and 24 were generated using OMEGA 3.1.2.2
[35] ([36]) followed by molecular alignment of benzene and
furan ring using ROCS 3.3.2.2 [37] ([38]) aiming to com-
pare molecular flexibility of those compounds.
Determination of minimal inhibitory concentration (MIC)
and minimal bactericidal concentration (MBC)
Compound 24 was employed in several predictions
because it was the active compound found in this study.
First, we used a target prediction approach reported by
Serafim et al. [39]. to suggest a potential molecular target
and guide a future search for its mechanism of action. In this
step, we retrieved experimentally known active compounds
against S. aureus and E. coli (MIC < 50 µM) from ChEMBL
database [40] and calculated the 3D similarity of compound
24 against all obtained compounds after structures pre-
paration (calculation of most stable conformer with
OMEGA 3.1.2.2 [35] ([36]) and ionization states with [41]).
The tridimensional similarities were calculated using ROCS
3.3.2.2 [37] ([38]) considering molecular shape and che-
mical functions and were expressed as Tanimoto coefficient
(Tc). Posteriorly, the most similar compounds were used to
suggest a possible action target for compound 24. Finally,
we also calculated physicochemical properties related to
pharmacokinetics parameters with SwissADME [42], Mar-
vinSketch 19.2 (ChemAxon, https://www.chemaxon.com)
and pkCSM [43] webservers to evaluate its druglikeness.
The broth micro-dilution method was performed according
to the Clinical and Laboratory Standards Institute (CLSI)
guideline M07-A9 [28], with little adjustments, using
Müeller-Hinton broth (MHB) (Difco Laboratories, Detroit,
MI, USA) to determine MIC values of 18 arylfuran deri-
vatives and ampicillin (AMP), chloramphenicol (CHL) and
levofloxacin (LEVO) (Sigma-Aldrich, St Louis, MO, USA)
against the three selected ATCC® strains aforementioned.
Arylfuran derivative and antibiotic stock-solutions were
prepared in dimethylsulfoxide (DMSO) and sterilized dis-
tilled water at the concentration of 1 mg/mL (w/v),
respecting the limit of 1% in the first microplate well [29].
In a sterile polystyrene 96-well microplate, twofold serial
dilutions of arylfuran derivatives (quadruplicate) and anti-
biotics (triplicate) were prepared in MHB at concentrations
ranging from 4 to 250 μg/mL. MIC values above 250 μg/mL
were not determined. Subsequently, 10 μL of standardized
bacteria suspension according to 0.5 McFarland scale were
added. After incubation at 35 2 °C for 16–20 h under

Medicinal Chemistry Research (2021) 30:1074–1086
1081
Scheme 1 General scheme for
the preparation of arylfurans
1–8. a HCl, NaNO2, 4-
bromoaniline or 4-chloroaniline
CuCl2.2H2O (45%; 25%);
b AgNO3, NaOH, EtOH, 80 °C
(93%); c (1) EDAC, NHS;
CH2Cl2; (2) corresponding
amine (ethanolamine,
propanolamine, propargylamine
or 1-(2-hydroxyethyl)
piperazine) (66–86%)
Scheme 2 General scheme for the preparation of azides 10 and 12 and
furan-triazole derivatives 13 and 14. a CHCl3, chloroacetic anhydride
(75%); b THF/H2O, NaN3, 60 °C (60%); c Ac2O, I2, r.t (99%); d HBr/
AcOH 12% v/v, 0 °C-r.t. (90%); e NaN3, acetone/H2O, r.t. (80%);
f Amide 7, azide derivative 10 or 12, THF, CuSO4.5H2O, sodium
ascorbate (44%;58%)
Results and discussion
copper (II) chloride as a catalyst (Meerwein arylation)
[44, 45]. Oxidation of 5-arylfurfural derivatives 1 or 2 in the
presence of silver nitrate resulted in the formation of the
corresponding carboxylic acid 3 or 4, respectively, which
was converted to amides 5-8 via carbodiimide/N-hydro-
xysuccinimide coupling (Scheme 1).
Synthesis
The first step for the synthesis of arylfurans involved direct
furfural arylation with the haloarenediazonium salt using

1082
Medicinal Chemistry Research (2021) 30:1074–1086
Scheme 3 General scheme for the preparation of hydantoin derivative 15 and amines 16–24. a DMF, 1-aminohydantoin, HCl (83%); b (1) CHCl3,
corresponding amine, Na2SO4; (2) Methanol, NaBH4 (37–81%)
The furan-triazole derivatives 13 and 14 were synthe-
sized using click reaction of the propargyl amide 7 and the
azide derivatives 10 and 12. The azide derivative 10 was
synthesized in two steps using chloroacetic anhydride and
morpholine as starting material. The peracetylated glycosyl
azide 12 was obtained from glycosyl halide 11 [25, 26] by
reaction with NaN3 in acetone/H2O at room temperature
[25, 46] (Scheme 2).
The arylfuran (2) was used as starting material for the
synthesis of hydantoin derivative 15 and amines 16–24
(Scheme 3). We hypothesized that the presence of an
additional heterocyclic ring in the compounds 13, 14 (tria-
zole), 8, 20 (piperazine), 13, 21 (morpholine) and 23 (furan)
or the attachment of a sugar moiety (compound 14) could
contribute favorably to the activity due to the possibility of
further interactions with the possible molecular target. In
addition, the presence of one or more basic nitrogen atoms
in the compounds 16–24 may be important to modulate pKa
and improve both the physicochemical and pharmacological
properties of the molecules.
Compounds 21 and 24 were active for both Gram-negative
(P. aeruginosa, ATCC® 27853™ and/or E. coli, ATCC®
25922™) and Gram-positive (S. aureus, ATCC® 29213™)
bacteria, suggesting that these compounds may exhibit a broad
spectrum of action. The amines 16, 22 and 23 were only active
against E. coli (ATCC® 25922™) (MIC values range from 125
to 250 µg/mL), while 18 and 19 exhibited activity against S.
aureus (ATCC® 29213™) (MIC = 250 µg/mL). None of the
tested amides (compounds 5–8 and 13 and 14) showed anti-
bacterial activity. These results indicate that the presence of an
ionizable amino group is essential for activity. The presence of
an ionizable nitrogen in amines can contribute for the solu-
bility and penetration into microorganism. In line with our
results, Parker et al. [47]. also obtained a new broad-spectrum
antibiotic compound after the introduction of an ionizable
amino group in its structure. The size of the side chain also
plays a significant role in the activity, since compounds with a
chain of three carbon atoms separating the nitrogen atom from
the substituent at the end of the chain (morpholine (compound
21) or phenyl (compound 24) groups) were the most active. In
addition, comparing the substituent on these two compounds
and their MIC values, it is possible to infer the importance of
the phenyl group for the activity of compound 24. In this case,
it is assumed that this group may be important for an inter-
action in a possible hydrophobic pocket on the target. It is
worth mentioning that compound 24 was the only one that
showed activity, even if modest, against P. aeruginosa
(ATCC® 27853™), demonstrating the potential of this com-
pound as a candidate for antibacterial drug.
In vitro antibacterial activity
Eighteen arylfuran derivatives were tested to establish their
in vitro antibacterial activity against S. aureus (ATCC®
29213™), E. coli (ATCC® 25922™) and P. aeruginosa
(ATCC® 27853™). Among them, eight arylfuran derivatives
(compounds 6, 16, 18, 19, and 21–24) demonstrated the
most interesting results (Table 1).

Medicinal Chemistry Research (2021) 30:1074–1086
Table 1 Minimal Inhibitory
1083
Compound MIC
MBC
Concentration (MIC) and
Minimal Bactericidal
E. coli
P. aeruginosa
S. aureus
E. coli
P. aeruginosa
S. aureus
(ATCC®
(ATCC®
(ATCC®
(ATCC®
(ATCC®
(ATCC®
Concentration (MBC) values
obtained with arylfuran
derivatives, ampicillin (AMP),
chloramphenicol (CHL) and
levofloxacin (LEVO) against the
three selected ATCC® bacterial
strains
25922™) µg/ 27853™) µg/mL 29213™) µg/ 25922™) µg/ 27853™) µg/mL 29213™) µg/
mL (µM)
(µM)
mL (µM)
mL (µM)
(µM)
mL (µM)
1
>250
>250
>250
>250
ND
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250 (770)
ND
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250 (990)
250 (940)
>250
>250
>250
>250
31 (98)
ND
3
>250
>250
>250
5
>250
>250
>250
6
>250
ND
>250
7
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250e (770)
>250
125
>250
>250
8
>250
>250
>250
13
14
15
16
17
18
19
20
21
22
23
24
AMP
CHL
LEVO
>250
>250
>250
>250
>250
>250
>250
125f (500)
>250
>250
>250
250 (1000)
>250
>250
>250
>250
250e (990)
250e (940)
>250
>250
>250
>250
>250
>250
250f (750)
250e (840)
250e (870)
31e (98)
<4a (<16)
<4c (<16)
<4d (<16)
250f (750)
>250
>250
250 (840)
250 (870)
31 (98)
ND
>250
16f (49)
<4b (<16)
16c (50)
ND
ND
ND
ND
<4d (<15)
ND
ND
ND
ND not determined; Note: activity results for active compounds are highlighted in bold
aMIC values for AMP, CHL and LEVO are within the ranges described by the Clinical and Laboratory
Standards Institute (CLSI), document M100-S24: MIC for AMP (Penicillin) (a) ≤8, 16 and ≥32 μg/mL
classify the bacteria as sensitive, intermediate and resistant, respectively, and (b) ≤0.12 and ≥0.25 μg/mL as
sensitive and resistant, in this order; MIC for CHL (c) ≤8, 16 and ≥32 μg/mL classify the bacteria as sensitive,
intermediate and resistant, respectively; MIC for LEVO (d) ≤2, 4 and ≥8 μg/mL classify the bacteria as
sensitive, intermediate and resistant, in this order. The experiments were performed in quadruplicate and in
triplicate for compounds and antibiotics, respectively
bMBC values >250 µg/mL were not determined because they were above the established gradient. The
antibacterial effect was classified as bactericidal (e) or bacteriostatic (f)
Despite the potential activity of triazole heterocycles, in the
present work the introduction of a triazole ring was unfa-
vorable for the activity. As already mentioned, it can be
speculated that the presence of the amide group in compounds
13 and 14 may have been responsible for this low activity,
since all active arylfuran derivatives have an amino group in
that position. The same can be hypothesized for hydantoin
derivative 15, which has no ionizable amino groups. The pKa
of compound 15 was predicted using MarvinSketch to be
8.23 (pKa referring to the acidic hydantoin NH).
compound 24. Therefore, we could not explore a molecular
target by similarity and, then, the molecular docking studies
were not carried out. On the other hand, the low similarity
with known antibacterial agents indicates the innovative
aspect of this compound. We also searched the DrugBank
repository [48] for FDA approved drugs with more than
50% structural similarity and no results were found corro-
borating our previous finding.
In addition, in silico studies were performed to investi-
gate the druglike properties and toxicity profile of the active
arylfurans (16, 19, 21–24).
Computational studies
These six compounds were predicted to exhibit druglike
profile since they do not violate any of Lipinski [49], Veber
[50], Ghose [51], Egan [52] and Muegge [53] rules for
predicting oral bioavailability (Table 2). Furthermore, the
From target prediction approach, no active compounds
retrieved from ChEMBL are more than 50% similar to

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Medicinal Chemistry Research (2021) 30:1074–1086
Table 2 Physicochemical
properties and prediction of
absorption-related parameters
Compound
HBAa HBDa MW (da)a ClogPa rtBa
PSA (Å2)a pKab GIa
HIA (%)c
16
19
21
22
23
24
2
3
4
2
3
2
1
2
1
1
1
1
249.74
265.74
334.64
297.78
287.74
325.83
3.49
2.59
2.97
4.14
3.46
4.73
4
6
7
5
5
7
25.17
45.40
37.64
25.17
38.31
25.17
8.85
8.47
8.62
7.88
7.03
8.98
High
High
High
High
High
High
90.82
89.89
92.11
91.07
92.50
90.95
HBA hydrogen-bond acceptor, HBD hydrogen-bond donor, MW molecular weight, ClogP consensus
prediction of the logarithm of n-octanol/water partition, rtB rotatable bonds, PSA polar surface area, pKa log
of acidity constant, GI gastrointestinal absorption, HIA human intestinal absorption
aCalculated using SwissADME webserver
bCalculated using MarvinSketch
cCalculated using pkCSM
Fig. 4 Electrostatic potential
surface of compounds 5 (A), 16
(B), 18 (C), and 24 (D) as well
as the color scale of charge
distribution (E) ranging from
most positive regions (red) to
most negative regions (purple).
The superposition of 30 lowest
energy conformers of the amide
5 (F) and amine 24 (G)
predictions of gastrointestinal absorption from SwissADME
and human intestinal absorption from pkCSM corroborate
the calculated druglikeness of compounds 16, 19, 21–24.
For comparison, the main difference between compound
24 (most active) and compounds 16, 19, and 21–23 is the
lipophilia (at least 0.7 logarithmic unity higher) indicating a
better ability to permeate membranes. Furthermore, the
nitrogen atom attached to furan of compound 24 is slightly
more basic than other compounds. But, clearly, the ClogP
difference could explain the activity profile of compounds
with similar structure.
In addition, there is a major difference between charge
distributions at molecular surface of amide (Fig. 4A) and
amino derivatives (Fig. 4B–D). This result corroborates the

Medicinal Chemistry Research (2021) 30:1074–1086
1085
importance of ionization for biological activity because the
presence of carbonyl of amide derivatives like compound 5
provides a negative electron density at the same regions
which is positively charged at amino derivatives. Further-
more, we also compared the flexibility of and amide (5) and
amino derivative (24) by superimposing the rigid part of
molecules composed by benzene and furan rings (Fig. 4F, G).
Then, the amide derivatives have a less flexible side chain
(Fig. 4F) than amino derivatives (Fig. 4G) indicating that
amino derivatives have more ability to acquire a suitable
conformation for interaction with the molecular target
binding site. Last but not least, the amides 5–7 have a
bromide as substituent at benzene rings while amino deri-
vatives possess a chloride and, therefore, the higher volume
of bromide may cause a steric hindrance at a potential
binding site, disfavoring the biological activities of these
amides.
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arylfuran derivative 24 was found to possess considerable
activity against both Gram-negative and Gram-positive
bacteria, indicating a broad spectrum of action of this novel
compound. It is worth mentioning that compound 24
showed potency similar (MIC = 49 µM) to that of CHL
(MIC = 50 µM), antibiotic used in the clinical practice,
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Acknowledgements The authors thank the Fundação de Amparo à
Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional
de Desenvolvimento Científico e Tecnológico (CNPq) and Coorde-
nação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for
financial support (Finance Code 001). The authors would also like to
thank OpenEye Scientific Software for OMEGA, ROCS and QUAC-
PAC academic licenses.
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Compliance with ethical standards
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