Synthesis, antimicrobial activity, and ion transportation investigation of four new [1 + 1] condensed furan and thiophene-based cycloheterophane amides

Article abstract of DOI:10.1002/jhet.3922

Four new macrocyclic compounds with thiophene (L1 and L2) and furan (L3 and L4) rings were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, and Q-TOF spectral data. Macrocyclic amides (L1, L2, L3, and L4) were tested for ion transportation with Na⁺ and K⁺ ions, and also, antimicrobial activities were investigated against the Gram-negative Escherichia coli ATCC 25922, Gram-positive Staphylococcus aureus ATCC 25923, Gram-negative Listeria monocytogenes ATCC 19115, Gram-negative Salmonella typhimurium ATCC 14028, Bacillus cereus bacteria, and Candida albicans ATCC 10231 for all amides.

Full text of DOI:10.1002/jhet.3922

Received: 20 November 2019
DOI: 10.1002/jhet.3922
Revised: 16 January 2020
Accepted: 20 January 2020
A R T I C L E
Synthesis, antimicrobial activity, and ion transportation
investigation of four new [1 + 1] condensed furan and
thiophene-based cycloheterophane amides
Betül Erkus¸ | Hafize Özcan
| Ömer Zaim
Department of Chemistry, Trakya
Abstract
University, Edirne, Turkey
Four new macrocyclic compounds with thiophene (L1 and L2) and furan (L3
and L4) rings were synthesized and characterized by IR, 1H NMR, 13C NMR, and
Q-TOF spectral data. Macrocyclic amides (L1, L2, L3, and L4) were tested for
ion transportation with Na+ and K+ ions, and also, antimicrobial activities were
investigated against the Gram-negative Escherichia coli ATCC 25922, Gram-
positive Staphylococcus aureus ATCC 25923, Gram-negative Listeria mono-
cytogenes ATCC 19115, Gram-negative Salmonella typhimurium ATCC 14028,
Bacillus cereus bacteria, and Candida albicans ATCC 10231 for all amides.
Correspondence
Hafize Özcan, Department of Chemistry,
Trakya University, Edirne 22030, Turkey.
Email: hafizeozcan@trakya.edu.tr
Funding information
TUTAGEM; Trakya University, Grant/
Award Number: TUBAP 2012/11
1 | INTRODUCTION
encounter the biomimetic synthesis of cyclic peptide ana-
logues[27] and marvelous new macrocyclic derivatives that
Macrocyclic compounds having heteroatoms like S,O,N
are common synthetic targets in drug chemistry,[1–4] coor-
dination chemistry,[5–7] material applications,[8–10] and
nanotechnology.[11] The importance of these cyclic and
macrocyclic structures is realized early in the development
of different areas.[12–15] Especially macrocyclic compounds
are advantageous over acyclic macro-compounds as they
have cavity with varying size.[16–18] One of these classes of
compounds, cyclophane peptides, which are known as
cyclic peptides, has been found extensively in natural
products and marine environment.[19–21] For example,
plitidepsin isolated from Aplidium albicans affects the
shrinkage of tumors in pancreas, stomach, bladder, and
prostate cancers.[22] Other popular macrocyclic peptide
drug vancomycin is made by the soil bacterium Amy-
colatopsis orientalis and used to treat a number of bacterial
infections as an antibiotic.[23] Gramicidin S is also a cyclic
peptide and an antibiotic that is used for some Gram-
positive and Gram-negative bacteria as well as some
fungi.[24] As seen in these examples, there are lots of mac-
rocyclic compounds derived from natural products that
then are used as commercial drugs, and as a result, the
interest of exploring these types of macrocyclic compounds
is increasing day by day.[25,26] In medicinal chemistry, we
are selective antimicrobials,[28–31] new therapeutic,[25] and
more resistant agents to proteolytic degradation[32,33] and
fluorescent.[34] Another important aspect of these macro-
cyclic compounds is that these compounds are carrier
for biologically important ions, neutral molecules, or
catalysts.[35–39]
In our recent studies, we have achieved the synthesis
of macrocyclic tetra-amides bearing nitrogen, sulphur,
and oxygen and investigated pharmacological and ion-
transporting properties of these compounds.[37,40–42] As a
continuation of our previous work, the macrocyclic
amides that have furan or thiophene ring were synthe-
sized by following the same experimental procedure, and
also, antimicrobial activities of these compounds were
explored. These compounds have been named according
to the IUPAC Phane Nomenclature System.[43,44]
2 | RESULTS AND DISCUSSION
All the macrocyclic amides were prepared with the route
that was shown in Scheme 1, predicated on the conden-
sation of diacid chlorides with diamines at low tempera-
ture in dry dichloromethane. The synthetic procedure to
J Heterocyclic Chem. 2020;1–7.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
ERKUS¸ ET AL.
c
a
O
b
Z
O
O
O
X
X
X
X
OH
d
OH
Cl
Y
O
OH
Y
OH
O
Y : Cl or OMs
O
O
e
X
Cl
X
S
S
S
S
NH2
H2N
NH
HN
Z
O
O
L1: X= S, Z= 1,3-C6H4
L2: X= S, Z= 2,6-C6H3N
L3: X= O, Z= 1,3-C6H4
L4: X= O, Z= 2,6-C6H4N
SCHEME 1 Reagents and conditions: a, CH3OH, SOCl2,
24 hours, 58% and 84%; b, THF, LiAlH4, 2 hours, 54% and 93%; c,
MsCl, Et3N, CH2Cl2, 38% and SOCl2, CH2Cl2, pyridine, 58%; d, K2CO3,
DMF, 2-aminothiophenol 84% and 83%; e, CH2Cl2, Et3N, 0 ꢀC,
5 hours, room temperature overnight 34%, 48%, 31%, and 28% yields
FIGURE 1 1,7(1,2)-dibenzena-4(2,6)-pyridina-2,6-diaza-
3,5-dioxo-8,12-dithia-10(2,5)-furanacyclododecafan (L4) 1H NMR,
13C NMR spectra in CDCl3-d and IR spectra [Color figure can be
viewed at wileyonlinelibrary.com]
obtain pyridine-2,6-dicarbonyl dichloride and benzene-2,-
6-dicarbonyl dichloride was concerted from the litera-
ture.[45] For the synthesis of 2,5-dihydroxymethylfuran
and 2,5-dihydroxymethylthiophene, 2,5-dicarboxylic
acids of the compounds were selected, and they were
converted to the ester forms by known procedure.[46] The
diols were prepared from related esters by reduction with
LiAlH4 and used without any purification.[47] The syn-
thetic procedure to obtain the mesylate and chloride was
adapted with some modifications.[48,49] Then, they were
reacted with 2-aminothiophenol to generate diamines.
The full procedure for the preparation of the compounds
is given in Section 4. The spectroscopic data from the Q-
TOF, FTIR, 1H NMR, and 13C NMR spectroscopy provide
useful information about their formation and structural
corresponding to free aniline NH2 ѵ(N H) (3410 cm−1)
were not observed in the IR spectra of the products, which
suggests complete condensation of the reactions and possi-
ble formation of amide linkages. Another signal carbonyl
of acid chloride COCl ѵ(CO) (1750 cm−1) disappeared in
the IR spectra possibly because of the amide formation.
2.3 | Magnetic resonance spectra
1
1
characterization. In Figure 1, H NMR, 13C NMR, and
The H NMR spectra of the (L1-L4) molecules in CDCl3
FTIR spectra of compound L4 are illustrated.
do
not
give
any
signal
corresponding
to
2-aminothiophenol NH2 (at 6.8 ppm); instead, they show
broad bands in the region of 8.30 to 10.40 ppm
corresponding to amide protons. When we compare the
methylene proton chemical shifts with the starting mate-
rial diamines, no significant changes were observed as
expected, and sharp singlets around 4 ppm were observed
belonging to the macrocyclic products. In the 13C NMR
spectra of the cyclic products, peaks related to the acid
chlorides COCl (C O) (~173 ppm) disappeared; instead,
(CONH) signals were observed between 166 and 171 ppm.
2.1 | Q-TOF spectra
The Q-TOF spectra of the macrocyclic compounds give
important structural information about the nature of the
compounds. The mass spectra show a molecular positive
ion peaks [M + H]+ for each corresponding molecule. The
Q-TOF values are compatible with the calculated ones.
2.2 | Vibrational spectra
2.4 | Ion transport
The characteristic wave regions for macrocyclic amides
are as follows: 3300 to 3200 cm−1 corresponding to ѵ
(H O H) lattice water, ѵ(N H) amides, and ѵ(C H) ali-
phatic; and aromatic characteristic modes are follows:
1670 to 800 cm−1 belonging to ѵ(CONH ) amides, ѵ
(C N), and ѵ(C C) aromatic vibration modes. The bands
Macrocycles with cavities are useful transport vehicles for
biologically important ions.[35] As an easy application, we
tried Na+ and K+ selectivities of macrocycles L1, L2, L3,
and L4. To examine the ion transportation, we used a U
tube. First, macrocyclic compound (L1) (124 mg,

ERKUS¸ ET AL.
3
0.20 mmol) was dissolved in dichloromethane and trans-
ferred to glass vessel as shown in Figure 2. Then, one arm
of the U tube was filled with distilled water (6 mL), and
the other arm was filled with distilled water (6 mL) con-
taining metal cations (NaCl, 0.585 g, 10 mmol; KCl,
0.740 g 10 mmol).
phases. Results were given at Table 1. For L1 and L2, the
experiments proved that K+ and Na+ ions were transported
by both cyclophane amides from one arm to the other over
with a very low rate, and there was no observed selectivity
of this process at all. But for L3 and L4, the observation
shows that K+ ion selectivity was better than Na+.
According to these results, thiophene ring had no effect on
Na+ or K+ ion selectivity; on the other hand, furan ring
increases K+ ion selectivity. The cavities and the coordina-
tion may not be appropriate for the selected ions with thio-
phene; however, using furan instead of thiophene in the
macrocycle has increased the selectivity of K+. These results
support that both the cavity and the ring components of the
macrocycles were important in the studies of ion selectiv-
ity.[35,37,42] Additionally, to prove the ion-carrying properties
of macrocyclic compounds, a single crystal of a coordina-
tion compound of macrocycles with Na+ or K+ ion was also
tried, but there was no success in those attempts.
Dichloromethane layer was stirred gently for 72 hours,
and elemental analysis was performed in AES for water
In order to show ion coordination of macrocyclic com-
pounds, especially L4, which carries relatively the highest
amount of ion, was examined by 1H NMR. Afterwards, the
1
methylene chloride phase in U tube was evaporated; H
NMR spectrum of residue showed slight chemical shifts
for SCH2 and the CONH signals towards downfield from
3.91 to 3.98 and from 10.39 to 10.46 ppm, respectively.
FIGURE 2 Apparatus used for ion transport study [Color
figure can be viewed at wileyonlinelibrary.com]
TABLE 1 Metal ion rate (mg, %) transport of macrocycles (L1,
L2, L3, and L4)
2.5 | Microbial activity
Macrocycle
Na+
K+
The results concerning in vitro antimicrobial activities of
the macrocycles and minimal inhibitory concentration
(MIC) values of associated antibiotic and antifungal
reagents are listed in Table 2.[50] Five different concentra-
tions were studied, and percentage of alive values was
related to the macrocyclic compounds that affect the
L1
L2
L3
L4
% 1,73
% 1,46
% 1,31
% 3,49
% 1.62
% 1,26
% 4,72
% 6,68
TABLE 2 Antimicrobial activity (MIC, μmol/mL) of the (L1-L4) compounds
MICs, μmol/mL
Gram positive
Gram negative
Listeria
monocytogenes
Yeast
Compounds Staphylococcus
Bacillus
cereus
Escherichia
coli
Salmonella
typhimurium
Candida
albicans
aureus
L1
>0.204
>0.204
>0.211
>0.211
-
>0.204
0.204
0.013
0.007
0.001
-
0.204
>0.204
0.211
0.211
-
>0.204
>0.204
0.105
0.105
-
>0.204
>0.204
>0.211
>0.211
-
>0.204
0.102
>0.211
>0.211
-
L2
L3
L4
GEN
AMP
Ab
0.046 -
-
0.046
-
0.046
-
0.046
-
-
-
0.002
Note: In each case, dual tests were performed, and the average was taken as the final reading.
Abbreviation: MIC, minimal inhibitory concentration.

4
ERKUS¸ ET AL.
microorganisms by different ways. Experimental results
indicated that compounds L3 and L4 show good activities
against Gram-positive pathogen Bacillus cereus, moderate
activity against Listeria, and low activity against
Escherichia coli. Compound L2 shows moderate activity
against Candida albicans and low activity against
B cereus and Listeria. Compound L1 shows low activity to
E coli. None of the compounds were effective on Salmo-
nella typhimurium and Staphylococcus aureus.
chloride (25 mL) and cooled to 0 ꢀC. Then, thionyl chlo-
ride (1.2 mL, 16.5 mmol) was added to reaction flask. The
mixture was heated to reflux under argon for 5 hours.
The product dried in vacuo (1.31 g, 86%).
4.1.2 | Benzene-1,3-dicarbonyl dichloride
According to the procedure,[45] benzene-1,3-dicarboxylic
acid was dissolved in methylene chloride (25 mL) and
reacted with thionyl chloride (1.2 mL, 16.5 mmol). The
product was obtained 90%.
3 | CONCLUSIONS
As a result, four new [1 + 1] condensed furan and
thiophene-based cycloheterophane amides were synthe-
sized and characterized by IR, NMR, and Q-TOF. These
compounds were tested against Gram-positive (S aureus
ATCC 25923 and B cereus ATCC 11778), Gram-negative
(E coli ATCC 25922 and Listeria monocytogenes ATCC
19115, and Salmonella typhimurium ATCC 14028) bacte-
ria, yeast culture (C albicans ATCC 10231), and especially
L3 and L4 were effective against B cereus. For ion trans-
portation, there was not any significant selectivity
between Na+ and K+ ions with L1 and L2, while the
selectivity for L3 and L4 was higher only for K+ ions.
4.1.3 | Thiophene-2,5-dicarboxylic acid
dimethyl ester
According to procedure,[46] thiophene-2,5-dicarboxylic acid
(4.87 g, 28.3 mmol) was dissolved in methanol (150 mL) and
cooled to 0 ꢀC in ice bath. Then, thionyl chloride (SOCl2)
(5 mL) was slowly added dropwise to the reaction flask. The
mixture was warmed to room temperature and refluxed for
3 hours. The reaction was monitored by TLC, and methanol
was removed under reduced pressure. Residue was washed
with cold methanol. White crystalline solid was obtained
(5.16 g, yield 92%). mp: 145 ꢀC 1H NMR (300 MHz, CDCl3),
δH ppm: 7.76 (s, 2H, CH), 3.92 (s, 6H, CH3).
4 | EXPERIMENTAL SECTION
4.1 | General
4.1.4 | 2,5-Bis(hydroxymethyl)thiophene
All chemicals including pyridine-2,6-dicarboxylic acid,
benzene-1,3-dicarboxylic acid, and solvents were reagent
grade, and they were used as purchased without further
purification except dichloromethane (molecular sieve
According to procedure,[47] LiAlH4 (0.8 g, 20 mmol) was
added in dry THF (50 mL) in the 250 mL two-necked
flask under argon atmosphere. Reaction mixture
was cooled to 0 ꢀC, and thiophene-2,5-dicarboxylic acid
dimethyl ester (1.65 g, 8.24 mmol) in THF (50 mL) was
added dropwise in the flask. The reaction mixture was
heated at reflux temperature for 3 h. Then, it was stirred
at room temperature for 1 hour. Respectively, water and
15% NaOH solution were added to the flask cautiously.
The reaction mixture was filtered, and solvent was evapo-
rated. Residue was extracted with ether (4 × 20 mL).
Combined organic phases were dried over MgSO4 and
concentrated in rotary evaporator. Yellowish oil was
obtained (1.11 g, yield 93%). 1H NMR (300 MHz, D6-
Acetone), δH ppm: 6,81 (s, 2H, CH), 4,71 (s, 4H, CH2).
1
under Ar) and THF (Na/benzophenone under Ar). H
NMR and 13C NMR spectra were recorded in
deuteriochloroform solution or deuterioacetone with a
Varian Mercury Plus 300 MHz spectrometer.
Infrared spectra were obtained on Perkin Elmer FTIR
Spectrophotometer Frontier as solid or liquid phase. Q-
TOF spectra were recorded on UPLC-UHR-Q/TOF
ABSCIEX Triple TOF 4600. TLC analysis was performed
on silica-gel plates (Merck, 60 F-254). Chemical shifts (δ)
are expressed in units of parts per million relatives to
TMS. The analytical data, mass, FTIR, NMR, and physi-
cal properties are summarized for each experiment.
4.1.5 | 2,5-
thiophenedimethylmethanesulfonate
4.1.1 | Pyridine-2,6-dicarbonyl dichloride
According to the procedure,[45] pyridine-2,6-dicarboxylic
acid (1.25 g, 7.5 mmol) was dissolved in methylene
According to procedure[48] 2.21 g, 2,5-bis(hydroxymethyl)
thiophene (15,35 mmol) was dissolved in CH2Cl2

ERKUS¸ ET AL.
5
(75 mL). 6 mL triethylamine (d = 0.73 g/mL) was slowly
added dropwise at 0 ꢀC over 30 minutes. Methane sulfo-
nyl chloride (2.5 mL, 32.3 mmol, d = 1.48 g/mL) was
then added dropwise. When the addition was com-
pleted, a reflux condenser was fitted, and reaction flask
was heated at reflux temperature for 1 hour. The mix-
ture was warmed to room temperature and washed with
saturated aqueous NaHCO3 (15 mL). Organic phase was
dried over MgSO4, and solvent was evaporated under
reduced pressure. After removal of the solvent, brown
slurry was obtained. It was dried under vacuum over-
4.1.8 | Synthesis of 2,5-bis
(2-aminothiophenoxymethyl)-furan
Same procedure with 2,5-bis(2-aminothiophenoxymethyl)-
thiophene was carried out. Brown slurry was obtained
1
(2.62 g, 84%). H NMR (300 MHz, CDCl3), δH ppm: 3.85
(s, 2CH2), 4.33 (s, 2NH2), 5.78 (s, 2CH), 6.57, 6.72 (m,
4CH), 7.12, 7.21 (m, 4CH). 13C NMR (300 MHz, CDCl3)
δC, ppm: 38.90, 109.08, 115.47, 118.45, 130.55, 131.84,
137.06, 148.87, 151.07. IR (katı, cm−1): 747, 1019, 1229,
1285, 1486, 2963, 3087, 3261, 3317.
1
night (2.5 g, yield 38%) H NMR (300 MHz, CDCl3), δH
ppm: 3.15 (s, 6H, CH3), 4.58 (s, 4H, CH2), 6.34 (s,
2H, CH).
4.2 | General procedure for [1 + 1]
condensed macrocyclic amide synthesis
4.1.6 | Synthesis of 2,5-bis
(2-aminothiophenoxymethyl)-thiophene
A 500-mL, two-necked, round-bottomed flask fitted with
two dropping funnels was charged with dry CH2Cl2
(100 mL) and Et3N (3 mL) at 0 ꢀC under the argon atmo-
sphere. A solution of diacid chloride (0.5 mmol) in dry
methylene chloride (50 mL) and a solution of diamine
(0.5 mmol) in dry methylene chloride (50 mL) were
simultaneously added dropwise to a well stirred solution
at the same rate under dry argon atmosphere in a day
while maintaining the temperature at 0 ꢀC. After the
addition was completed, reaction mixture was left for
stirring at room temperature overnight. Solvent was
evaporated in a rotary evaporator under vacuum, and the
residue was added very slowly into 1 L of ice-cold dis-
tilled water with vigorous stirring for 3 days. Solid prod-
uct was decanted, washed several times with cold water,
and dried under vacuum.[37]
According to procedure,[46] 2-aminothiophenol (3.5 g,
28 mmol) in DMF (50 mL) was charged to two-necked
flask, and K2CO3 (4.5 g, 32.5 mmol) was added to the mix-
ture. The reaction mixture was stirred for 2 hours. Follow-
ing, 2,5-bis(chloromethyl)-thiophene (3.09 g, 17 mmol) in
DMF (20 mL) was added dropwise to the reaction flask
with dropping funnel and then stirred at room tempera-
ture for 2 days. Then, DMF was removed under reduced
pressure; residue was dissolved in CH2Cl2 (5 mL) and
added slowly dropwise into 500 mL of ice-cold distilled
water vigorous stirring for 2 days. The slurry was decanted
1
and air-dried (4.16 g, 83%). H NMR (300 MHz, CDCl3),
δH ppm: 4.03 (s, 2CH2), 4.21 (s, 2NH2), 6.40 (s, 2CH), 6.73
(m, 4CH), 7.16 (m, 4CH). 13C NMR (75 MHz, CDCl3) δC,
ppm: 34.70, 115.56, 117.30, 118.81, 126.15, 130.39, 136.77,
140.97, 149.17, IR (katı, cm−1): 3464, 3352 ν(N H), 2928
ν(C H), 1497 ν(C C), 783 ν(C H).
4.2.1 | 1,7(1,2),4(1,3)-Tribenzena-
2,6-diaza-3,5-dioxo-8,12-dithia-10(2,5)-
thiophenacyclododecafan (L1)
4.1.7 | Synthesis of 2,5-bis
(chloromethyl)-furan
3 mL triethylamine in CH2Cl2 (100 mL), benzene
1,3-dicarbonyl chloride (100 mg, 0.5 mmol) in CH2Cl2
(50 mL), and 2,6-bis(2-aminothiophenoxymethyl) thio-
phene (180 mg, 0.5 mmol) in CH2Cl2 (50 mL) were
reacted, and light yellow solid product was obtained
(250 mg, 34%). Thermal decomposition temperature
(TDT): 186 ꢀC. HRMS (ESI-MS): calcd for C26H20N2O2S3:
489.0765 [M + H]+; found: 489.0740. FTIR (solid, cm−1):
3377, 3360 ν(N H), 1672 ν(C O), 1501 ν(C C),
760 ν(C H). 1H NMR (CDCl3-d), δH ppm: 4.07 (s, 2CH2),
6.17 (s, 2CH), 7.15 (t, 2CH, J = 7.43 Hz), 7.42 (t, 2CH,
J = 7.82 Hz), 7.61 (m, 4CH), 8.09 (d, 2CH, J = 10.16 Hz),
8.44 (d, 2CH, J = 8.31 Hz), 9.08 (s, NH). 13C NMR
(CDCl3-d), δC ppm: 36.1, 119.4, 121.4, 122.2, 125.0,
125.23, 129.2, 131.1, 134.1, 134.8, 139.1, 139.7, 163.9.
According to procedure,[49] 2,5-bis(hydroxymethyl)-furan
(2.20 g, 17.2 mmol) was dissolved in 20 mL CH2Cl2.
Then, pyridine (3 mL, 37.09 mmol, d = 0.978 g/mL) and
thionyl chloride (5 mL, 68.5 mmol, d = 1.631 g/mL) were
added to flask at 0 ꢀC. Reaction mixture was stirred for a
night under N2 and washed with saturated aqueous
NaHCO3 (15 mL). Organic phase was dried over MgSO4,
and solvent was evaporated under reduced pressure. It
was dried under vacuum overnight and used without any
1
purification. Brown slurry was obtained (1.65 g 58%). H
NMR (300 MHz, CDCl3), δH ppm: 4.51 (s, 2CH2), 6.27
(s, 2CH).

6
ERKUS¸ ET AL.
4.2.2 | 1,7(1,2)-Dibenzena-4(2,6)-pyridina-
2,6-diaza-3,5-dioxo-8,12-dithia-10(2,5)-
thiophenacyclododecafan (L2)
474.0946 [M + H]+; found: 474.0965. FTIR (solid, cm−1):
3376, 3265 ν(N H), 1684 ν(C O), 1525 ν(C C),
747 ν(C H). 1H NMR (CDCl3-d), δH ppm: 3.91 (s, 2CH2),
5.67 (s, 2CH), 7.15 (t, 2CH, J = 7.69 Hz), 7.34 (t, 2CH,
J = 7.44 Hz), 7.59 (d, 2CH, J = 7.69 Hz), 8.03 (d, 2CH,
J = 7.99 Hz), 8.08 (t, CH, J = 7.44 Hz), 8.41(d, 2CH,
J = 7.74 Hz), 10.39 (s, 2NH). 13C NMR (CDCl3-d), δC
ppm: 39.01, 109.9, 123.4, 125.8, 126.3, 127.7, 129.8, 135.3,
138.8, 139.8, 149.0, 150.30, 162.22.
3 mL triethylamine in CH2Cl2 (100 mL), pyridine-2,6-
dicarbonyl chloride (100 mg, 0.5 mmol) in CH2Cl2 (50 mL),
and 2,6-bis(2-aminothiophenoxymethyl) thiophene (180 mg,
0.5 mmol) in CH2Cl2 (50 mL) were reacted, and light yellow
solid product was obtained (350 mg, 48%). TDT: 166 ꢀC.
HRMS (ESI-MS): calcd for C25H19N3O2S3:490.0718 [M
+ H]+; found: 490.0716. FTIR (solid, cm−1): 3367, 3290
ν(N H), 2924 ν(C H), 1687 ν(C O), 1515 ν(C C),
4.3 | Pharmacology microorganisms
1
750 ν(C H). H NMR (CDCl3-d), δH ppm: 4.05 (s, CH2),
6.14 (s, 2CH), 7.20 (d, 2CH, J = 7.19 Hz), 7.30 (t, 2CH,
J = 7.69 Hz), 7.62 (d, 2CH, J = 8.00 Hz), 8.06 (m, 3CH), 8.42
(d, 2CH, J = 7.79 Hz), 10.09 (s, 2NH). 13C NMR (CDCl3-d),
δC ppm: 37.4, 123.6, 125.5, 126.0, 126.3, 126.9, 129.9, 135.4,
139.4, 139.6, 141.6, 149.6, 162.3.
For the biological assay, broth microdilution method,
which is recommended by Clinical Laboratory Standards
Institute (CLSI), was used.[51] Selected bacteria were
Gram-negative E coli ATCC 25922, Gram-positive
S aureus ATCC 25923, Gram-negative L monocytogenes
ATCC 19115, Gram-negative Salmonella typhimurium
ATCC 14028, B cereus bacteria, and C albicans ATCC
10231, which were studied as a yeast. Ampicillin and gen-
tamicin were used in bacterial cultures as antibiotic con-
trol, and amphotericin B was used in yeast culture.
4.2.3 | 1,7(1,2),4(1,3)-Tribenzena-
2,6-diaza-3,5-dioxo-8,12-dithia-10(2,5)-
furanacyclododecafan (L3)
3 mL triethylamine in CH2Cl2 (100 mL), benzene
1,3-dicarbonyl chloride (100 mg, 0.5 mmol) in CH2Cl2
(50 mL), and 2,6-bis(2-aminothiophenoxymethyl) furan
(180 mg, 0.5 mmol) in CH2Cl2 (50 mL) were reacted, and
light brown solid product was obtained (212 mg, 31%).
TDT: 168 ꢀC. HRMS (ESI-MS): calcd for C26H20N2O3S2:
473.0994 [M + H]+; found: 473.0996. FTIR (solid, cm−1):
3357, 3337 ν(N H), 2923 ν(C H), 1675 ν(C O), 1578
4.4 | Antimicrobial screening
4.4.1 | Dilution method
Screening of the antibacterial and antifungal activities
was carried out by preparing a broth microdilution, fol-
lowing the procedure outlined in Manual of Clinical
Microbiology.[51] DMSO was used as a solvent. All the
bacteria were incubated and activated into nutrient broth
at 30 ꢀC for 24 hours, and the yeasts were incubated in
malt extract broth for 48 hours in tryptic soy broth. For
comparing antimicrobial activity, ampicillin, gentamycin,
and amphotericin B were used. The extracts, sterilized by
0.45-μm Millipore filters, were added to MH broth
medium. Serial dilutions were made that furnished a con-
centration range from 6.25 to 100 μg/mL. Absorbance
values were determined at 600 nm, and percentage of
alive values was calculated.
1
(C C), 751 ν(C H). H NMR (CDCl3-d), δH ppm: 4.06
(s, 2CH2), 5.85 (s, 2CH), 7.21 (t, 2CH, J = 7.43 Hz), 7.42
(t, 2CH, J = 7.42 Hz), 7.62 (d, 2CH, J = 7.74 Hz), 7.70
(d, CH, J = 7.91 Hz), 7.96 (s, 2NH), 8.24 (d, 2CH,
J = 7.92 Hz), 8.37 (d, 2CH, J = 7.76 Hz), 9.00 (s, CH). 13C
NMR (CDCl3-d), δC ppm: 34.05, 109.53, 121.84, 122.05,
124.39, 125.38, 130.00, 130.49, 132.85, 134.36, 135.68,
139.21, 149.87, 165.18.
4.2.4 | 1,7(1,2)-Dibenzena-4(2,6)-pyridina-
2,6-diaza-3,5-diokso-8,12-ditiya-10(2,5)-
furanasiklododekafan (L4)
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support of scien-
tific research project commission of Trakya University
(TUBAP 2012/11) and TUTAGEM for the antimicrobial
activity tests and Q-TOF analyses.
3 mL triethylamine in CH2Cl2 (100 mL), pyridine-2,-
6-dicarbonyl chloride (100 mg, 0.5 mmol) in CH2Cl2
(50 mL), and 2,6-bis(2-aminothiophenoxymethyl) furan
(180 mg, 0.5 mmol) in CH2Cl2 (50 mL) were reacted, and
light brown solid product was obtained (195 mg, 28%).
TDT: 170 ꢀC. HRMS (ESI-MS): calcd for C25H19N3O3S2:
ORCID
Hafize Özcan https://orcid.org/0000-0002-8031-6755

ERKUS¸ ET AL.
7
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How to cite this article: Erkus¸ B, Özcan H,
Zaim Ö. Synthesis, antimicrobial activity, and ion
transportation investigation of four new [1 + 1]
condensed furan and thiophene-based
cycloheterophane amides. J Heterocyclic Chem.
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