Synthesis of novel 1,4-naphthoquinone derivatives: Antibacterial and antifungal agents

Article abstract of DOI:10.1007/s00044-012-0300-y

A novel series of substituted 1,4-naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity. The structures of the novel products were characterized by spectroscopic methods. Among the tested compounds, 3a and 9 are the most effective compounds against M. luteum as potent antibacterial and C. tenuis and A. niger as potent antifungal. These two compounds are promising as biologically active compounds.

Full text of DOI:10.1007/s00044-012-0300-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:2879–2888
DOI 10.1007/s00044-012-0300-y
ORIGINAL RESEARCH
Synthesis of novel 1,4-naphthoquinone derivatives: antibacterial
and antifungal agents
•
Cemil Ibis Amac Fatih Tuyun Hakan Bahar Sibel Sahinler Ayla
•
•
•
•
Maryna V. Stasevych Rostyslav Ya. Musyanovych
•
•
Olena Komarovska-Porokhnyavets Volodymyr Novikov
Received: 5 June 2012 / Accepted: 20 October 2012 / Published online: 2 November 2012
Ó Springer Science+Business Media New York 2012
Abstract A novel series of substituted 1,4-naphthoqui-
none derivatives was synthesized and evaluated for anti-
bacterial and antifungal activity. The structures of the
novel products were characterized by spectroscopic meth-
ods. Among the tested compounds, 3a and 9 are the most
effective compounds against M. luteum as potent antibac-
terial and C. tenuis and A. niger as potent antifungal. These
two compounds are promising as biologically active
compounds.
Sahinler Ayla, 2011; Ibis and Deniz, 2010). Addition of
sulfur or nitrogen nucleophiles to naphthoquinones repre-
sents a common synthetic route to many fused heterocyclic
rings which have been used as synthetic intermediates in
medicinal chemistry and for dyestuffs (Corral et al., 2006;
Ibis et al., 2011; Voskiene et al., 2011; Takagi et al., 1998;
Matsumoto et al., 2002). Structure–activity relationship
studies of quinonoid compounds showed that the position
and number of nitrogen atoms were considerably important
factors to affect the biological activity properties (Shaikh
et al., 1986; Ryu et al., 2004).
Keywords Thio and amino substituted ꢀ
1,4-naphthoquinones ꢀ Antibacterial and antifungal activity
The evaluation of electrochemical properties of naph-
tho- and benzoquinones have also received a considerable
attention because of wide range of quinone’s biological
process from cellular respiration to blood coagulation
(Voet and Voet, 1995). The biological activity of quinones
results from their ability to accept one or two electrons to
form the corresponding radical anion or dianion species.
Since many biologic redox reactions including those with
quinones take place in hydrophobic membrane, aprotic
solvents are used in many electrochemical experiments
(Frontana and Gonzalez, 2005; Guin et al., 2011).
Introduction
The chemistry of quinones has been studied for over a
century since this class of compounds exist in many natural
products and numerous important synthetic products
(Lamourex et al., 2008; Eyong et al., 2006; Tandon et al.,
2005; Paramapojin et al., 2008; Ibis et al., 2011; Ibis and
Due to their redox potentials (Gutierrez, 1989), various
hetero-1,4-naphthoquinones have been found to possess
potent antiviral (Ganapaty et al., 2006), antimolluscidal
(Silva et al., 2005), antimalarial (Biot et al., 2004; Eyong
et al., 2006), antileishmanial (Mantyla et al., 2004), anti-
cancer, antibacterial, and antifungal activity (Ryu et al.,
2000a, b; Tandon et al., 2009).
C. Ibis (&) ꢀ H. Bahar ꢀ S. S. Ayla
Department of Chemistry, Engineering Faculty,
Istanbul University, Istanbul, Turkey
e-mail: ibiscml@istanbul.edu.tr
A. F. Tuyun
Department of Chemical Engineering, Engineering and
Architecture Faculty, Beykent University, Istanbul, Turkey
M. V. Stasevych ꢀ R. Ya. Musyanovych ꢀ
Results and discussion
O. Komarovska-Porokhnyavets ꢀ V. Novikov
Department of Technology of Biologically Active Substances,
Pharmacy and Biotechnology, National University
‘‘Lviv Polytechnic’’, Lviv, Ukraine
We have earlier synthesized various hetero-1,4-naphtho-
quinones as potent antibacterial and antifungal agents (Ibis
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Med Chem Res (2013) 22:2879–2888
et al., 2011). In continuation of our previous work for the
synthesis of biologically active quinones, we carried out
the reactions of 2,3-dichloro-1,4-naphthoquinone 1 with
sulfur nucleophiles 2 using Na2CO3 or Et3N (Scheme 1). It
is pertinent to note that further nucleophilic substitution
reactions with nitrogen nucleophiles 11a–11f did proceed
in satisfactory yields. The nucleophilic substitution reac-
tion in the presence of base is highly chemoselective
leading to formation of exclusively aminated monosulfanyl
products 12a–12f in high yields (Scheme 2).
m/z 417 (M ? Na)?, 462 (M)?, and 405 (M - H)-,
respectively.
The constitution of compounds 3a–3b is a result of an
addition to 1 followed by chloride elimination to afford a
quinonyl intermediate that then reacts with a thiol nucle-
ophile to yield the final product. In the absence of thiol
nucleophile, the alcohol that is used as reaction media
attacks the structure and 4a and 4e are formed.
In the 13C NMR spectra of compounds 3a–3b, 4d, and
4e, carbon atoms of the carbonyl groups are observed at
around 175 and 180 ppm as two peaks while the carbon
atom signals of carbonyl groups of 5a, 5c, and 5d are
around 179 ppm as one peak only. This data support the
structural assignments in Scheme 1.
The reactions of 2,3-dichloro-1,4-naphthoquinone (1)
with different thiols in ethanol in the presence of Na2CO3
gave 3a, 3b, 4d, 4e, 5a, 5c, and 5d compounds (Scheme 1).
While compounds 3a–3b are mono(thio)-substituted
naphthoquinone, the naphthoquinones 4d and 4e are
mono(thio)-substituted ethoxy derivatives. In the mass
spectrum of the compounds 4d and 4e, the measurement of
the molecular ion peak are observed at m/z 325 (M - H)-
Furthermore, the reaction of 2,3-dichloro-1,4-naphtho-
quinone 1 with 1,4-butanedithiol 8 resulted in an intramo-
lecular cyclization to yield novel interesting heterocyclic
polythioether compound 9 with diquinone moetiy as shown in
Scheme 1. The reaction resulted in the intramolecular cycli-
1
and 314 (M)?, respectively. In the H-NMR spectra of 4d
and 4e, protons in methylene group (–O–CH2–) are
observed as a multiplet at 4.2 ppm. However, these peaks
are not observed in the spectra of mono(thio)-substituted
naphthoquinones 3a–3b and bis(thio)-substituted naphtho-
quinones 5a, 5c, and 5d. In the mass spectra of compounds
5a, 5c, and 5d, the molecular ion peaks were observed at
zation because of the difunctional thiol compound. In the 13
C
NMR spectra of compound 9, the carbon atoms of the car-
bonyl groups are observed at around 180 ppm as one peak
only because of the symmetric structure of compound 9. In the
mass spectrum of compound 9, the measurement of the
molecular ion peak was observed at m/z 575 (M ? Na)?.
Scheme 1 Reaction of 1,
4-naphthoquinones with thiols,
1,4-butandithiol and diphenyl-
4-piperidinemethanol
O
O
O
O
O
S
S
S
S
SR1
9
R1
2,3,4,5
Cl
EtOH
NEt3
SH
a
CH3-O-CO-CH2-CH2-
Cl
HS
O
3
8
Cl
Cl
O
O
R1SH
2
EtOH
Na2CO3
b
SR1
Cl
Cl
Cl
Cl
OCH2CH3
O
O
O
c
d
e
1
4
O
SR1
HN
OH
HO
CH2Cl2
Na2CO3
SR1
N
O
N
H3C
5
6
O
O
N
OH
Cl
7
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Med Chem Res (2013) 22:2879–2888
2881
Scheme 2 Reactions
Cl
Cl
of 2-chloro-3-((4-chlorobenzyl)
thio) naphthalene-1,4-dione (10)
with cyclic secondary amines
O
O
S
S
N
N
Ph
O
12f
O
12e
S
OH
Ph
Ph
Ph
HN
OH
S
HN
11f
11e
Cl
Cl
Cl
F
O
O
NH
N
HN
O
O
O
S
S
S
11d
11a
N
Cl
N
O
N
F
O
H
N
O
12d
10
12a
HN
11b
11c
Cl
Cl
O
O
S
S
N
N
O
12b
O
12c
The amination of 1,4-naphthoquinone was achieved
through the substitution of the secondary cyclic amine
diphenyl(piperidin-4-yl)methanol 6, and aminosubstituted
1,4-naphthoquinone derivative 7 was obtained. The IR
spectra of compound 7 showed characteristic hydroxyl
band (–OH) at 3,520 cm-1. In the 13C NMR spectra of
compound 7, carbon atoms of the carbonyl groups are
observed at around 178 and 181 ppm as two peaks.
The reaction of 2,3-dichloro-1,4-naphthoquinone (1)
with 4-chloro-benzyl thiol in ethanol in the presence of
Na2CO3 gave 2-chloro-3-((4-chlorobenzyl)thio)naphtha-
lene-1,4-dione 10 (Ibis et al., 2011). The novel N,
S-substituted compounds 12a–f were obtained from the
reactions of compound 10 with N-nucleophiles.
The electrochemical parameters, including cathodic
peak potentials (Epc1 and Epc2), the half-wave peak
potentials (E1,‘), and the difference between the first oxi-
dation and reduction processes (DEp) are given at Table 1.
The cyclic voltammograms are shown in Fig. 1 for
DMF ? 0.1 M TBAP on Glassy Carbon Electrode at
0.1 V s-1. The compound 9 showed two monoelectronic
waves, related with the reversible or quasi-reversible one-
electron transfer process to form semiquinone (Qꢁꢂ) and
dianion (Q2-) (Frontana and Gonzalez, 2005).
Q þ eꢂ $ Qꢁꢂ
Qꢂ þ eꢂ $ Q2ꢂ
The compound 5a showed similar cathodic peaks with
an intensity decrease of the two quinone reduction waves
compared with compound 9. But the additional peaks were
observed in the voltammogram Fig. 1b (Abreu et al.,
2004).
The mass spectra of compounds 12a–f in the positive ion
mode for ESI technique confirmed the proposed structure; the
molecular ion peaks with sodium adduct were identified at
m/z 422, 420, 406, 515, and 602, respectively. In the 1H NMR
spectra of compound 12f, proton in hydroxyl group (–OH) is
observed as a singlet at 5.48 ppm.
In our new endeavors, we have synthesized different
(hetero)cyclic naphthoquinones and evaluated their anti-
fungal activity against fungi Candida tenuis VKM Y-70 and
Aspergillus niger F-1119 by the diffusion method (Murray
et al., 1995) and serial dilution method (National Com-
mittee for Clinical Laboratory Standard, 1998) with a view
to developing therapeutic agents having broad spectrum in
antifungal activity. Antibacterial activity of the synthesized
Some of the novel naphthoquinone derivatives were
studied by cyclic voltammetry in aprotic media (DMF)
using tetrabutylammonium perchlorate (TBAP) (0.10 M)
as supporting electrolyte at 100 mVs-1. Anhydrous DMF
was dried overnight with Na2SO4. A conventional three-
electrode cell was used to carry out the experiments using a
glassy carbon disk as a working electrode.
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Med Chem Res (2013) 22:2879–2888
Data presented in Tables 2, 3, and 4 show that there are
substances with antibacterial and fungicidal action among
the study compounds. The test-culture E. coli appeared not
to be sensitive to any compounds. The S. aureus was not
sensitive to compounds 3b, 4d, 4e, 5c, 7, and 12a–12f and
moderately sensitive to compounds 3a, 5a, 5d, and 9 by the
diffusion method. The M. luteum strain was sensitive to
compounds 5a and 9 at a concentration of 0.5 % (diameter
of the inhibition zone was 19.7 and 25.4 mm, respectively).
Antifungal activity against C. tenuis was observed for 5a
at concentration of 0.5 % (d = 15 mm). C. tenuis was
sensitive to compounds 3a and 9 at a concentration of
0.5 % (diameter of the inhibition zone was 13 and
11.4 mm, respectively). Compounds 3b, 4d, 5c, 7, and
12a–12f have no antifungal activity against A. niger at 0.5
and 0.1 % evaluated concentrations by the diffusion
method.
Table 1 Half-wave potentials (for the 1st wave) and electrochemical
data for novel naphthoquinone derivatives (10-3 M) in DMF/TBAP
0.1 M, t = 100 mV s-1
Compound Ep (Ic) (V) Ep (IIc) (V) DEp1 (mV) Ep1,1/2 (V)
3a
-0.372
-0.272
-0.459
-0.486
-0.542
-0.621
-0.671
-0.763
-1.057
-1.010
-1.087
-1.067
-1.224
-1.210
-1.583
-1.599
–
76
–
3b
5a
-0.2344
-0.4329
-0.4569
-0.4908
-0.5767
-0.5985
-0.6573
54
5c
57
9
102
90
12a
12b
12c
145
147
DEp1 = Epa1 - Epc1
E1,1/2 = (Epa1 ? Epc1)/2
compounds was elucidated against Escherichia coli B-906,
Staphylococcus aureus 209-P, and Mycobacterium luteum
B-917 by the diffusion method and serial dilution method
as shown in Tables 2 and 3. Their activities were compared
with those of the known antibacterial agent Vancomycin
and the antifungal agent Nystatin. Afterward, on the basis
of structure–activity relationship of antifungal activity of
the (hetero)cyclic quinone derivatives, we have further
synthesized and screened compounds of 3a–3b and
12a–12f for antibacterial and antifungal activity by the
diffusion method as shown Table 2.
Compounds 3a, 4e, and 5d were found to exhibit low
antifungal activity against A. niger on comparison with
antifungal drug Nystatin evaluated by diffusion method.
Compounds 5a and 9 (at 0.5 % concentration) had better
antifungal activity against A. niger on comparison with
Nystatin Compound 9 was equipotent with Nystatin against
A. Niger.
Comparison of antibacterial activity with antibacterial
drug Vancomycin (at 0.1 % concentration) showed that
3a (at 0.5 % concentration), 5a (at 0.5 and 0.1 %
Fig. 1 Cyclic voltammograms
of compounds 9 (a, D) and 5a
(b, O) in DMF ? 0.1 M TBAP
on Glassy Carbon Electrode at
0.1 V s-1
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Med Chem Res (2013) 22:2879–2888
2883
Table 2 Antibacterial and
antifungal activities of
compounds by diffusion method
Compounds
Concentration
(%)
Inhibition diameter of microorganism
growth, mm
Antibacterial activity
Antifungal activity
E. coli
S. aureus
M. luteum
C. tenuis
A. niger
3a
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.1
0
0
8.0
6.0
0
18.0
9.0
0
13.0
10.4
11.0
0
12.4
0
3b
4d
4e
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
12.0
0
0
0
0
0
5a
0
13.4
10.0
0
19.7
15.4
8.0
0
15.0
10.0
0
14.7
12.4
0
0
5c
0
0
0
0
0
5d
7
0
9.7
6.0
0
12.7
7.0
9.0
7.5
25.4
21.4
8.0
7.0
9.0
0
0
8.0
0
0
0
0
0
0
0
0
0
0
9
0
12.0
10.4
0
11.4
9.7
0
19.4
16.4
0
0
12a
12b
12c
12d
12e
12f
Ca
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
14.4
8.7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
a
Vancomycine was used as a
control in the tests of
0
0
13.4
7.0
0
0
0
0
0
0
0
antibacterial activity of the
synthesized compounds, and
Nystatin was used in the tests of
antifungal activity of the
synthesized compounds
0
0
0
0
0
0
0
0
0
14.0
15.0
18.0
19.0
20.0
concentration), and 9 (at 0.5 and 0.1 % concentration) had
better activity against M. luteum, with only 5a superior for
S. Aureus.
respectively. Evaluation of antifungal activity of com-
pounds 5d, 12c, 12e, and 12f showed MIC = 7.8 lg/mL
against test-culture C. tenuis. MIC of 3a, 5c, 5d, 4d, 4e, 5a,
9, and 12c were observed at 7.8–15.6 lg/mL against test-
culture A. niger (Table 4).
The biological results of the compounds were classified
as follows: the antibacterial activity was considered as
significant when the MIC was 100 lg/mL or less; moder-
ate, when the MIC was 100–500 lg/mL; weak, when the
MIC was 500–1,000 lg/mL; and inactive, when the MIC
was above 1,000 lg/mL. Evaluation of the antibacterial
activity of the synthesized compounds showed that 3a and
5a have MIC (minimum inhibition concentration) =
7.8 lg/mL, but 9 was the most potent with MIC = 1.9 lg/
mL for M. luteum (Table 3).
The biological activities of the synthesized compounds
can be correlated with their structures. It has been observed
that the compounds 3a and 5a having the long chain ester
group show more significant antibacterial activity among
the other compounds. The heterocyclic dinaphthoquinone
compound 9 also has a powerful effect on both antibacte-
rial and antifungal activity. It can be related with the cyclic
and dinaphthoquinone structure of compound 9.
Notable activity for 3a and 9 was observed against
C. tenuis fungi at 1.9 and 3.9 lg/mL concentrations,
We have synthesized compound 10 with a slight anti-
fungal activity in our previous study (Ibis et al., 2011). In
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Med Chem Res (2013) 22:2879–2888
Conclusion
Table 3 Antibacterial activities of compounds by serial dilution
method
In conclusion, compounds especially 3a and 9 have been
discovered as potent antibacterial and antifungal agents. A
convenient synthesis route to prepare 2- and 2,3-substituted
naphthalene-1,4-diones from 2,3-dichloro-1,4-naphthoqui-
none has been reported. The synthesized compounds have
been employed to prepare new antifungal agents with low
MICs against S. aureus, M. luteum bacteria and C. tenuis
and A. niger fungi in comparison with controls. The results
showed that some of the compounds (9 and 3a) have strong
activity against M. Luteum; and 3a, 9, 5d, 12c, 12e, and 12f
have strong activity against both C. tenuis and A. niger.
Whereas, the some compounds (7, 12a, 12b, and 12d) did
not show any significant antifungal and antibacterial
activity against fungi and bacteria species. Among the
tested compounds, 3a and 9 are the most effective
compounds against M. luteum as potent antibacterial
and C. tenuis and A. niger as potent antifungal. These
two compounds are promising as biologically active
compounds.
Compounds
MIC (lg/mL)
E. coli
S. aureus
M. luteum
3a
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
?
7.8
?
3b
4d
4e
?
?
125.0
?
?
5a
250.0
?
7.8
?
5c
5d
7
125.0
?
250.0
?
9
500.0
?
1.9
?
12a
12b
12c
12d
12e
12f
?
250.0
125.0
?
250.0
?
?
125.0
?
?
?: Growth of microorganisms
Table 4 Antifungal activities
of compounds by serial dilution
method
Compounds MIC (lg/mL)
C. tenuis A. niger
Experimental section
Melting points were measured using a Buchi B-540 melt-
ing point apparatus and are uncorrected. Elemental analy-
ses were performed on a Thermo Finnigan Flash EA 1112
elemental analyzer. Infrared (IR) spectra were recorded in
KBr pellets in Nujol mulls on a Perkin Elmer Precisely
3a
1.9
125.0
7.8
250.0
3b
4d
4e
31.2
250.0
15.6
125.0
7.8
?
15.6
15.6
15.6
7.8
7.8
?
1
5a
Spectrum One FTIR spectrometer. H NMR (500 MHz)
and 13C NMR (125 MHz) spectra were recorded in
CD3OD, CDCl3, and DMSO on a Varian Unity INOVA
spectrometer. Mass spectra were obtained on a Thermo
Finnigan LCQ Advantage MAX LC/MS/MS spectrometer
using the ESI technique. Products were isolated by column
chromatography on silica gel (Fluka silica gel 60, particle
size 63–200 lm). Thin-layer chromatography (TLC) was
performed on Merck silica gel plates (60F254), and detec-
tion was carried out with ultraviolet light (254 nm). All
chemicals were reagent grade and used without further
purification.
5c
5d
7
9
3.9
?
15.6
?
12a
12b
12c
12d
12e
12f
?
?
7.8
?
15.6
?
7.8
7.8
31.2
31.2
?: Growth of microorganisms
Cyclic Voltammetry measurements were performed in a
this study, the compound 10’s antifungal activity signifi-
cantly increased after the substitution of thiomorpholine
and pyrrolidine moiety. For example, compounds 12c and
12e show antifungal activities against C. tenuis. Piperidine
derivative 12b has no activity for antifungal evaluation.
But piperidine derivative with hydroxyl and phenyl
group show better antifungal activity with a MIC value of
7.8 lg/mL for C. tenuis. The compound 10’s antifungal
activity has decreased after the substitution of morpholine,
piperidine, and phenylpiperazine.
conventional three-electrode cell using a computer-
controlled system of a Gamry Reference 600 Model
potentiostat/galvanostat. A glassy carbon disk was used as
a working electrode. The surface of the working electrode
was polished with alumina before each run. A platinum
wire served as the counter electrode. The reference elec-
trode was an Ag/AgCl electrode. Electrochemical grade
tetrabutylammonium perchlorate (TBAP) in extra pure
DMF was employed as the supporting electrolyte at a
concentration of 0.10 M. Prior to each run solutions were
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Med Chem Res (2013) 22:2879–2888
2885
purged with nitrogen. Measurements were made over a
(3b): Yellow solid; yield 1.62 g (78 %); m.p.
265–266 °C; Rf: 0.57 (PET:CHCl3 = 2:1); IR (KBr): t
(cm-1) 3311 (C–Harom), 1589, 1538 (C=C), 1665 (C=O);
1H NMR (500 MHz, CDCl3): d 7.89–7.91 (d, J = 7.32 Hz,
1H, CHarom), 8.10–8.11 (d, J = 7.32 Hz, 1H, CHarom),
7.64–7.71 (m, 2H, CHarom); 13C-NMR (125 MHz, CDCl3):
d 135.60, 134.02, 133.51, 133.28, 131.47, 130.71, 130.51,
130.13, 126.67, 126.56 (Carom), 144.69, 139.74 (=C–S),
176.75, 174.14 (C=O); Anal. Calcd. for C16H4Cl6O2S (M,
472.98): C, 40.63; H, 0.85; S, 6.78 %. Found C, 40.53; H,
0.90; S, 7.45 %.
potential range between 1 and -2 V with a step rate of
0.1 V s-1
.
General procedures for the synthesis of 1,
4-naphthoquinones
General procedure 1: for the synthesis of mono-,
disulfanyl-1,4-naphthoquinones, and ethoxy sulfanyl-
1,4-naphthoquinones
Sodium carbonate (1.52 g) was dissolved in ethanol as
reaction media (65 mL). 2,3-Dichloro-1,4-naphthoquinone
(1) and thiol (2a–2e) were added to the solution. Without
heating, the mixture was stirred for 6–8 h. The color of the
solution changed quickly, and the extent of the reaction
was monitored by TLC. The reaction mixture was extracted
in a Soxhlet extractor with dichloromethane. After recov-
ery of the solvent, the crude product was purified by col-
umn chromatography.
2-(4-Hydroxyphenylthio)-3-ethoxynaphthalene-1,4-dione
(4d) and 2,3-bis(4-hydroxyphenylthio)naphthalene-1,4-dione
(5d) were synthesized by the reaction of 1 (1 g, 4.38 mmol)
and 2d (0.555 g, 4.38 mmol) by general procedure 1.
(4d): Black solid, yield 0.51 g (33 %); m.p. 288–289 °C;
Rf: 0.85 (CHCl3); IR (KBr): t (cm-1) 3374 (O–H), 2959 (C–
H
arom), 2925 (C–Haliph), 1661(C=O), 1593 (C=C); 1H NMR
(500 MHz, CDCl3): d 1.2 (t, J = 6.83, 3H, CH3), 4.2 (q, 2H,
O–CH2), 5.6 (s, 1H, O–H), 6.6–8 (m, 8H, CHarom); 13C-NMR
(125 MHz, CDCl3): d 14.57 (CH3), 69 (O–CH2), 125.50,
125.73 (–C–S), 129.44, 130.42, 131.15, 132.32, 132.86,
133.12, 134.33 (Carom), 154.98 (C–O), 157.16 (C–OH),
178.74, 181.46 (C=O); MS (–ESI): 325 (M - H)-; Anal.
Calcd. for C18H14O4S (M, 326.37): C, 66.24; H, 4.32; S,
9.82 %. Found C, 66.65; H, 4.54; S, 10.12 %.
Methyl
3-(2-chloro-1,4-dihydro-1,4-dioxonaphthalen-
3-ylthio)propanoate (3a) and 3,30-((1,4-Dioxo-1,4-dihydro-
naphthalen-2,3-diyl)di(sulfandiyl)) dipropanoate (5a) were
synthesized by the reaction of 1 (1 g, 4.38 mmol) and 2a
(0.49 mL, 4.38 mmol) by general procedure 1.
(3a): Yellow solid; yield 0.71 g (52 %); m.p.
126–127 °C; Rf: 0.44 (CHCl3); IR (KBr): t (cm-1) 3310,
3032 (C–Harom), 2953 (C–Haliph), 1588, 1512 (C=C), 1670,
1727 (C=O); 1H NMR (500 MHz, CDCl3): d 2.71 (t,
J = 7.32 Hz, 2H, (C=O)–CH2–), 3.55 (t, J = 7.32 Hz, 2H,
S–CH2), 3.63 (s, 3H, O–CH3), 7.65–7.69 (m, 2H, CHarom),
8.01–8.08 (m, 2H, CHarom);13C NMR (125 MHz, CDCl3):
d 29.33 ((C=O)–CH2–), 35.55 (S–CH2), 52.21 (O–CH2–),
134.44, 134.15, 132.79, 131.42, 127.63, 127.50 (Carom),
148.37, 140.68 (=C–S), 179.99, 175.23, 171.86 (C=O); MS
(?ESI): 333 (M ? Na)?; Anal. Calcd. for C14H11ClO4S
(M, 310.75): C, 54.11; H, 3.57; S, 10.32 %. Found C,
54.06; H, 3.45; S, 12.25 %.
(5d): Black solid; yield 0.47 g (30 %); m.p.
240–241 °C; Rf: 0.75 (CHCl3); IR (KBr): t (cm-1) 3406
(O–H), 2978 (C–Harom), 2926 (C–Haliph), 1662(C=O), 1587
1
(C=C); H NMR (500 MHz, CDCl3): d 5.1 (s, 2H, O–H),
6.6–7.4 (m, 12H, CHarom); 13C-NMR (125 MHz, CDCl3): d
115.12, 115.18, 130.35, 131.86, 132.04, 132.98 (Carom
,
CHarom), 127.59 (=C–S), 154.94, 176.22 (C=O); MS
(–ESI): 405 (M - H)-; Anal. Calcd. for C22H14O4S2 (M,
406.47): C, 65.01; H, 3.47; S, 15.78 %. Found C, 65.65; H,
3.66; S, 15.21 %.
2-(1-Methyl-1H-imidazol-2-ylthio)-3-ethoxynaphthalene-1,
4-dione (4e) was synthesized by the reaction of 1 (1 g,
4.38 mmol) and 2e (0.503 g, 4.38 mmol) by general proce-
dure 1.
(5a): Red solid; yield 0.61 g (35 %); m.p. 85–86 °C; Rf:
0.16 (CHCl3); IR (KBr): t (cm-1) 3298, 3021 (C–Harom),
2955 (C–Haliph), 1589 (C=C), 1658, 1732 (C=O); 1H NMR
(500 MHz, CDCl3): d 2.65 (t, J = 7.32 Hz, 4H, (C=O)–
CH2–), 3.41 (t, J = 7.32 Hz, 4H, S–CH2), 3.59 (s, 6H, O–
CH3), 7.59–7.63 (m, 2H, CHarom), 7.93–7.97 (m, 2H,
CHarom); 13C NMR (125 MHz, CDCl3): d 30.03 ((C=O)–
CH2–), 35.49 (S–CH2), 52.09 (O–CH2–), 133.81, 133.02,
127.14 (Carom), 147.50 (=C–S), 178.92, 171.96 (C=O); MS
(?ESI): 417 (M ? Na)?; Anal. Calcd. for C18H18O6S2 (M,
394.46): C, 54.81; H, 4.60; S, 16.26 %. Found C, 53.96; H,
4.78; S, 17.54 %.
(4e): Red solid; yield 0.68 g (45 %); m.p. 152–153 °C;
Rf: 0.7 (CHCl3); IR (KBr): t (cm-1) 2980 (C–Harom), 2929
(C–Haliph), 1679 (C=O), 1620 (–C=N), 1593 (C=C); 1H-NMR
(500 MHz, CDCl3): d 1.3 (t, J = 7.32, 3H, CH3), 3.6
(s, 3H, N–CH3), 4.2 (q, 2H, –OCH2), 6.6 (d, 1H, C–
H
imidazole), 6.8 (d, 1H, C–Himidazole); 13C-NMR (125 MHz,
CDCl3): d 14.81 (CH3), 34.43 (N–CH3), 69.11 (O–CH2),
125.77, 125.87 (N–C=C), 124.47, 130.05, 130.15, 132.78
(CHarom), 133.60 (=C–S), 155.41 (S–C =), 164.43 (=C–O),
178.62, 179.93 (C=O); MS (?ESI): 314 (M)?; Anal.
Calcd. for C16H14N2O3S (M, 314.36): C, 61.13; H, 4.49; S,
10.20; N, 8.91 %. Found C, 61.28; H, 4.10; S, 10.01; N,
8.83 %.
2-Chloro-3-(perchlorophenylthio)naphthalene-1,4-dione
(3b) was synthesized by the reaction of 1 (1 g, 4.38 mmol)
and 2b (1.24 g, 4.38 mmol) by general procedure 1.
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2,3-Bis(2-phenoxyethylthio)naphthalene-1,4-dione (5c)
was synthesized by the reaction of 1 (1 g, 4.38 mmol) and
2c (0.679 g, 4.38 mmol) by general procedure 1.
was stirred for 4–6 h. The color of the solution changed
quickly, and the extent of the reaction was monitored by
TLC. The reaction mixture was extracted in a Soxhlet
extractor with dichloromethane. After recovery of the
solvent, the crude product was purified by column
chromatography.
(5c): Orange solid; yield 0.51 g (30 %); m.p. 83–84 °C;
Rf: 0.75 (CHCl3); IR (KBr): t (cm-1) 3068 (C–Harom),
2963 (C–Haliph), 1660 (C=O), 1589 (C=C); 1H NMR
(500 MHz, CDCl3): d 3.5(t, J = 6.35 Hz, 4H, –S–CH2),
4.3 (t, J = 6.34 Hz, 4H, O–CH2), 6.7–8.1 (m, 14H,
CHarom); 13C-NMR (125 MHz, CDCl3): d 33.76 (S–CH2),
76.74 (CH2–O), 114.45, 114.5, 121.00, 121.01, 126.97,
129.41, 133.02, 133.54 (Carom, CHarom), 147.71 (–C–S),
158.17 (=C–O), 178.82 (C=O); MS (?ESI): 462 (M)?;
Anal. Calcd. for C26H22O4S2 (M, 462.58): C, 67.51; H,
4.79; S, 13.86 %. Found C, 67.25; H, 4.92; S, 13.66 %.
2-Chloro-3-(4-(hydroxydiphenylmethyl)piperidin-1-yl)naph-
thalene-1,4-dione (7) was synthesized by the reaction of 1 (1 g,
4.38 mmol) and 6 (4.71 g, 8.76 mmol) by general procedure 3.
(7): Red solid; yield 1.50 g (74 %); m.p. 151–152 °C;
Rf : 0.29 (CHCl3); IR (KBr): t (cm-1) 3520 (–OH), 3058,
3020 (C–Harom), 2952, 2854 (C–Haliph), 1592, 1553 (C=C),
1672, 1642 (C=O); 1H NMR (500 MHz, CD3OD): d
2.81–2.86 (m, 1H, CHpiperidine), 3.91 (m, 2H, CH2piperidine),
3.36 (m, 2H, CH2piperidine), 1.76 (m, 2H, CH2piperidine), 1.60
(m, 2H, CH2piperidine), 5.48 (s, 1H, OH), 7.14–7.17 (m, 2H,
CHarom), 7.27–7.31 (m, 4H, CHarom), 7.55–7.57 (m, 4H,
CHarom), 7.68–7.74 (m, 4H, CHarom), 7.97–7.99 (d,
J = 7.32 Hz, 1H, CHarom), 8.01–8.02 (d, J = 7.32 Hz, 1H,
CHarom); 13C NMR (125 MHz, CD3OD): d 27.74, 43.95
(CH2piperidine), 52.39 (CH2piperidine), 79.37 ((Ph)2–C–OH),
133.94, 133.09, 131.88, 131.74, 127.81, 126.73, 126.13,
126.03, 125.99, 125.91, 121.10, 115.45 (Carom), 146.64
(=C–Cl), 151.23 (=C–N), 181.66, 178.38 (C=O); MS
(?ESI): 458 (M ? H)?; Anal. Calcd. for C28H24ClNO3
(M, 457.95): C, 73.44; H, 5.28; N, 3.06 %. Found C, 73.19;
H, 5.31, N, 3.16 %.
General procedure 2: for the synthesis of cyclic 1,4-
naphthoquinone
2,3-Dichloro-1,4-naphthoquinone (1 g, 4.38 mmol) was
dissolved in ethanol as reaction media (65 mL). Subse-
quently, 1,4-butanedithiol (8) (0.51 mL, 4.38 mmol) and
triethylamine (catalytic amount) were added to the solu-
tion. Without heating, the mixture was stirred for 6–8 h.
The color of the solution changed quickly, and the extent of
the reaction was monitored by TLC. The reaction mixture
was extracted in a Soxhlet extractor with dichloromethane.
After recovery of the solvent, the crude product was puri-
fied by column chromatography.
2-(4-Chlorobenzylthio)-3-morpholinonaphthalene-1,4-dione
(12a) was synthesized by the reaction of 10 (0.2 g, 0.57 mmol)
and 11a (0.10 g, 1.14 mmol) by general procedure 3.
(12a):Purple oil; yield 0.198 g(86 %);Rf: 0.3(CHCl3);IR
(KBr): t (cm-1) 3064 (C–Harom), 2984, 2944 (C–Haliph),
1591, 1494 (C=C), 1661, 1653 (C=O); 1H–NMR (500 MHz,
CDCl3): d 3.68 (t, J = 4.39 Hz, 4H, CH2morpholine), 3.33
(t, J = 4.39 Hz, 4H, CH2morpholine), 4.00 (s, 2H, S–CH2),
7.04–7.03 (d, J = 8.30 Hz, 2H, CHarom), 7.08–7.10 (d,
J = 8.30 Hz, 2H, CHarom), 7.55–7.63 (m, 2H, CHarom),
7.87–7.89 (d, J = 7.81 Hz, 1H, CHarom), 8.00–8.02 (d,
J = 8.30 Hz, 1H, CHarom); 13C-NMR (125 MHz, CDCl3): d
53.38 (CH2morpholine), 67.61 (CH2morpholine), 38.61 (S–CH2),
136.85, 134.09, 133.12, 132.17, 130.49, 128.69, 126.89,
126.55, 123.08 (Carom), 155.70 (=C–S), 181.97, 181.95
(C=O); MS (?ESI): 422 (M ? Na)?, 363 (M-Cl)?; Anal.
Calcd. for C21H18ClNO3S (M, 399.89): C, 63.07; H, 4.54; N,
3.50; S, 8.02 %. Found C, 63.10; H, 4.20, N, 3.45; S, 7.50 %.
2-(4-Chlorobenzylthio)-3-(piperidin-1-yl)naphthalene-1,
4-dione (12b) was synthesized by the reaction of 10 (0.4 g,
1.15 mmol) and 11b (0.196 g, 2.30 mmol) by general
procedure 3.
7,8,9,10,19,20,21,22-octahydrodinaphtho[2,3-b:20,30-j]
[1,4,9,12]tetrathiacyclohexadecine-5,12,17,24-tetraone (9)
was synthesized by the reaction of 1 (1 g, 4.38 mmol) and
8 (0.51 mL, 4.38 mmol) by general procedure 2.
(9): Red solid; yield 0.22 g (9 %); m.p. 115–116 °C; Rf:
0.59 (CHCl3); IR (KBr): t (cm-1) 3281, 3068 (C–Harom),
2918, 2896 (C–Haliph), 1587, 1499 (C=C), 1655 (C=O); 1H
NMR (500 MHz, CDCl3): d 2.01 (m, 8H, S–CH2–CH2),
3.48 (t, J = 5.86 Hz, 8H, S–CH2), 7.61–7.62 (dd,
J = 3.42, 5.37 Hz, 2H, CHarom), 7.99–8.01 (dd, J = 3.41,
5.37 Hz, 2H, CHarom);13C NMR (125 MHz, CDCl3): d
28.40 (S–CH2–CH2), 32.39 (S–CH2), 133.96, 132.32,
127.32 (Carom), 147.52 (=C–S), 180.73 (C=O); MS (?ESI):
575 (M ? Na)?; Anal. Calcd. for C28H24O4S4 (M, 552.75):
C, 60.84; H, 4.38; S, 23.20 %. Found C, 61.16; H, 4.26; S,
22.71 %.
General procedure 3: for amination of 1,4-
naphthoquinones
Sodium carbonate (1.52 g) was dissolved in dichloro-
methane as reaction media (50 mL). 2,3-Dichloro-1,
4-naphthoquinone (1) or 2-chloro-3-((4-chlorobenzyl)thio)
naphthalene-1,4-dione (10) and the secondary cyclic amine
were added to the solution. Without heating, the mixture
(12b): Brown oil; yield 0.41 g (90 %); Rf : 0.67
(CHCl3); IR (KBr): t (cm-1) 3064 (C–Harom), 2935, 2853
(C–Haliph), 1593, 1533 (C=C), 1669, 1634 (C=O); 1H–
NMR (500 MHz, CDCl3): d 3.25 (t, J = 5.86 Hz, 4H,
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Med Chem Res (2013) 22:2879–2888
2887
CH2piperidine), 1.57 (m, 6H, CH2piperidine), 3.93 (s, 2H, S–
CH2), 7.00–7.02 (d, J = 8.30 Hz, 2H, CHarom), 7.04–7.06
(d, J = 8.30 Hz, 2H, CHarom), 7.49–7.58 (m, 2H, CHarom),
7.82–7.84 (d, J = 7.32 Hz, 1H, CHarom), 7.97–7.99 (d,
J = 7.81 Hz, 1H, CHarom); 13C-NMR (125 MHz, CDCl3):
d 25.75, 23.08 (CH2piperidine), 53.40 (CH2piperidine), 37.31
(S–CH2), 135.81, 132.62, 131.97, 131.66, 131.54, 131.09,
129.24, 127.29, 125,52, 125.11, 119.85 (Carom), 155.77
(=C–S), 181.04, 180.59 (C=O); MS (?ESI): 420
(M ? Na)?; Anal. Calcd. for C22H20ClNO2S (M, 397.92):
C, 66.40; H, 5.07; N, 3.52; S, 8.06 %. Found C, 66.07; H,
4.97, N, 3.56; S, 7.56 %.
2-((4-Chlorobenzyl)thio)-3-thiomorpholinonaphthalene-
1,4-dione (12e) was synthesized by the reaction of 10
(0.45 g, 1.29 mmol) and 11e (0.27 g, 2.58 mmol) by gen-
eral procedure 3.
(12e):Purple oil; yield 0.49 g (91 %); Rf: 0.83 (CHCl3);IR
(KBr): t (cm-1) 3063 (C–Harom), 2958, 2909, 2840
(C–Haliph), 1592, 1537 (C=C), 1667, 1642 (C=O); 1H-NMR
(500 MHz, CDCl3): d 2.66 (t, J = 4.88 Hz, 4H, CH2thi-
omorpholine), 3.47 (t, J = 4.88 Hz, 4H, CH2thiomorpholine), 4.03
(s, 2H, S–CH2), 7.03–7.05 (d, J = 8.29 Hz, 2H, CHarom),
7.08–7.11 (d, J = 8.30 Hz, 2H, CHarom), 7.56–7.64 (m, 2H,
CHarom), 7.88–7.89 (d, J = 7.32 Hz, 1H, CHarom), 8.00–8.02
(d, J = 6.83 Hz, 1H, CHarom);13C-NMR (125 MHz, CDCl3):
d 55.27 (CH2thiomorpholine), 28.27 (CH2thiomorpholine), 38.51
(S–CH2), 136.80, 134.04, 133.28, 133.19, 133.01, 132.21,
130.48, 128.73, 126.92, 126.57, 125.69 (Carom), 156.65
(=C–S), 182.21, 181.88 (C=O); MS (?ESI): 438 (M ? Na)?,
379 (M-Cl)?; Anal. Calcd. for C21H18ClNO2S2 (M, 415.96):
C, 60.64; H, 4.36; N, 3.37; S, 15.42. Found C, 60.33; H, 4.25,
N, 3.30; S, 14.95 %.
2-(4-Chlorobenzylthio)-3-(pyrrolidin-1-yl)naphthalene-
1,4-dione (12c) was synthesized by the reaction of 10
(0.4 g, 1.15 mmol) and 11c (0.163 g, 2.30 mmol) by gen-
eral procedure 3.
(12c): Brown oil; yield 0.42 g (95 %); Rf: 0.38 (CHCl3);
IR (KBr): t (cm-1) 3064 (C–Harom), 2973, 2875 (C–Haliph),
1592, 1506 (C=C), 1674, 1621 (C=O); 1H-NMR
(500 MHz, CDCl3): d 1.74 (m, 4H, CH2pyrrolidine), 3.62 (m,
4H, CH2pyrrolidine), 3.73 (s, 2H, S–CH2), 7.00–7.02 (d,
J = 8.79 Hz, 2H, CHarom), 7.09–7.10 (d, J = 8.30 Hz, 2H,
CHarom), 7.48–7.61 (m, 2H, CHarom), 7.76–7.78 (d,
J = 7.80 Hz, 1H, CHarom), 8.00–8.02 (d,3J = 6.35 Hz, 1H,
CHarom); 13C-NMR (125 MHz, CDCl3): d 24.42 (CH2pir-
olidin), 53.37 (CH2pyrrolidine), 38.36 (S–CH2), 135.87,
132.96, 132.64, 131.66, 130.77, 130.72, 129.26, 127,28,
125.06, 124.73, 105.38 (Carom), 155.73 (=C–S), 183.18,
179.61 (C=O); MS (?ESI): 406 (M ? Na)?, 348 (M-Cl)?;
Anal. Calcd. for C21H18ClNO2S (M, 383.89): C, 65.70; H,
4.73; N, 3.65; S, 8.34 %. Found C, 65.50; H, 4.60, N, 3.53;
S, 7.35 %.
2-((4-Chlorobenzyl)thio)-3-(4-(hydroxydiphenylmeth-
yl)piperidin-1-yl)naphthalene-1,4-dione (12f) was syn-
thesized by the reaction of 10 (0.50 g, 1.44 mmol) and
11f (0.768 g, 2.88 mmol) by general procedure 3.
(12f): Purple solid; yield 0.75 g (90 %); m.p.
101–102 °C; Rf : 0.15 (CHCl3); IR (KBr): t (cm-1) 3064
(C–Harom), 2935, 2853 (C–Haliph), 1593, 1533 (C=C), 1669,
1634 (C=O); 1H-NMR (500 MHz, CD3OD): d 1.53 (m, 2H,
CH2piperidine), 1.69 (t, J = 7.32 Hz, 2H, CH2piperidine), 2.78
(m, 1H, CHpiperidine), 3.25 (m, 2H, CH2piperidine), 3.64 (t,
J = 7.32 Hz, 2H, CH2piperidine), 3.93 (s, 2H, S–CH2), 5.48
(s, 1H, OH), 7.07–7.11 (m, 4H, CHarom), 7.15–7.18 (m, 2H,
CHarom), 7.27–7.31 (m, 4H, CHarom), 7.53–7.55 (m, 4H,
CHarom), 7.68–7.72 (m, 2H, CHarom), 7.88–7.87 (d,
J = 7.32 Hz, 1H, CHarom), 7.97–7.99 (d, J = 7.32 Hz, 1H,
CHarom); 13C-NMR (125 MHz, CD3OD): d 53.82, 43.83,
27.64 (CH2piperidine), 37.79 (S–CH2), 79.38 ((Ph)2–C–OH),
146.56, 137.16, 133.75, 132.97, 132.75, 132.51, 132.28,
130.51, 128.07, 127.80, 126,37, 126.14, 125.73, 119.20
(Carom), 157.53 (=C–S), 182.05, 182.01 (C=O); MS
(?ESI): 602 (M ? Na)?, 544 (M-Cl)?; Anal. Calcd. for
C35H30ClNO3S (M, 580.14): C, 72.46; H, 5.21; N, 2.41; S,
5.53 %. Found C, C, 72.10; H, 5.20, N, 2.01; S, 4.65 %.
2-(4-Chlorobenzylthio)-3-(4-(2-fluorophenyl)piperazin-
1-yl)naphthalene-1,4-dione (12d) was synthesized by the
reaction of 10 (0.4 g, 1.15 mmol) and 11d (0.42 g,
2.30 mmol) by general procedure 3.
(12d): Brown oil; yield 0.50 g (88 %); Rf: 0.59
(CHCl3); IR (KBr): t (cm-1) 3066, 3015 (C–Harom), 2903,
2839 (C–Haliph), 1592, 1532 (C=C), 1669, 1638 (C=O);
1H-NMR (500 MHz, CDCl3): d 3.09 (t, J = 4.88 Hz, 4H,
CH2piperazin), 3.50 (t, J = 6.35 Hz, 4H, CH2piperazine), 3.99
(s, 2H, S–CH2), 6.86–7.02 (m, 5H, CHarom), 7.02–7.04 (d,
J = 8.30 Hz, 2H, CHarom), 7.06–7.08 (d, J = 8.80 Hz, 2H,
CHarom), 7.54–7.62 (m, 2H, CHarom), 7.87–7.89 (d,
J = 7.80 Hz, 1H, CHarom), 8.00–8.02 (d, J = 7.80 Hz, 1H,
CHarom); 13C-NMR (125 MHz, CDCl3): d 53.05, 51.46
(CH2piperazine), 38.66 (S–CH2), 156.99, 155.03, 136.90,
134.07, 133.11, 132.24, 130.53, 128.70, 126.90, 126.54,
124.79, 124.77, 123.19, 122.90, 119.46, 119.44, 116.39
(Carom), 156.01 (=C–S), 182.07, 181.98 (C=O); MS
(?ESI): 515 (M ? Na)?; Anal. Calcd. for C27H22
ClFN2O2S (M, 492.99): C, 65.78; H, 4.50; N, 5.68; S,
6.50 %. Found C, 65.48; H, 4.25, N, 5.38; S, 5.96 %.
Antifungal and antibacterial evaluation
Diffusion technique
Antibacterial activity of compounds was evaluated by
diffusion in peptone on nutrient medium (meat-extract agar
for bacteria; wort agar for fungi). The microbial loading
was 109 cells (spores)/1 mL. The required incubation
periods were as: 24 h at 35 °C for bacteria and 48–72 h at
123

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Acknowledgments The financial support from TUBITAK for
Ukraine-Turkey agreement (Project No. 109T617) and from State
Agency on Science, Innovations and Informatization of Ukraine
(Project No. M/309-2011) are gratefully acknowledged.
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