Synthesis and in Vitro Biological Evaluation of Aminonaphthoquinones and Benzo[ b ]phenazine-6,11-dione Derivatives as Potential Antibacterial and Antifungal Compounds

Article abstract of DOI:10.1155/2015/645902

A series of 2-arylamino-3-chloro-1,4-naphthoquinone derivatives (3a-h) by the reaction of 2,3-dichloro-1,4-naphthoquinone with aryl amines (2a-h) and benzo[b]phenazine-6,11-dione derivatives (4a-c) by the treatment of 2-arylamino-3-chloro-1,4-naphthoquino

Full text of DOI:10.1155/2015/645902

Hindawi Publishing Corporation
Journal of Chemistry
Volume 2015, Article ID 645902, 8 pages
http://dx.doi.org/10.1155/2015/645902
Research Article
Synthesis and In Vitro Biological
Evaluation of Aminonaphthoquinones and
Benzo[b]phenazine-6,11-dione Derivatives as Potential
Antibacterial and Antifungal Compounds
Amaç Fatih Tuyun,1 Nilüfer Bayrak,2 Hatice YJldJrJm,2 Nihal Onul,2
Emel Mataraci Kara,3 and Berna Ozbek Celik3
1
˘
Chemical Engineering Department, Engineering and Architecture Faculty, Beykent University, Ayazaga, 34396 Istanbul, Turkey
2Chemistry Department, Engineering Faculty, Istanbul University, Avcılar, 34320 Istanbul, Turkey
3Pharmaceutical Microbiology Department, Pharmacy Faculty, Istanbul University, Beyazit, 34116 Istanbul, Turkey
Correspondence should be addressed to Amac¸ Fatih Tuyun; afuyun@gmail.com and Nihal Onul; yilm@istanbul.edu.tr
Received 30 March 2015; Revised 8 June 2015; Accepted 10 June 2015
Academic Editor: Marco Radi
Copyright © 2015 Amac¸ Fatih Tuyun et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
A series of 2-arylamino-3-chloro-1,4-naphthoquinone derivatives (3a–h) by the reaction of 2,3-dichloro-1,4-naphthoquinone
with aryl amines (2a–h) and benzo[b]phenazine-6,11-dione derivatives (4a–c) by the treatment of 2-arylamino-3-chloro-1,4-
naphthoquinone derivatives (3a–h) with sodium azide were synthesized and tested for their in vitro antibacterial and antifungal
activities. e results suggest that compounds 3d and 3g had potent antifungal activity against Candida albicans (MIC =
78.12 ꢀg/mL). All synthesized compounds (3a–h, 4a–c) possessed activity against E. faecalis with MIC values of between 312.5 and
1250 ꢀg/mL. Benzo[b]phenazine-6,11-dione derivatives (4a–c) were mostly active against Gram-positive bacteria. e structures
1
of the new members of the series were established on the basis of their spectral properties (IR, H NMR, 13C NMR, and mass
spectrometry).
1. Introduction
1,4-naphthoquinones have shown an interesting variety of
biological properties, such as antimalarial [10–12], antibac-
terial [13–16], antifungal [17–20], antitumor [21, 22], anti-
inflammatory [23, 24], and antiallergic [25, 26] activities, due
to their redox potentials [27]. Some important compounds
shown in Figure 1 are good examples for emphasizing their
important biological properties [28, 29]. All findings showed
that the position and the number of nitrogen atoms in the
structure could improve the redox potential of the quinone
system for biological properties [30]. It has been reported
that, generally, increase of the number of the nitrogen atoms
and the rings enhances the activities [19].
e reactions of amines and their derivatives with 1,4-
naphthoquinones to give 2-aryl(alkyl)amino-1,4-naphthoqu-
inone derivatives have been known for several years [31].
A lot of studies related to 1,4-naphthoquinones containing
a nitrogen [32, 33], sulfur [34], or an oxygen atom [35] in
Quinones are active compounds used widely as raw materials
in pharmaceuticals and agrochemical industries. Particularly,
(hetero)cyclic quinone moieties not only exist in many nat-
ural products and pharmaceutical compounds, but also are
well-known and versatile building blocks for the synthesis of
quinones derived from benzoquinone, naphthoquinone, or
anthracenequinone condensed with five-membered hetero-
cycles [1–3] such as isoxazoles [4], six-membered heterocy-
cles [3, 5], and seven-membered heterocycles [6, 7] such as
1,4-benzodiazepines [8] in order to evaluate their important
bioactivities. erefore, among the bioactive quinones, 1,4-
naphthoquinones have been extensively studied since those
ones contain two ketone groups as a crucial pharmacophore
for their bioactivities because of their ability to accept elec-
trons [9]. A considerable number of natural and synthetic

2
Journal of Chemistry
O
O
O
OH
CH3
N
NH2
O
N
CH3
O
O
OH
O
NH2
H3C
HO
N
H
H3C
O
O
R
H3C
Streptonigrin
Griffithazanone A
O
O
O
O
O
N
N
R
N
N
H
N
NH
CH3
O
CH3
Pyrido[2,3-b]phenazine-6,11-dione [29].
Figure 1: Examples of bioactive aminonaphthoquinones.
Calothrixin B
2-Aminonaphthoquinones
the 2-position or 2,3-positions have been reported up to
now because of their use in a variety of medical and bio-
logical applications as mentioned above. e reactions of
2-arylamino-3-chloro-1,4-naphthoquinone derivatives with
sodium azide to give heterocyclic phenazine derivatives have
been described previously [29, 36, 37]. Analogously, the
reactions of 2-sulfanyl-3-chloro-1,4-naphthoquinone deriva-
tives with sodium azide to give heterocyclic phenothiazine
derivatives have been also reported [17, 34]. Addition-
ally, the cyclization of 2-arylamino-1,4-naphthoquinones to
benzo[b]phenazine-6,11-dione 5-oxides by the treatment with
nitrosylsulfuric acid as a new group of tetracyclic diaza-
quinones has been recently reported [38].
2. Results and Discussion
2.1. Chemistry. It is known that the reactions of 2,3-dichloro-
1,4-naphthoquinone (1) with aryl and alkyl amines proceed
by nucleophilic substitution [15–17, 28, 39–43]. A series
of 2-arylamino-1,4-naphthoquinone derivatives (3a–h) were
synthesized via the nucleophilic substitution reaction of 2,3-
dichloro-1,4-naphthoquinone (1) by appropriate aryl amines
(2a–h) in refluxing ethanol as shown in Scheme 1. e
aminonaphthoquinones (3a–h) were obtained in around 55–
60% yields as dark orange, red, dark red, and purple solid.
Structures of the aminonaphthoquinone derivatives were
confirmed by spectroscopic methods comprising 1H and 13
C
NMR, IR, and MS. In the MS of aminonaphthoquinones,
the molecular ion peaks of compounds 3a, 3f, and 3g were
observed at 343 [M]+, 362 [M–H]+, and 362 [M–H]+ , respec-
tively. Some of the IR spectra of aminonaphthoquinones
revealed the absorption bands of the N–H group at around
3300 cm−1 and of >C=O moiety at 1683 cm−1. e 1H NMR
spectra exhibited aromatic protons at around 6.50–8.00 ppm.
e methylene protons of alkoxy groups in 3a appeared
at around 3.5–4 ppm as a singlet. e methylene protons
Keeping in mind that 1,4-naphthoquinones are involved
in a wide range of biological studies and the presence of
nitrogen atoms would improve the bioactivity, herein, a series
of 2-arylamino-1,4-naphthoquinone derivatives (3a–h) were
synthesized by using the standard procedure [16, 17, 28]
via nucleophilic displacement reaction of 2,3-dichloro-1,4-
naphthoquinone (1) with aryl amines (2a–h) as shown in
Scheme 1. Subsequently, the final compounds, new ben-
zo[b]phenazine-6,11-dione derivatives (4a–c), were synthe-
sized via intramolecular cyclization with sodium azide of 2-
arylamino-1,4-naphthoquinone derivatives (3a–h) in accor-
dance with the literature [29, 36, 37]. Finally, synthesized
compounds were investigated for their antimicrobial activity
against both Gram-positive and Gram-negative bacteria, in
addition to fungi. Structures of the synthesized new compou-
of compound 3d (–OCH –) were observed as a triplet at
2
3.96 ppm. e singlet peak at around 8-9 ppm was assigned
to the NH proton in aminonaphthoquinones. In addition,
aromatic protons of aminonaphthoquinones are displayed
at 6.50–8.00 ppm. In the 13C NMR spectra, characteristic
signals of two carbonyl carbons of aminonaphthoquinones
were visible at chemical shif at around 175 and 182 ppm.
Further reactions of 2-arylamino-1,4-naphthoquinone
derivatives (3a–h) with sodium azide for cyclization in DMF
1
nds were determined by using FT-IR, H NMR, 13C NMR,
and mass spectrometry.

Journal of Chemistry
3
R1
R1
O
O
O
H2N
NH
Cl
Cl
Cl
R2
R3
R2
R3
EtOH
Reflux
+
O
R4
R4
1
2
3
2a: R2 = R4 = H; R1 = R3 = OCH3
2b: R1 = R3 = H; R2 = R4 = OCH3
2c: R2 = R3 = H; R1 = R4 = OCH3
2d: R1 = R2 = R4 = H; R3 = O(CH2)5CH3
2e: R1 = R2 = R4 = H; R3 = CF3
3a: R2 = R4 = H; R1 = R3 = OCH3
3b: R1 = R3 = H; R2 = R4 = OCH3
3c: R2 = R3 = H; R1 = R4 = OCH3
3d: R1 = R2 = R4 = H; R3 = O(CH2)5CH3
3e: R1 = R2 = R4 = H; R3 = CF3
2f: R1 = R2 = R4 = H; R3 = SO2OH
2g: R1 = R3 = R4 = H; R2 = SO2OH
2h: R1 = R2 = R4 = H; R3 = SO2NH2
3f: R1 = R2 = R4 = H; R3 = SO2OH
3g: R1 = R3 = R4 = H; R2 = SO2OH
3h: R1 = R2 = R4 = H; R3 = SO2NH2
NaN3
Δ
DMF, H2O
R1
O
O
N
N
R2
R3
R4
4
4a: R1 = R3 = H; R2 = R4 = OCH3
4b: R2 = R3 = H; R1 = R4 = OCH3
4c: R1 = R2 = R4 = H; R3 = O(CH2)5CH3
Scheme 1: Preparation of 2-arylamino-3-chloro-1,4-naphthoquinones (3a–h) and benzo[b]phenazine-6,11-dione derivatives (4a–c).
at 90–100∘C overnight afforded the expected benzo[b]phe-
nazine-6,11-dione derivatives (4a–c). e reaction is believed
to proceed via the formation of the unstable intermedi-
ate compound (2-arylamino-3-azido-1,4-naphthoquinones)
as mentioned in the literature [29]. e mass spectra
of benzo[b]phenazine-6,11-dione derivatives (4a–c) showed
molecular ion peak at 321 [M+H]+, 343 [M+Na]+, and 361
[M+H]+, respectively. e formation of benzo[b]phenazine-
6,11-dione derivatives (4a–c) was confirmed by the absence
of both a singlet at 8-9 ppm attributable to the NH pro-
ton in the 1H NMR spectra and absorption bands of
the N–H group at around 3300 cm−1 in the IR spectra.
One of the methoxy derivatives of benzo[b]phenazine-
6,11-dione (4a) was obtained from both 2-chloro-3-[(2,4-
dimethoxyphenyl)amino]naphthalene-1,4-dione (3a, 21%)
and 2-chloro-3-[(3,5-dimethoxyphenyl)amino]naphthalene-
1,4-dione (3b, 51%).
in vitro antibacterial activities against three Gram-positive
(Staphylococcus aureus ATCC 29213, Staphylococcus epider-
midis ATCC 12228, and Enterococcus faecalis ATCC 29212)
and four Gram-negative bacteria (Pseudomonas aeruginosa
ATCC 27853, Escherichia coli ATCC 25922, Klebsiella pneu-
moniae ATCC 4352, and Proteus mirabilis ATCC 14153). e
antifungal activity was tested against a yeast Candida albicans
ATCC 10231. All the synthesized and screened antimicrobial
assay results of 2-arylamino-3-chloro-1,4-naphthoquinones
(3a–h) and benzo[b]phenazine-6,11-dione derivatives (4a–c)
are given in Table 1.
Results shown in Table 1 reveal that compounds 3d and 3g
have exhibited moderate activity against both Gram-positive
and Gram-negative bacteria, except E. coli for 3d. All of
the synthesized compounds (3a–h, 4a–c) possessed activity
against E. faecalis with MIC values of between 312.5 and
1250 ꢀg/mL. In addition to E. faecalis, all of the compounds,
except 4b, possessed activity against P. aeruginosa with MIC
values of between 625 and 1250 ꢀg/mL. e synthesized com-
pounds, except 3e and 4a, also showed good antibacterial act-
ivity against S. epidermidis. e test-culture E. coli appeared
2.2. Antimicrobial Activity. All the synthesized 2-arylamino-
3-chloro-1,4-naphthoquinones (3a–h) and benzo[b]phena-
zine-6,11-dione derivatives (4a–c) were evaluated for their

4
Journal of Chemistry
Table 1: In vitro antibacterial and antifungal activity of the synthesized compounds.
MIC values (ꢀg/mL)
Microorganisms
Fungi
C. albicans
Gram-positive bacteria
S. aureus
3a
—
—
3b
—
—
3c
3d
3e
3f
—
3g
3h
—
—
4a
4b
4c
Reference antimicrobials
—
78.12
—
78.12
312.5
—
—
—
4.9 (Clotrimazole)
1250 312.5
—
—
625
1250 1250 1250
1250 156.2
1.2 (Cefuroxime-Na)
9.8 (Cefuroxime)
128 (Amikacin)
S. epidermidis
E. faecalis
1250 1250 1250 312.5
312.5 1250 1250 625
1250 312.5 1250
—
1250 1250 312.5 1250 1250 1250 1250
Gram-negative bacteria
P. aeruginosa
E. coli
K. pneumoniae
P. mirabilis
1250 1250 1250 1250
625
—
1250 1250 1250 1250
—
—
—
—
1250
—
1250
—
2.4 (Cefazidime)
4.9 (Cefuroxime-Na)
4.9 (Cefuroxime-Na)
2.4 (Cefuroxime-Na)
—
—
—
—
—
—
—
—
—
—
—
—
625
1250
1250
—
—
—
—
—
—
1250 1250
1250 1250
—
not to be susceptible to synthesized compounds except that
3g. Evaluation of the antifungal activity of the synthesized
compounds showed that 3d and 3g were the most potent with
MIC (minimum inhibition concentration) 78.12 ꢀg/mL for C.
albicans (Table 1). e results also reveal that compounds 3d
and 3g were the most active among the synthesized com-
pounds; they have both antibacterial and antifungal activities.
On the other hand, benzo[b]phenazine-6,11-dione derivatives
(4a–c) were mostly active against Gram-positive bacteria.
ꢁ 76.0 ppm, respectively. Other solvents are as follows:
DMSO-d6: 2.49, 3.30 ppm (1H), 40.27 ppm (13C). Standard
abbreviations indicating multiplicity were used as follows:
s (singlet), br s (broad singlet), d (doublet), t (triplet), and
m (multiplet). Coupling constants J are given in Hz. IR
spectra were recorded as ATR on either ermo Scientific
Nicolet 6700 spectrometer or Alpha T FTIR spectrometer.
Mass spectra were obtained on either a ermo Finnigan
LCQ Advantage MAX MS/MS spectrometer equipped with
ESI (electrospray ionization) sources or GC-MS Shimadzu
QP2010 Plus. Melting points (mp) were determined with an
Electrothermal IA9000 series and were uncorrected.
We found that replacing the sulfonic acid group (–SO H)
3
position in 2-arylamino-3-chloro-1,4-naphthoquinones from
the meta position to the para position led to activity loss.
Additionally, replacing the sulfonic acid group (–SO H) at
3
the para position by a sulfonamide group (–SO NH ) and
2
2
3.2. General Procedure for the Preparation of 2-Arylamino-3-
chloro-1,4-naphthoquinones (3a–h). Compounds 3a–h were
prepared using the following general procedure according
to the reported literature [10, 16, 17, 28, 39–43]: aryl amine
(2.42 mmol) was added to the solution of 2,3-dichloro-
1,4-naphthoquinone (2.20 mmol) in ethanol (100 mL) and
refluxed. en the reaction mixture was cooled, and the pre-
cipitate was filtered. e filtered precipitate was isolated afer
purification either by column chromatography on silica gel or
recrystallized from ethanol.
trifluoromethyl (–CF ) did not show any progress against C.
3
albicans but showed an increase in activity against some of the
Gram-negative bacteria. By contrast, replacing this sulfonic
acid group (–SO H) at the para position by a hexyloxy group
3
(–O(CH ) CH ) led to an increase in activity against C.
2 5
3
albicans and no significant increase in activity against some
of the Gram-positive and Gram-negative bacteria. Changing
this hexyloxy group (–O(CH ) CH ) by the methoxy groups
2 5
3
at different positions, unfortunately, led to activity loss again.
3. Experimental Section
3.2.1. 2-Chloro-3-[(2,4-dimethoxyphenyl)amino]naphthalene-
1,4-dione (3a). It was synthesized from 2,3-dichloro-1,4-
naphthoquinone and 2,4-dimethoxyaniline. Yield: 63%. Mp:
156–158∘C. IR (ATR) ] (cm−1): 3252 (NH); 3010 (Ar–H); 1669,
1636 (C=O); 1592, 1563 (C=C). 1H NMR (500 MHz, DMSO-
d6) ꢁ (ppm): 3.68 (s, 3H, OCH ), 3.77 (s, 3H, OCH ), 6.50
3.1. Materials and Equipment. All reagents were commer-
cially obtained from commercial supplier and used with-
out further purification unless otherwise noted. Petroleum
ether had a boiling range of 40–60∘C. Analytical thin layer
chromatography (TLC) was purchased from Merck KGaA
(silica gel 60 F254) based on Merck DC-plates (aluminum
based). Visualization of the chromatogram was performed
by UV light (254 nm). Column chromatographic separations
were carried out using silica gel 60 (Merck, 63–200 ꢀm par-
3
3
(dd, J = 8.78, 2.44 Hz, 1H, CHaromatic), 6.57 (d, J = 2.44 Hz,
1H, CHaromatic), 7.08 (d, J = 8.78 Hz, 1H, CHaromatic), 7.71–7.80
(td, J = 7.81, 1.46 Hz, 1H, CHaromatic), 7.80–7.88 (td, J = 7.32,
1.47 Hz, 1H, CHaromatic), 7.94–8.03 (td, J = 8.78, 0.98 Hz, 2H,
CHaromatic), 8.77 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6)
1
ticle size, 60–230 mesh). H NMR and 13C NMR spectra
were recorded with VarianUNITY INOVA spectrometers with
ꢁ (ppm): 56.1, 56.3 (OCH ), 99.2, 104.8, 121.4, 126.7, 127.1, 127.9,
3
1
500 MHz frequency for H and 125 MHz frequency for 13C
130.7, 132.7, 133.7, 135.6, 144.9, 159.4 (Caromatic), 111.8 (C=C–Cl),
1
NMR in ppm (ꢁ). H NMR spectra and 13C NMR spectra
155.2 (C=C–NH), 176.7, 180.5 (>C=O). MS (GC-MS), (m/z
in CDCl refer to the solvent signal center at ꢁ 7. 19 and
%): 343 (100, [M]+). Anal. Calcd for C H ClNO (343.76).
3
18 14
4

Journal of Chemistry
5
3.2.2. 2-Chloro-3-[(3,5-dimethoxyphenyl)amino]naphthalene-
1,4-dione (3b). It was prepared from 2,3-dichloro-1,4-naph-
thoquinone and 3,5-dimethoxyaniline as described in the
literature reported previously [39]. Mp: 175–177∘C (lit. 169–
171∘C [39] and 185–185.5∘C [39]).
(ATR) ] (cm−1): 3384 (OH); 3255 (NH); 1671, 1639 (C=O);
1591, 1566 (C=C). 1H NMR (500 MHz, CDCl ) ꢁ (ppm): 4.24
3
(s, NH), 4.75 (br s, OH), 7.67–7.69 (m, 2H, CHaromatic), 7.73–
7. 76 (m, 2H, CHaromatic), 8.01–8.03 (m, 1H, CHaromatic), 8.07–
8.09 (m, 1H, CHaromatic), 8.12–8.15 (m, 2H, CHaromatic). 13C
NMR (125 MHz, CDCl ) ꢁ (ppm): 126.0, 126.8, 129.9, 130.1,
3
132.9, 133.3, 133.7, 142.6, 175.1 (Caromatic), 125.9 (C=C–Cl), 155.8
(C=C–NH), 177.6, 178.7 (>C=O). MS (−ESI), (m/z %): 364
(38, [M+H]+), 363 (18, [M]+), 362 (100, [M–H]+). MS2 (−ESI,
3.2.3. 2-Chloro-3-[(2,5-dimethoxyphenyl)amino]naphthalene-
1,4-dione (3c). It was prepared from 2,3-dichloro-1,4-naph-
thoquinone and 2,5-dimethoxyaniline as described in the
literature reported previously [28, 40]. Mp: 145-146∘C (lit.
146.7–146.9∘C [40] and 146–149∘C [28]).
362), (m/z %): 326 (100, [M–Cl]+), 282 (9, [M–SO H]+). Anal.
3
Calcd for C H ClNO S (363.77).
16 10
5
3.2.8. 4-[(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)am-
ino]benzenesulfonamide (3h). It was prepared from 2,3-
dichloro-1,4-naphthoquinone and 4-aminobenzenesulfon-
amide as described in the literature reported previously [10,
43]. Mp > 300∘C (lit. >300∘C [10, 43]).
3.2.4. 2-Chloro-3-{[4-(hexyloxy)phenyl]amino}naphthalene-
1,4-dione (3d). It was synthesized from 2,3-dichloro-1,4-
naphthoquinone and 4-(hexyloxy)aniline as described in the
literature reported recently [28]. Yield: 58%. Mp: 125–127∘C
(lit. [28] 130–133∘C). IR (ATR) ] (cm−1): 3219 (NH); 3069
(Ar–H); 2924, 2853 (Aliphatic-CH); 1675, 1631 (C=O); 1595,
3.3. General Procedure for the Preparation of Benzo[b]phen-
azine-6,11-dione Derivatives (4a–c). Compounds 4a–c were
prepared using the following general procedure according to
the reported literature [29, 36, 37]: to a solution of the cor-
responding 2-arylamino-3-chloro-1,4-naphthoquinone (3a–
d) in DMF (15 mL), sodium azide (20 mmol), suspended in
2.5 mL water, was added and refluxed. e reaction mixture
was diluted with dichloromethane and the organic phase was
1
1561 (C=C). H NMR (500 MHz, DMSO-d6) ꢁ (ppm): 0.88
(t, J = 6.83 Hz, 3H, CH ), 1.26–1.36 (m, 4H, CH –CH ),
3
2
2
1.37–1.46 (m, 2H, CH ), 1.71 (q, J = 6.84 Hz, 2H, CH ), 3.96 (t,
2
2
J = 6.34 Hz, 2H, OCH ), 6.87 (d, J = 8.79 Hz, 2H, CHaromatic),
2
7.07 (d, J = 8.79 Hz, 2H, CHaromatic), 7.77–7.81 (td, J = 7.81,
1.47 Hz, 1H, CHaromatic), 7.84–7.87 (td, J = 7.81, 1.47 Hz, 1H,
CHaromatic), 8.01–8.04 (m, 2H, CHaromatic), 9.18 (s, 1H, NH).
13C NMR (125 MHz, DMSO-d6) ꢁ (ppm): 14.6 (CH ), 22.8,
3
washed twice with water and then dried over CaCl . Afer
2
25.9, 29.4, 31.7 ((CH ) ), 68.3 (OCH ), 114.4, 126.7, 127.2,
2 4
2
evaporating the solvent, the crude product was purified by
column chromatography on silica gel to yield the correspond-
ing benzo[b]phenazine-6,11-dione derivatives (4a–c).
127.8, 130.8, 132.2, 132.8, 133.7, 135.5, 144.1 (Caromatic), 112.9
(C=C–Cl), 156.8 (C=C–NH), 177.2, 180.9 (>C=O).
3.2.5. 2-Chloro-3-{[4-(trifluoromethyl)phenyl]amino}naph-
thalene-1,4-dione (3e). It was prepared from 2,3-dichloro-1,4-
naphthoquinone and 4-(trifluoromethyl)aniline as described
in the literature reported previously [41].
3.3.1. 1,3-Dimethoxybenzo[b]phenazine-6,11-dione (4a). It
was synthesized from 2-chloro-3-[(2,4-dimethoxyphen-
yl)amino]naphthalene-1,4-dione (3a). Yellow crystals. Yield:
21%. Mp > 300∘C. IR (ATR) ] (cm−1): 3108, 3054 (Ar–H);
1
1686, 1614 (C=O); 1588, 1565. H NMR (500 MHz, CDCl )
3
3.2.6. 4-[(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)am-
ino]benzenesulfonic Acid (3f). It was synthesized from 2,3-
dichloro-1,4-naphthoquinone and 4-aminobenzenesulfonic
acid as described in the general procedure reported previ-
ously [10, 42]. Yield: 60%. IR (ATR) ] (cm−1): 3419 (OH);
3231 (NH); 3070 (Ar–H); 1673, 1645 (C=O); 1591, 1565 (C=C).
1H NMR (500 MHz, DMSO-d6) ꢁ (ppm): 2.06 (s, 1H, OH),
7.05 (d, J = 8.30 Hz, 2H, CHaromatic), 7.52 (d, J = 8.30 Hz, 2H,
CHaromatic), 7.80 (t, J = 7.32 Hz, 1H, CHaromatic), 7.85 (t, J =
7. 32 Hz, 1H, CHaromatic), 8.02 (d, J = 7.32 Hz, 2H, CHaromatic),
9.30 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) ꢁ (ppm):
123.4, 126.0, 126.8, 127.2, 131.0, 132.6, 133.9, 135.5, 139.6, 143.8
(Caromatic), 115.7 (C=C–Cl), 144.7 (C=C–NH), 177.4, 180.8
(>C=O). MS (−ESI), (m/z %): 364 (37, [M+H]+), 363 (22,
[M]+), 362 (100, [M–H]+). MS2 (−ESI, 362), (m/z %): 326
ꢁ (ppm): 3.96 (s, 3H, OCH ), 4.05 (s, 3H, OCH ), 6.79
3
3
(s, 1H, CHaromatic), 7.26 (s, 1H, CHaromatic), 7.82–7.83 (m,
2H, CHaromatic), 8.40–8.43 (m, 2H, CHaromatic). 13C NMR
(125 MHz, CDCl ) ꢁ (ppm): 55.4, 55.6 (OCH ), 98.9, 104.1,
3
3
127.1, 132.7, 133.1, 133.2, 133.7, 134.1, 139.6, 143.7, 145.8, 156.1,
164.1 (Caromatic), 179.5, 180.7 (>C=O). MS (+ESI), (m/z %):
343 (38, [M+Na]+), 321 (100, [M+H]+). Anal. Calcd for
C H N O (320.30).
18 12
2
4
Alternatively, 4a was prepared from 2-chloro-3-[(3,5-
dimethoxyphenyl)amino]naphthalene-1,4-dione (3b) by
using the general procedure. Yield: 51%. Spectroscopic data
are in accordance with 4a which is prepared from 2-chloro-
3-[(3,5-dimethoxyphenyl)amino]naphthalene-1,4-dione
(3a).
(100, [M–Cl]+), 282 (58, [M–SO H]+). Anal. Calcd for
3
3.3.2. 1,4-Dimethoxybenzo[b]phenazine-6,11-dione (4b). It
was synthesized from 2-chloro-3-[(2,5-dimethoxyphen-
yl)amino]naphthalene-1,4-dione (3c). Yellow crystals. Yield:
C H ClNO S (363.77).
16 10
5
3.2.7. 3-[(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)am-
ino]benzenesulfonic Acid (3g). It was synthesized from 2,3-
dichloro-1,4-naphthoquinone and 3-aminobenzenesulfonic
acid as described in the general procedure. Yield: 62%. IR
29%. Mp > 300∘C. IR (ATR) ] (cm−1): 3075 (Ar–H); 1686,
1613 (C=O); 1587, 1486. 1H NMR (500 MHz, CDCl ) ꢁ (ppm):
3
4.05 (s, 6H, 2OCH ), 7.15 (s, 2H, CHaromatic), 7.83–7.85 (m,
3
2H, CHaromatic), 8.42–8.43 (m, 2H, CHaromatic). 13C NMR

6
Journal of Chemistry
(125 MHz, CDCl ) ꢁ (ppm): 55.5 (OCH ), 110.2, 127.2, 133.0,
spectroscopic methods. ese new compounds possess high
solubility in various organic solvents such as chloroform and
dichloromethane while they are insoluble in water and these
compounds have shown good stability. On the basis of screen-
ing data for the presented compounds, the in vitro antimicro-
bial activities were evaluated against different Gram-positive
and Gram-negative bacterial strains in addition to the
antifungal activities. e test-culture E. coli appeared not
to be susceptible to most of the synthesized compounds.
Results revealed that compounds 3d and 3g have remarkable
activity against both Gram-positive and Gram-negative
bacteria and against the tested fungi (C. albicans), while all of
the synthesized compounds (3a–h, 4a–c) possessed activity
against E. faecalis with MIC values of between 312.5 and
1250 ꢀg/mL. Benzo[b]phenazine-6,11-dione derivatives (4a–
c) were mostly active against Gram-positive bacteria.
3
3
134.1, 135.7, 141.9, 148.9 (Caromatic), 179.6 (>C=O). MS (+ESI),
(m/z %): 343 (100, [M+Na]+). Anal. Calcd for C H N O
18 12
2
4
(320.30).
3.3.3. 2-(Hexyloxy)benzo[b]phenazine-6,11-dione (4c). It was
synthesized from 2-chloro-3-{[4-(hexyloxy)phenyl]ami-
no}naphthalene-1,4-dione (3d). Yellow crystals. Yield: 56%.
Mp: 167–169∘C. IR (ATR) ] (cm−1): 3066 (Ar–H); 2952,
1
2919, 2859 (Aliphatic-CH); 1681, 1607 (C=O); 1517, 1484. H
NMR (500 MHz, CDCl ) ꢁ (ppm): 0.85 (t, J = 6.83 Hz, 3H,
3
CH ), 1.23–1.34 (m, 4H, CH –CH ), 1.39–1.48 (m, 2H, CH ),
3
2
2
2
1.78–1.97 (m, 2H, CH ), 4.11 (t, J = 6.59 Hz, 2H, OCH ), 7.53
2
2
(dd, J = 9.28, 2.93 Hz, 1H, CHaromatic), 7.58 (d, J = 2.93 Hz,
1H, CHaromatic), 7.78–7.84 (m, 2H, CHaromatic), 8.22 (d, J =
9.27, 1H, CHaromatic), 8.36–8.40 (m, 2H, CHaromatic). 13C NMR
(125 MHz, CDCl ) ꢁ (ppm): 13.0 (CH ), 21.5, 24.6, 27.7, 30.5
3
3
((CH ) ), 68.4 (OCH ), 106.7, 127.1, 127.7, 131.0, 132.7, 132.9,
Conflict of Interests
2 4
2
133.9, 134.1, 139.8, 140.9, 143.2, 145.3, 162.4 (Caromatic), 180.1,
180.5 (>C=O). MS (+ESI), (m/z %): 361 (100, [M+H]+). Anal.
Calcd for C H N O (360.40).
e authors declare no conflict of interests.
22 20
2
3
Authors’ Contribution
3.4. Biological Assays. Antimicrobial activity against Staphy-
lococcus aureus ATCC 29213, Staphylococcus epidermidis
ATCC 12228, Escherichia coli ATCC 25922, Klebsiella pneu-
monia ATCC 4352, Pseudomonas aeruginosa ATCC 27853,
Proteus mirabilis ATCC 14153, Enterococcus faecalis ATCC
29212, and Candida albicans ATCC 10231 was determined by
the microbroth dilutions technique using the Clinical Labo-
ratory Standards Institute (CLSI) recommendations [44, 45].
Mueller-Hinton broth for bacteria and RPMI-1640 medium
for yeast strain were used as the test medium. Serial twofold
dilutions ranging from 5000 mg/L to 4.8 mg/L were prepared
in medium. e inoculum was prepared using a 4–6 h broth
culture of each bacteria type and 24 h culture of yeast strains
adjusted to a turbidity equivalent to 0.5 McFarland standard,
diluted in broth media to give a final concentration of 5 ×
105 cfu/ml for bacteria and 5 × 103 cfu/mL for yeast in the
test tray. e trays were covered and placed into plastic bags
to prevent evaporation. e trays containing Mueller-Hinton
broth were incubated at 35∘C for 18–20 h while the trays
containing RPMI-1640 medium were incubated at 35∘C for
46–50 h. e MIC was defined as the lowest concentration of
compound giving complete inhibition of visible growth. As
control, antimicrobial effects of the solvents were investigated
against test microorganisms. According to values of the
controls, the results were evaluated. e MIC values of the
compounds are given in Table 1.
Amac¸ Fatih Tuyun, Nilu¨fer Bayrak, Hatice Yıldırım, Nihal
Onul, Emel Mataraci Kara, and Berna Ozbek Celik con-
tributed equally to this work.
Acknowledgments
e authors thank the Research Fund of Istanbul University
for the financial support of this work (Project no. 42383) and
the Board of Trustees of Beykent University for supplying the
equipment and materials.
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