Brominated plastoquinone analogs: Synthesis, structural characterization, and biological evaluation

Article abstract of DOI:10.1016/j.molstruc.2020.128560

A series of brominated PQ analogs (BrPQ1-13) was synthesized by employing two different routes: 1) dibromination followed by oxidation and amination of dimethyl hydroquinone, respectively, 2) oxidation of dimethyl hydroquinone followed by amination and bromination, respectively. In addition to the single-crystal X-ray structural characterization of two analogs (BrPQ2 and BrPQ3), the structures of all analogs were determined based on spectral (FTIR, ¹H NMR, ¹³C NMR, and HRMS) data. We evaluated the analogs for in vitro antibacterial and antifungal activity against ATCC strains (panel of seven bacterial strains with three Gram-positive and four Gram-negative bacteria and three fungi) using the broth microdilution method. The structure–activity relationship of brominated PQ analogs indicated that the electron-withdrawing group (EWG) on the phenyl ring (-CF₃, trifluoromethyl group) has a positive effect on antibacterial activity. These in vitro data show that brominated analogs, especially for BrPQ 1, BrPQ2, and BrPQ3, have the potential to be developed as new antibacterial agents against S. aureus and/or S. epidermidis with low MIC values.

Full text of DOI:10.1016/j.molstruc.2020.128560

Journal of Molecular Structure 1219 (2020) 128560
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Brominated plastoquinone analogs: Synthesis, structural
characterization, and biological evaluation
Nilüfer Bayrak a, Mahmut Yıldız b, Hatice Yıldırım a, Emel Mataracı Kara c,
,
*
Berna Ozbek Celik c, Amaç Fatih Tuyun d
a Department of Chemistry, Engineering Faculty, Istanbul University-Cerrahpasa, Avcilar, 34320, Istanbul, Turkey
b Department of Chemistry, Gebze Technical University, Gebze, 41400, Kocaeli, Turkey
c Department of Pharmaceutical Microbiology, Pharmacy Faculty, Istanbul University, Beyazit, 34116, Istanbul, Turkey
d Department of Chemistry, Faculty of Science, Istanbul University, Vezneciler, 34134, Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of brominated PQ analogs (BrPQ1-13) was synthesized by employing two different routes: 1)
dibromination followed by oxidation and amination of dimethyl hydroquinone, respectively, 2) oxidation
of dimethyl hydroquinone followed by amination and bromination, respectively. In addition to the
single-crystal X-ray structural characterization of two analogs (BrPQ2 and BrPQ3), the structures of all
analogs were determined based on spectral (FTIR, 1H NMR, 13C NMR, and HRMS) data. We evaluated the
analogs for in vitro antibacterial and antifungal activity against ATCC® strains (panel of seven bacterial
strains with three Gram-positive and four Gram-negative bacteria and three fungi) using the broth
microdilution method. The structureeactivity relationship of brominated PQ analogs indicated that the
electron-withdrawing group (EWG) on the phenyl ring (-CF3, trifluoromethyl group) has a positive effect
on antibacterial activity. These in vitro data show that brominated analogs, especially for BrPQ 1, BrPQ2,
and BrPQ3, have the potential to be developed as new antibacterial agents against S. aureus and/or
S. epidermidis with low MIC values.
Received 26 April 2020
Received in revised form
16 May 2020
Accepted 28 May 2020
Available online 4 June 2020
Keywords:
Aminobenzoquinone
Bromine
Plastoquinones
Aromatic amines
Antibacterial activity
Antifungal activity
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
(Plastoquinones and Ubiquinones, Fig. 1A) [23,24]. One of the
structural analogs of Plastoquinones (PQs) and Ubiquinones is
Over the last decades, the quinone scaffold as an attractive
target for multiple aspects of medicinal chemistry has been
appealing to the researchers due to their excellent properties [1e7].
The quinone moiety is usually found in biologically active com-
pounds with a number of different pharmacological actions e. g.
anti-inflammatory [8], antitrypanosomal [9], antimalarial [10],
antiviral [11], antibacterial [12,13], antifungal [14], anticancer
[15,16], and antitubercular activity [17]. Some important studies
have revealed that the biological activity of redox-active quinone
compounds was caused by their redox cycling properties [18e20].
Quinone related compounds are present in many of the clini-
cally approved or still in different stages of clinical or preclinical
drug development [21,22]. Synthetic and/or natural 1,4-quinone
molecules were part of a large spectrum of redox processes in or-
ganisms and plants, such as two important prenylquinones
Idebenone (Fig. 1A) which is developed by Takeda Pharmaceutical
Company Ltd. for the treatment of emotional disturbances associ-
ated with cerebrovascular diseases [25]. An antitumor and anti-
biotic natural aminoquinone Streptonigrin (Fig. 1A) was isolated
from cultures of Streptomyces flocculus [26,27] and showed a broad
range of cytotoxic activity against different cancer cell lines such as
breast, melanoma, and lung [19]. Additionally, some studies on
natural Cribrostatin 5 (Fig. 1A) among the Cribrostatin family has
shown that Cribrostatin 5 is the most potent compound of the se-
ries on different cell types such as the pancreas (BXPC-3), ovarian
(OVCAR-3), CNS (SF-295), lung-NSC (NCIeH460), colon (KM20L2),
prostate (DU-145), and mouse leukemia (P-388) [28,29]. Some
drugs containing quinone moiety, e.g., Mitomycin C, Mitoxantrone,
and Doxorubicin (Fig. 1B), have been approved by the U.S. Food and
Drug Administration (FDA) for clinical use [29,30]. Aminoquinones
(AQs, Fig. 1C) and the related compounds, e. g. natural abenquine
and analogs isolated from Streptomyces sp. strain DB634 [31],
epoxyquinomicins A and B, as the new antibiotics obtained from
* Corresponding author.
E-mail addresses: aftuyun@gmail.com, aftuyun@istanbul.edu.tr (A.F. Tuyun).
https://doi.org/10.1016/j.molstruc.2020.128560
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
Fig. 1. A) Natural products and their analogs containing quinone moiety; B) FDA approved drugs containing quinone moiety; C) AQs and the related compounds.
the culture broth of Amycolatopsis sp. MK299-95F4 [32], and PI-083
exhibiting antitumor activity, especially for malignant over normal
cells either in vivo or in vitro [33], are promising molecules in many
areas of chemistry [13,34e40].
hydrogen or chlorine atom for the structure-activity relationship
(SAR) study (both the presence of a bromine atom on the 1,4-
quinone moiety and the introduction of an aryl amino group con-
taining different substituents on the 1,4-quinone moiety). Thus, the
modification was conducted on the 1,4-quinone moiety, and new
series of structurally related BrPQ analogs were designed as shown
in Fig. 2, synthesized, structurally characterized, and evaluated for
their in vitro antimicrobial activity against a panel of gram-positive
and gram-negative bacterial strains in addition to three fungal
strains.
Considering all of the above-mentioned information, we pre-
sumed that the combination of 1,4-quinone moiety, especially
based on the main structure of Plastoquinones, with the substituted
aromatic amines in the same molecule, could be a valuable key
point in the development of new antimicrobial agents. Inspired by
our previous studies on the investigation of N-aryl-based PQ ana-
logs, our group is currently looking for the synthesis of new analogs
by using different routes reported previously in the literature
[41,42]. Different substituent effects (amines and chlorine) in the
target analogs have been investigated and the chlorine atom ap-
pears to be essential for biological activity [33,43e46]. In the light
of these remarkable studies, we have modified the 1,4-quinone
moiety by means of inserting the bromine atom instead of the
2. Materials and methods
2.1. Apparatus and chemicals
1H and 13C NMR spectra were recorded on either Bruker
400 MHz frequency for 1H NMR and 100 MHz frequency for 13C

N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
3
Fig. 2. The design strategy of BrPQs.
NMR or VarianUNITY INOVA 500 MHz frequency for 1H NMR and
125 MHz frequency for 13C NMR spectrometers at 25 ꢀC, unless
otherwise noted. All chemical shifts (d) and coupling constants (J)
[54]. Aromatic and aliphatic C-bound H atoms were positioned
geometrically and refined using a riding mode. The crystallographic
and structure refinement data are summarized in Table 1. The
selected bond lengths and bond angles are given in Tables 2 and 3.
The crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre, and CCDC reference numbers are
1996771 for BrPQ2 and 1996772 for BrPQ3. The data can be ob-
tained available free of charge from http://www.ccdc.cam.ac.uk/
conts/retrieving.html or from the Cambridge Crystallographic
Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK;
fax: þ44 (0)1223336033; email: deposit@ccdc.cam.ac.uk. We also
thank Sadık Metin Ceyhan for helpful discussions on crystal
structure analyses.
were reported in parts per million (ppm) and hertz (Hz), respec-
tively. Standard abbreviations indicating multiplicity were used as
follows: br s (broad singlet), s (singlet), d (doublet), t (triplet), q
(quartet), hept (heptet), td (triplet of doublets), and m (multiplet).
Carbon spectra were recorded with complete proton decoupling.
Mass spectra were obtained using either Thermo Finnigan LCQ
Advantage MAX MS/MS spectrometer equipped with an ESI (Elec-
trospray ionization) sources or BRUKER Microflex LT by MALDI
(Matrix Assisted Laser Desorption Ionization)-TOF technique via
the addition of 1,8,9-anthracenetriol (DIT, dithranol) as the matrix.
High-resolution mass spectra (HRMS) were recorded either Waters
SYNAPT G1 MS or Agilent 6530 Accurate-MassQ-TOF LC/MS. FTIR
spectra were recorded with Alpha T FTIR spectrometer with single
reflection diamond ATR module. All solvents, reagents, and chem-
icals used were purchased from various commercial sources with a
minimum purity of 95% and were used as received without further
purification, unless otherwise noted. All column chromatography
2.3. General procedures for the synthesis of the brominated
plastoquinone analogs (BrPQs)
General Procedure 1 [42]: To a solution of the 2,3-dibromo-5,6-
dimethyl-1,4-benzoquinone (4) (0.100 g, 1 equiv) in ethanol was
added dropwise corresponding substituted aromatic amines (1.1
equiv) in ethanol over 5 min and the resulting mixture was stirred
at room temperature for 8e16 h until consumption of the dibro-
mobenzoquinone (4). After ethanol was evaporated under reduced
pressure, CH2Cl2 (50 mL) was added, and the solution was washed
sequentially with water (3 ꢁ 30 mL). The organic layer was dried
over CaCl2, filtered, and concentrated under reduced pressure.
Finally, the residue was chromatographed over silica gel to provide
the corresponding BrPQ.
was performed using Silica gel 60 (63e200
mm particle sized)
purchased from Merck with appropriate solvent system as eluents.
Thin layer chromatography (TLC) was performed with Merck DC-
plates (aluminum based, silica gel 60 F254) purchased from
Merck KGaA. Visualization of TLC plates was performed by means of
UV light (254 nm). Melting points were determined in capillary
tubes on a Buchi B-520 melting point apparatus and were uncor-
rected.
The
precursor,
2,3-dibromo-5,6-dimethyl-1,4-
benzoquinone, (4) was synthesized using the reported method in
the literature [47]. Additionally, aminoquinones to approach BrPQ
used in the bromination pathway have been synthesized and re-
ported previously by our group [45,48].
General Procedure 2 [66]: To a solution of the aminoquinones
(AQs) (0.100 g, 1 equiv) in methanol was added dropwise N-bro-
mosuccinimide (NBS) (1 equiv) in methanol over 5 min and the
resulting mixture was stirred at room temperature for 2e8 h until
consumption of the aminobenzoquinone. Once the reaction is
completed, CH2Cl2 (50 mL) was added, and the solution was
washed sequentially with water (3 ꢁ 30 mL). The organic layer was
dried over CaCl2, filtered, and concentrated under reduced pres-
sure. Finally, the residue was chromatographed over silica gel to
provide the corresponding BrPQ.
2.2. X-ray diffraction analysis
Data for the single crystal compounds were obtained with
Bruker APEX II QUAZAR three-circle diffractometer. Crystal struc-
ture validations and geometrical calculations were performed us-
ing the Platon software [49]. Mercury software [50] was used for
visualization of the.cif files. Each of the structures has been solved
and refined using the Bruker SHELXTL Software Package [51].
Indexing was performed using APEX2 [52]. Data integration and
reduction were carried out with SAINT [53]. Absorption correction
was performed by multi-scan method implemented in SADABS
2.3.1. 2-Bromo-5,6-dimethyl-3-(phenylamino)-1,4-benzoquinone
(BrPQ1) [55]
By using the aminoquinone (AQ1, 0.100 g, 0.44 mmol) and NBS
(0.078 g, 0.44 mmol) according to the general procedure 2 the
target analog was obtained as a purple solid. Yield: 39%, mp

4
N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
Table 1
Crystallographic data for the brominated PQ analogs (BrPQ2 and BrPQ3).
Identification code
BrPQ2
BrPQ3
Chemical formula
C15H11BrF3NO2
374.16
296(2)
C15H11BrF3NO2
374.16
296(2)
Formula weight (g molꢂ1
Temperature (K)
)
Radiation
l
(Å)
0.71073
0.71073
Crystal system
Space groups, Z 4
Unit cell dimensions (Å)
triclinic
P ꢂ1
monoclinic
P 1 21/c 1
a ¼ 5.0761(13)
b ¼ 12.587(3)
c ¼ 23.789(5) Å
a ¼ 4.9121(4)
b ¼ 25.751(2)
c ¼ 12.1007(11)
a
g
,
b
¼ 90ꢀ
a
b
,
g
¼ 90ꢀ
¼ 94.117 (14)ꢀ
¼ 94.513 (5)ꢀ
Volume (Å3)
1516.0(6)
1525.9(2)
Crystal sizes (mm)
0.067 ꢁ 0.104 x 0.221
0.071 ꢁ 0.165 x 0.269
dcalc (g cmꢂ3
)
1.639
1.629
Absorption coefficient (mmꢂ1
)
2.749
2.731
Absorption correction, Tmin, Tmax
qmax, deg
0.62 and 0.84
25.0
0.992
0.51 and 0.83
25.0
1.088
Goodness-of-fit on F2
Index ranges
ꢂ4ꢃh ꢃ 6
ꢂ5ꢃh ꢃ 5
ꢂ12 ꢃ k ꢃ 14
ꢂ28 ꢃ l ꢃ 27
11096
ꢂ24 ꢃ k ꢃ 30
ꢂ14 ꢃ l ꢃ 12
10504
Reflections collected
Independent reflections
Final R indices [I > 2s(I)]
5238 [R(int) ¼ 0.2078]
2672 [R(int) ¼ 0.0477]
1659 data;
2032 data;
R1 ¼ 0.1007
wR2 ¼ 0.1783
R1 ¼ 0.3015
wR2 ¼ 0.2547
Full-matrix least-squares on F2
5238/2/402
0.570 and ꢂ0.563
0.116
R1 ¼ 0.0562
wR2 ¼ 0.1405
R1 ¼ 0.0730
wR2 ¼ 0.1516
Full-matrix least-squares on F2
2672/1/201
0.991 and ꢂ0.786
0.104
R indices (all data)
Refinement method
Data/restraints/parameters
Largest diff. peak and hole (eÅꢂ3
)
R.M.S. deviation from mean (eÅꢂ3
)
Table 2
Selected bond lengths (Å) for the brominated PQ analogs (BrPQ2 and BrPQ3).
BrPQ2
BrPQ3
C1eC2
C1eF1
1.61(4)
1.18(3)
C16eC17
C16eF4
C23eC24
C24eBr2
C21eN2
C23eN2
C25eO3
C30eO4
1.50(3)
1.22(2)
Br1eC4
C4eC5
C5eN1
C9eN1
C6eO1
C3eO2
C12eC15
1.886(5)
1.360(7)
1.357(6)
1.404(7)
1.218(6)
1.227(6)
1.473(10)
C15eF1
C15eF2
C5eC6
C4eC5
C7eC8
1.297(12)
1.191(10)
1.506(7)
1.360(7)
1.502(7)
0.86
C8eC9
C9eBr1
C6eN1
C8eN1
C10eO1
C15eO2
1.394(19)
1.849(14)
1.387(18)
1.341(17)
1.201(17)
1.241(19)
1.411(19)
1.862(14)
1.385(17)
1.313(16)
1.205(16)
1.232(17)
N1eH1
C12eC13
1.378(9)
Table 3
Selected bond angles (o) for the brominated PQ analogs (BrPQ2 and BrPQ3).
BrPQ2
BrPQ3
C10eC9eBr1
C25eC24eBr2
N1eC8eC9
117.2(12)
114.3(11)
127.5(13)
131.9(14)
126.6(13)
134.3(13)
121.6(17)
119.6(15)
116.1(15)
119.5(17)
C3eC2eC1
C3eC4eBr1
C5eC4eBr1
N1eC5eC6
C5eN1eC9
C10eC9eN1
O2eC3eC4
O1eC6eC7
C5eN1eH1
C14eC9eN1
115.4(5)
115.0(3)
123.6(4)
113.0(4)
128.8(4)
118.3(5)
121.9(5)
121.6(5)
115.6
C8eN1eC6
N2eC23eC24
C23eN2eC21
N1eC6eC7
N2eC21eC22
O4eC30eC23
O2eC15eC8
121.6(5)
147e148 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3233 (NH), 3059 (CHaromatic), 2963
179.5 (>C]O), 143.9, 142.1, 137.4, 136.9, 131.5, 128.5, 125.8, 124.5,
103.4 (Caromatic and Cq), 13.9, 12.3 (CH3). MS (þESI) m/z (%): 308
(100, [Mþ3H]þ), 307 (23, [Mþ2H]þ), 306 (98, [MþH]þ); Anal. Calcd.
for C14H12BrNO2 (305.01); HRMS(þESI) m/z calcd for C14H12BrNO2
[M]þ: 305.0051; found: 305.0058.
(CHaliphatic), 1657 (>C]O), 1573, 1504, 1488, 1444, 1374, 1282, 1247,
1199, 1145. 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.46 (br s, 1H, NH),
7.34 (t, J ¼ 7.8 Hz, 2H, CHaromatic), 7.20 (t, J ¼ 7.4 Hz, 1H, CHaromatic),
7.05 (d, J ¼ 7.7 Hz, 2H, CHaromatic), 2.15 (d, J ¼ 0.8 Hz, 3H, CH3), 2.08
(d, J ¼ 0.7 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 182.3,

N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
5
2.3.2. 2-Bromo-5,6-dimethyl-3-(3-(trifluoromethyl)phenyl)amino-
1,4-benzoquinone (BrPQ2)
By using the aminoquinone (AQ2, 0.100 g, 0.34 mmol) and NBS
(0.061 g, 0.34 mmol) according to the general procedure 2 the
CHaromatic), 6.96 (d, J ¼ 8.3 Hz, 2H, CHaromatic), 2.36 (s, 3H, CH3),
2.19e2.12 (m, 3H, CH3), 2.08 (d, J ¼ 1.1 Hz, 3H, CH3). 13C NMR
(125 MHz, CDCl3) d (ppm): 182.3, 179.4 (>C]O), 144.0, 142.2, 136.7,
135.5, 134.8, 129.0, 124.7, 102.5 (Caromatic and Cq), 21.0, 13.9, 12.3
(CH3). HRMS(þESI) m/z calcd for C15H15BrNO2 [M þ H]þ: 320.0286;
found: 320.0284.
Alternatively, BrPQ5 was prepared from 2,3-dibromo-5,6-
dimethyl-1,4-benzoquinone (4) (1 equiv, 0.34 mmol) and p-tolui-
dine (1.1 equiv, 0.374 mmol) by using the general procedure 1.
Yield: 27%. Spectroscopic data are in accordance with the BrPQ5
prepared from aminoquinone (AQ5).
target analog was obtained as
142e143 ꢀC. FTIR (ATR) (cmꢂ1): 3230 (NH), 3050 (CHaromatic),
2963, 2822 (CHaliphatic), 1660 (>C]O), 1576, 1512, 1453, 1335, 1250,
1197, 1114, 1091. 1H NMR (400 MHz, CDCl3)
(ppm): 7.40 (br s, 1H,
a red solid. Yield: 32%, mp
y
d
NH), 7.36e7.29 (m, 2H, CHaromatic), 7.20e7.16 (m, 1H, CHaromatic),
7.14e7.09 (m, 1H, CHaromatic), 2.07 (d, J ¼ 1.2 Hz, 3H, CH3), 2.00 (d,
J ¼ 1.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d (ppm): 182.1, 179.4
2
(>C]O), 143.9, 141.7, 138.0, 137.3, 130.9 (q, JC-F ¼ 32.8 Hz), 129,
1
3
3
123.7 (q, JC-F ¼ 272.5 Hz), 121.7 (q, JC-F ¼ 3.7 Hz), 120.8 (q, JC-
2.3.6. 2-Bromo-3-((2-isopropylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ6)
¼ 3.7 Hz), 105.4 (Caromatic and Cq), 13.9, 12.4 (CH3). MS (þESI) m/z
F
(%): 376 (99, [Mþ3H]þ), 375 (14, [Mþ2H]þ), 374 (100, [MþH]þ);
Anal. Calcd. for C15H11BrF3NO2 (372.99); HRMS(þESI) m/z calcd for
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
2-isopropylaniline (0.051 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a red oil. Yield: 34%.
C
15H11BrF3NO2 [M]þ: 372.9925; found: 372.9936.
FTIR (ATR)
(CHaliphatic), 1655 (>C]O), 1590, 1575, 1496, 1477, 1450, 1374, 1300,
1282, 1247, 1188, 1149, 1082. 1H NMR (500 MHz, CDCl3)
(ppm):
y
(cmꢂ1): 3311 (NH), 3067 (CHaromatic), 2962, 2930, 2867
2.3.3. 2-Bromo-5,6-dimethyl-3-((4-(trifluoromethyl)phenyl)
amino)-1,4-benzoquinone (BrPQ3)
d
By using the aminoquinone (AQ3, 0.100 g, 0.34 mmol) and NBS
(0.061 g, 0.34 mmol) according to the general procedure 2 the
target analog was obtained as a dark red solid. Yield: 81%, mp
7.33e7.27 (m, 3H, (NH and CHaromatic)), 7.16 (td, J ¼ 7.5, 1.7 Hz, 1H,
CHaromatic), 7.00 (d, J ¼ 7.8 Hz, 1H, CHaromatic), 3.16 (hept, J ¼ 6.9 Hz,
1H, CH(CH3)2), 2.16 (q, J ¼ 1.2 Hz, 3H, CH3), 2.09 (q, J ¼ 1.2 Hz, 3H,
CH3), 1.26 (s, 3H, CH3), 1.25 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3)
185e186 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3235 (NH), 2959, 2922, 2852
(CHaliphatic), 1657 (>C]O), 1582, 1523, 1496, 1413, 1320, 1287, 1252,
1202,1180,1154,1106,1067. 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.49
d
(ppm): 182.3,179.4 (>C]O),144.2,144.2,142.8,136.5,135.0,127.3,
127.3, 125.9, 125.5, 101.0 (Caromatic and Cq), 28.5 (CH), 22.9, 13.9, 12.3
(d, J ¼ 8.5 Hz, 2H, CHaromatic), 7.36 (br s, 1H, NH), 7.00 (d, J ¼ 8.7 Hz,
2H, CHaromatic), 2.07 (q, J ¼ 1.2 Hz, 3H, CH3), 2.01 (q, J ¼ 1.2 Hz, 3H,
(CH3). HRMS(þESI) m/z calcd for C17H19BrNO2 [M þ H]þ: 348.0599;
found: 348.0599;
346.0443.
C17H17BrNO2 [M
ꢂ
H]þ: 346.0443; found:
CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 182.0, 179.4 (>C]O),
2
3
143.7, 141.6, 140.6, 137.4, 126.6 (q, JC-F ¼ 32.8 Hz), 125.6 (q, JC-
¼ 3.8 Hz), 125.5 (q, 3JC-F ¼ 3.7 Hz), 124.0 (q, 1JC-F ¼ 271.7 Hz), 123.3,
F
123.1, 106.6 (Caromatic and Cq), 13.8, 12.4 (CH3). MS (MALDI TOF) m/z:
2.3.7. 2-Bromo-3-((3-isopropylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ7)
372 [M
ꢂ
H]þ; Anal. Calcd. for C15H11BrF3NO2 (372.99);
HRMS(þESI) m/z calcd for C15H10BrF3NO2 [M ꢂ H]þ: 371.9847;
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
3-isopropylaniline (0.051 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a dark purple solid.
found: 371.9847.
Yield: 47%, mp 77e78 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3293 (NH), 3044
2.3.4. 2-Bromo-5,6-dimethyl-3-(m-tolylamino)-1,4-benzoquinone
(BrPQ4)
(CHaromatic), 2961, 2922, 2863 (CHaliphatic), 1662 (>C]O), 1578, 1513,
1485, 1426, 1378, 1302, 1276, 1204, 1181, 1147, 1106, 1047. 1H NMR
By using the aminoquinone (AQ4, 0.100 g, 0.41 mmol) and NBS
(0.073 g, 0.41 mmol) according to the general procedure 2 the
target analog was obtained as a purple sticky oil. Yield: 86%. FTIR
(500 MHz, CDCl3)
d (ppm): 7.41 (br s, 1H, NH), 7.19e7.15 (m, 1H,
CHaromatic), 6.98 (d, J ¼ 7.7 Hz, 1H, CHaromatic), 6.83e6.77 (m, 2H,
CHaromatic), 2.82 (hept, J ¼ 6.9 Hz, 1H, CH(CH3)2), 2.07 (q, J ¼ 1.2 Hz,
3H, CH3), 2.00 (q, J ¼ 1.2 Hz, 3H, CH3), 1.18 (s, 3H, CH3), 1.16 (s, 3H,
(ATR)
phatic), 1660 (>C]O), 1571, 1509, 1485, 1372, 1284, 1215, 1171, 1054.
1H NMR (500 MHz, CDCl3)
(ppm): 7.45 (br s, 1H, NH), 7.21 (t,
y
(cmꢂ1): 3245 (NH), 3019 (CHaromatic), 2921, 2852 (CHali-
CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 182.4, 179.5 (>C]O),
d
J ¼ 8.1 Hz, 1H, CHaromatic), 7.00 (d, J ¼ 7.6 Hz, 1H, CHaromatic), 6.85 (d,
149.2, 144.0, 142.1, 137.2, 136.8, 128.3, 123.7, 122.7, 121.8, 102.9
(Caromatic and Cq), 34.0 (CH), 23.8, 13.9, 12.3 (CH3). HRMS(þESI) m/z
calcd for C17H18BrNO2 [M]þ: 347.0521; found: 347.0531.
J ¼ 6.9 Hz, 2H, CHaromatic), 2.35 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.07 (s,
3H, CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 182.3, 179.4 (>C]O),
143.9, 142.1, 138.3, 137.2, 136.8, 128.2, 126.2, 125.1, 121.5, 103.3
(Caromatic and Cq), 21.4, 13.9, 12.3 (CH3). HRMS(þESI) m/z calcd for
C
15H15BrNO2 [M þ H]þ: 320.0286; found: 320.0288; C15H13BrNO2
2.3.8. 2-Bromo-3-((4-isopropylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ8)
[M ꢂ H]þ: 318.0130; found: 318.0122.
Alternatively, BrPQ4 was prepared from 2,3-dibromo-5,6-
dimethyl-1,4-benzoquinone (4) (1 equiv, 0.34 mmol) and m-tolui-
dine (1.1 equiv, 0.374 mmol) by using the general procedure 1.
Yield: 74%. Spectroscopic data are in accordance with the BrPQ4
prepared from aminoquinone (AQ4).
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
4-isopropylaniline (0.051 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a dark purple solid.
Yield: 77%, mp 93e94 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3223 (NH), 3030
(CHaromatic), 2960, 2926, 2870 (CHaliphatic), 1663 (>C]O), 1569, 1517,
1500, 1415, 1372, 1302, 1280, 1252, 1205, 1149, 1053. 1H NMR
2.3.5. 2-Bromo-5,6-dimethyl-3-(p-tolylamino)-1,4-benzoquinone
(BrPQ5)
(500 MHz, CDCl3)
d
(ppm): 7.35 (s, 1H, NH), 7.10 (d, J ¼ 1.1 Hz, 2H,
CHaromatic), 6.90 (d, J ¼ 8.4 Hz, 2H, CHaromatic), 2.83 (hept, J ¼ 6.9 Hz,
1H, CH(CH3)2), 2.06 (q, J ¼ 1.1 Hz, 3H, CH3), 1.98 (q, J ¼ 1.2 Hz, 3H,
CH3), 1.18 (s, 3H, CH3), 1.17 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3)
By using the aminoquinone (AQ5, 0.100 g, 0.41 mmol) and NBS
(0.073 g, 0.41 mmol) according to the general procedure 2 the
target analog was obtained as a purple sticky oil. Yield: 74%. FTIR
d
(ppm): 182.3,179.4 (>C]O),146.5,143.9,142.2,136.7, 135.0,126.4,
(ATR)
1570, 1494, 1374, 1281, 1252, 1198, 1145, 1108, 1049. 1H NMR
(500 MHz, CDCl3)
(ppm): 7.43 (br s, 1H, NH), 7.14 (d, J ¼ 8.2 Hz, 2H,
y
(cmꢂ1): 3240 (NH), 2922, 2859 (CHaliphatic), 1651 (>C]O),
124.6, 102.6 (Caromatic and Cq), 33.6 (CH), 24.0, 13.9, 12.3 (CH3).
HRMS(þESI) m/z calcd for C17H19BrNO2 [M þ H]þ: 348.0599; found:
348.0608.
d

6
N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
2.3.9. 2-Bromo-3-((2,3-dimethylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ9)
2.3.13. 2-Bromo-3-((4-(diethylamino)phenyl)amino)-5,6-dimethyl-
1,4-benzoquinone (BrPQ13)
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
2,3-dimethylaniline (0.045 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a purple solid. Yield:
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
N,N-diethyl-p-phenylenediamine (0.061 g, 0.374 mmol) according
to the general procedure 1 the target analog was obtained as a dark
37%, mp 119e120 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3272 (NH), 3070 (CHar-
blue sticky oil. Yield: 62%. FTIR (ATR) y
(cmꢂ1): 3286 (NH), 3057
omatic), 2924, 2852 (CHaliphatic), 1663 (>C]O), 1627, 1566, 1493,
(CHaromatic), 2978, 2926 (CHaliphatic), 1656 (>C]O), 1610, 1567, 1517,
1466, 1379, 1302, 1265, 1203, 1154, 1091, 1073. 1H NMR (500 MHz,
1503, 1394, 1376, 1355, 1296, 1254, 1184, 1156, 1051. 1H NMR
CDCl3)
d
(ppm): 7.28 (br s, 1H, NH), 7.13e7.03 (m, 2H, CHaromatic),
(500 MHz, CDCl3)
d
(ppm): 7.46 (br s, 1H, NH), 6.94 (d, J ¼ 7.8 Hz, 2H,
6.90 (d, J ¼ 7.1 Hz, 1H, CHaromatic), 2.33 (s, 3H, CH3), 2.16 (s, 3H, CH3),
CHaromatic), 6.61 (d, J ¼ 7.5 Hz, 2H, CHaromatic), 3.37 (d, J ¼ 6.8 Hz, 4H,
2.15 (s, 3H, CH3), 2.08 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3)
NCH2), 2.15 (d, J ¼ 1.2 Hz, 3H, CH3), 2.06 (s, 3H, CH3), 1.19 (t,
d
(ppm): 182.2, 179.4 (>C]O), 144.2, 142.8, 137.5, 136.4, 136.2,133.2,
J ¼ 6.8 Hz, 6H, CH3). 13C NMR (125 MHz, CDCl3)
d (ppm): 182.5,179.3
128.4, 125.1, 124.7, 100.8 (Caromatic and Cq), 20.4, 14.5, 13.9, 12.3
(CH3). HRMS(þESI) m/z calcd for C16H15BrNO2 [M ꢂ H]þ: 332.0286;
found: 332.0286.
(>C]O), 146.3, 144.3, 142.4, 136.2, 126.7, 125.4, 111.1 (Caromatic and
Cq), 44.5 (NCH2), 13.9, 12.5, 12.3 (CH3). HRMS(þESI) m/z calcd for
C
18H21BrN2O2 [M]þ: 376.0786; found: 376.0789.
2.4. Antimicrobial activity
2.3.10. 2-Bromo-3-((2,5-dimethylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ10)
2.4.1. Determination of minimum inhibitory concentrations (MICs)
Antimicrobial activities against Staphylococcus aureus ATCC
29213, Staphylococcus epidermidis ATCC 12228, Escherichia coli
ATCC 25922, Klebsiella pneumoniae ATCC 4352, Pseudomonas aer-
uginosa ATCC 27853, Proteus mirabilis ATCC 14153, Enterococcus
faecalis ATCC 29212, Candida albicans ATCC 10231, Candida para-
psilosis ATCC 22019, and Candida tropicalis ATCC 750 were deter-
mined by the broth microdilution technique using the Clinical
Laboratory Standards Institute (CLSI) recommendations [56,57].
Mueller-Hinton broth for bacteria and RPMI-1640 medium for the
yeast strain were used as the test media. Serial twofold dilutions
ranging from 2500 mg/L to 1.2 mg/L were prepared in the media.
The inoculum was prepared using a 4e6 h broth culture of each
bacteria and 24 h culture of yeast strains adjusted to a turbidity
equivalent of a 0.5 McFarland standard, diluted in broth media to
give a final concentration of 5 ꢁ 105 cfu/mL for bacteria and
0.5 ꢁ 103 to 2.5 ꢁ 103 cfu/mL for yeast in the test tray. The trays
were covered and placed in plastic bags to prevent evaporation. The
trays containing MuellereHinton broth were incubated at 35 ꢀC for
18e20 h while the trays containing RPMI-1640 medium were
incubated at 35 ꢀC for 46e50 h. The MIC was defined as the lowest
concentration of compound giving complete inhibition of visible
growth. As a control, the antimicrobial effects of the solvents were
investigated against test microorganisms. The results were evalu-
ated according to the values of the controls.
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
2,5-dimethylaniline (0.045 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a dark red solid.
Yield: 26%, mp 90e91 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3305 (NH), 3065
(CHaromatic), 2920, 2848 (CHaliphatic), 1656 (>C]O), 1588, 1511, 1483,
1376, 1298, 1255, 1215, 1106, 1049. 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.25 (br s, 1H, NH), 7.10 (d, J ¼ 7.4 Hz, 1H, CHaromatic), 7.00
(d, J ¼ 7.8 Hz, 1H, CHaromatic), 6.83 (s, 1H, CHaromatic), 2.31 (s, 3H,
CH3), 2.21 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.08 (s, 3H, CH3). 13C NMR
(125 MHz, CDCl3) d (ppm): 182.2, 179.4 (>C]O), 144.2, 142.5, 136.5,
135.9, 135.6, 130.9, 130.1, 127.5, 127.1, 101.1 (Caromatic and Cq), 20.9,
17.8, 13.9, 12.3 (CH3). HRMS(þESI) m/z calcd for C16H15BrNO2
[M ꢂ H]þ: 332.0286; found: 332.0284.
2.3.11. 2-Bromo-3-((3,4-dimethylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ11)
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
3,4-dimethylaniline (0.045 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a dark purple solid.
Yield: 62%, mp 152e153 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3239 (NH), 3015
(CHaromatic), 2919 (CHaliphatic), 1658 (>C]O), 1571, 1500, 1453, 1372,
1311, 1285, 1215, 1167, 1054. 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.41
(br s, 1H, NH), 7.08 (d, J ¼ 7.7 Hz, 1H, CHaromatic), 6.84 (s, 1H, CHar-
omatic), 6.80 (d, J ¼ 7.8 Hz, 1H, CHaromatic), 2.26 (s, 6H, CH3), 2.15 (s,
3H, CH3), 2.07 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3)
d
(ppm):
3. Results and discussion
182.4, 179.4 (>C]O), 144.0, 142.2, 136.7, 136.6, 135.0, 134.1, 129.4,
125.8, 122.0, 102.4 (Caromatic and Cq), 19.8, 19.3, 13.9, 12.3 (CH3).
HRMS(þESI) m/z calcd for C16H17BrNO2 [M þ H]þ: 334.0443; found:
334.0443.
3.1. Chemical synthesis
The reactions between amines and quinones to furnish AQs have
already been known procedures [58,59]. To the best of our
knowledge, general procedures have been reported in the literature
for the synthesis of AQs and related compounds; (1) by the
nucleophilic addition reactions of 1,4-quinones with amines
[59,60], (2) by the reaction between hydroquinone and amines in
the presence of oxidizing agent [41] or fungal laccases from Tra-
metes spec. and Myceliophthora thermophile [61], and (3) by nucle-
ophilic substitution reaction of the halogen or methoxy derivative
of 1,4-quinones with amines in aqueous [62,63] and non-aqueous
media (Fig. 3) [35,64].
2.3.12. 2-Bromo-3-((3,5-dimethylphenyl)amino)-5,6-dimethyl-1,4-
benzoquinone (BrPQ12)
By using the dibromobenzoquinone (4, 0.100 g, 0.34 mmol) and
3,5-dimethylaniline (0.045 g, 0.374 mmol) according to the general
procedure 1 the target analog was obtained as a dark purple solid.
Yield: 73%, mp 153e154 ꢀC. FTIR (ATR)
y
(cmꢂ1): 3232 (NH), 3004
(CHaromatic), 2915, 2852 (CHaliphatic), 1658 (>C]O), 1574, 1508, 1448,
1376, 1291, 1221, 1174, 1141, 1125, 1058. 1H NMR (500 MHz, CDCl3)
d
(ppm): 7.42 (br s, 1H, NH), 6.84 (s, 1H, CHaromatic), 6.67 (s, 2H,
CHaromatic), 2.31 (s, 6H, CH3), 2.16 (s, 3H, CH3), 2.08 (s, 3H, CH3). 13
NMR (125 MHz, CDCl3) (ppm): 182.4, 179.5 (>C]O), 143.9, 142.1,
In our previous works [45,46], a set of PQ analogs with chlorine
atom on the quinone moiety was prepared, also shown to be active,
clarifying that chlorine atom on the quinone moiety is important
for activity, and it was hypothesized for this study that inserting
bromine atom could form new brominated PQ analogs (BrPQs),
similar to the Plastoquinones core (Fig. 2). A library of brominated
C
d
138.4, 138.1, 137.0, 136.8, 127.2, 123.8, 122.1, 103.2 (Caromatic and Cq),
23.9, 21.3, 13.9, 12.3 (CH3). HRMS(þESI) m/z calcd for C16H17BrNO2
[M þ H]þ: 334.0443; found: 334.0435.

N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
7
Fig. 3. General procedures for the preparation of AQs and the related compounds.
PQ analogs (BrPQ1-13) was prepared with different functional
as shown in Scheme 1 (route 1), the 2,3-dimethyl hydroquinone (1)
groups at different positions (Scheme 1) with two routes. Initially,
was dibrominated in two steps and then smoothly oxidized to the
Scheme 1. Synthesis of the brominated PQ analogs (BrPQ1-13) by route 1 (dibromination followed by oxidation and amination) and/or route 2 (oxidation of 1 followed by
amination and bromination, respectively).

8
N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
Fig. 4. ORTEP drawings of the BrPQ2 and BrPQ3 at 50% probability level.
corresponding dibrominated 1,4-benzoquinones (4) according to
the literature [47]. Brominated PQ analogs were obtained from the
dibromobenzoquinone (4) by nucleophilic substitution reaction of
the bromine of 1,4-quinones with corresponding substituted aro-
matic amines in ethanol according to the reported method but in
the absence of catalyst and heating [42]. On the other hand, the
second route started with the synthesis of the 2,3-dimethyl-1,4-
benzoquinone (5) by oxidizing the 2,3-dimethyl hydroquinone (1)
using KBrO3 in 98% yield (as shown in route 2, Scheme 1) according
to the reported method [65]. Route 2 involved the amination of
dimethylbenzoquinone (5) with corresponding substituted aro-
matic amines under basic conditions (in refluxing ethanol) and
followed by bromination in methanol with N-bromosuccinimide
according to the reported method [66] to form the brominated PQ
analogs. Among these analogs, BrPQ1 is known in the literature
[55], while the other brominated PQ analogs are novel molecules.
The structures of the brominated PQ analogs (BrPQ1-13) were
established by analyzing their FTIR, NMR (1H NMR and 13C NMR),
and HRMS spectroscopic data. Furthermore, the X-ray crystal
structure of the BrPQ2 and BrPQ3 confirmed the structures ob-
tained by slow evaporation of ethanol solution with single-crystal
X-ray diffraction analysis (For details, please see the Supplemen-
tary file). With respect to the synthesis, two routes are presented.
The route 1 embedded within Scheme 1 consisted of four steps, and
was employed in the synthesis of BrPQ4 (75% yield) and BrPQ5
(27%). Another route (route 2) was also investigated with the same
starting material, from which, three steps were required to obtain
BrPQ analogs. When route 2 was applied in the synthesis of BrPQ4
and BrPQ5, the yields increased up to 86% and 74% for BrPQ4 and
BrPQ5, respectively. Comparatively, route 2 is more attractive with
respect to step count and yield, but not practically feasible for the
preparation of BrPQ analogs due to the difficult purification process
(required lots of column chromatography). Considering the disad-
vantage of route 2, route 1 is welcomed for the BrPQ5-13 produc-
tion of PQ.
ortho, meta, and para positions. The signals at around 2.80 ppm
assigned to methine hydrogen in the isopropyl group. The 13C NMR
spectra displayed signals of two carbonyl groups (C]O) at around
180 and 179 ppm which confirm substitution reaction. The carbons
atoms of methyl groups within the quinone moiety were appeared
at around 13 ppm and the mass spectra of the brominated PQ an-
alogs proved the proposed structures with the molecular ion peaks.
Additionally, the analogs (BrPQ2 and BrPQ3) were proved by X-ray
crystallography (Fig. 4 and Table 1). The crystallographic and
structure refinement data of brominated PQ analogs (BrPQ2 and
BrPQ3) are summarized in Table 1. BrPQ2 was crystallized in the
triclinic crystal system (space group P-1) and BrPQ3 was crystal-
lized in the monoclinic crystal system (space group P 1 21/c 1). The
ORTEP diagrams of BrPQ2 and BrPQ3 are reported in Fig. 1. The
distances between the C and O atoms of the quinone groups in the
brominated PQ analogs are range from 1.20 to 1.24 Å, confirming
them as typical double bonds. The average values of bond lengths of
BrPQ2 and BrPQ3 are about 1.37 Å for CeN bond, 1.23 Å for CeF
bond, 1.87 Å for CeBr bond, respectively. The carbon-halogen
bond length depends upon the size of the halogen atom that in-
creases as moving down the group in the periodic table. Larger the
size of the halogen atom, greater is C-X bond length. Since the
fluorine atom is smaller than bromine atom the carbon-halogen
bond length increases from CeF to CeBr (Table 2). The CeCeC
and CeCeO angles of the brominated PQ analogs (BrPQ2 and
BrPQ3) are very close to 120.8ꢀ which supports structures
involving sp2 hybridized atoms. The CeNeC angles of the bromi-
nated PQ analogs (BrPQ2 and BrPQ3) are about 133.0ꢀ and 128.8ꢀ
(Table 3).
3.2. Evaluation of antimicrobial activity
With thirteen BrPQ analogs (BrPQ1-13) in hand, four Gram-
negative bacteria, three Gram-positive bacteria for antibacterial
activity and three yeast for antifungal activity were used to pre-
liminarily screen their antibacterial and antifungal activity
employing the standard drugs using the broth microdilutions
method according to the Clinical Laboratory Standards Institute
(CLSI) recommendations [56,57]. The MIC (minimum inhibitory
concentration) values were summarized in Tables 4 and 5. Our
exploration started with the preparation of the series (BrPQ1-13)
by modifications at the phenyl ring in the amino group. Taken
together, with MIC values, the results identified that most of the
tested compounds showed better activity against Gram-positive
microorganisms. The test-cultures P. aeruginosa, E. coli,
FTIR spectra of the brominated PQ analogs revealed the pres-
ence of NH and C]O bands at around 3250 and 1650 cmꢂ1
,
respectively. The 1H NMR spectra showed the signals of two methyl
protons at around 2.05 and 2.10 ppm and the amino proton signals
at around 7.40 ppm. In the aromatic proton region, the proton
signals of the PQ analogs were observed between 6.60 and
7.40 ppm. The protons in the methyl group attached to the amino
ring were appeared at around 2.20 and 2.30 ppm. Another three-
protons in the methyl group at 1.20 ppm confirmed the presence
of the isopropyl group connected to the aminophenyl ring in the

N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
9
Table 4
In vitro antibacterial activity results of the brominated PQ analogs (BrPQ1-13).
ID
Microorganisms
Gram-negative Bacteria
(MIC, mg/L)
Gram-positive Bacteria
(MIC, mg/L)
R1
R2
R3
R4
P. aeruginosa
E. coli
K. pneumoniae
P. mirabilis
S. aureus
S. epidermidis
E. faecalis
BrPQ1
BrPQ2
BrPQ3
BrPQ4
BrPQ5
BrPQ6
BrPQ7
BrPQ8
H
H
H
H
H
CF3
H
CH3
H
H
H
H
CF3
H
CH3
H
H
CH(CH3)2
H
H
CH3
H
H
H
H
H
H
H
H
H
CH3
H
CH3
H
e
e
e
e
78.12
78.12
19.53
625
625
1250
1250
e
78.12
156.25
1250
1250
e
e
1250
e
1250
e
1250
e
1250
e
1250
1250
1250
e
1250
1250
e
e
1250
e
1250
1250
e
H
1250
e
CH(CH3)2
H
H
CH3
CH3
H
H
H
e
e
e
CH(CH3)2
H
e
e
e
e
156.2
1250
1250
625
1250
1250
e
e
e
e
e
e
e
BrPQ9
CH3
H
CH3
CH3
H
e
e
e
e
e
e
BrPQ10
BrPQ11
BrPQ12
BrPQ13
Ceftazidime
Cefuroxime-Na
Cefuroxime
Amikacin
e
e
e
e
1250
1250
e
e
e
e
e
e
e
H
e
e
e
e
e
N(CH2CH3)2
e
e
e
e
1250
e
e
2.4
e
e
e
e
e
e
4.9
e
4.9
e
2.4
e
1.2
e
e
e
e
9.8
e
e
e
e
e
e
e
128
Table 5
In vitro antifungal activity results of the brominated PQ analogs (BrPQ1-13).
ID
Microorganisms
Fungi
(MIC, mg/L)
R1
R2
R3
R4
C. albicans
C. parapsilosis
C. tropicalis
BrPQ1
BrPQ2
BrPQ3
BrPQ4
BrPQ5
BrPQ6
BrPQ7
BrPQ8
H
H
H
H
H
CF3
H
CH3
H
H
H
H
CF3
H
CH3
H
H
CH(CH3)2
H
H
CH3
H
H
H
H
H
H
H
H
H
CH3
H
CH3
H
1250
1250
1250
1250
1250
e
e
1250
1250
1250
1250
1250
e
e
e
e
H
e
CH(CH3)2
H
H
CH3
CH3
H
H
H
78.12
78.12
312.5
312.5
e
CH(CH3)2
H
156.2
625
625
625
625
78.12
e
-
-
-
-
-
-
BrPQ9
CH3
H
CH3
CH3
H
BrPQ10
BrPQ11
BrPQ12
BrPQ13
Clotrimazole
Amphotericin B
e
H
156.25
e
N(CH2CH3)2
312.5
e
4.9
e
e
0.5
1
- : Not determined.
K. pneumoniae, and P. mirabilis in addition to E. faecalis appeared as
resistant to the most of the brominated PQ analogs except that
BrPQ2, BrPQ4, and BrPQ5. Most of the analogs possessed activity
against S. epidermidis which had the MIC values between 78.12 and
1250 mg/L. As indicated in Table 4, among the brominated PQ an-
alogs, two analogs (BrPQ2 and BrPQ7) showed moderate antibac-
terial activity against S. epidermidis which had the MIC value of
156.25 mg/L compared to that of Cefuroxime. BrPQ1, which con-
tains unsubstituted aniline, exhibited the best inhibitory activity
against S. epidermidis than the other compounds (78.12 mg/L). In
addition, most of the analogs possessed the activity against
S. aureus that had the MIC value between 19.53 and 1250 mg/L.
Among the brominated PQ analogs, BrPQ3 showed the best
inhibitory activity against S. aureus with the MIC value of 19.53 mg/
L. Two analogs (BrPQ1 and BrPQ2) showed moderate antibacterial
activity against S. aureus which had the MIC value of 78.12 mg/L.
Concerning on the antifungal activity of the tested brominated PQ
analogs, BrPQ6 and BrPQ7 could induce appreciable growth
inhibitory activity against C. parapsilosis with the MIC value of
78.12 mg/L. Taken as completely, these results indicate some
important points. We could say that the in vitro inhibitory activity
of brominated PQ analogs does not fully correspond to the Gram-
negative bacteria strains. For the analogs containing methyl group
on the phenyl ring, they showed too low inhibitory activity against
E. faecalis. Brominated PQ analogs containing the electron-
withdrawing group (EWG) on the phenyl ring (-CF3, tri-
fluoromethyl group), at different position displayed better activity
than having electron-donating group (EDG) on the phenyl ring
(such as methyl and isopropyl group for antibacterial activity
against S. aureus. It is evident that structural modification of the
BrPQ1 by the introduction of the trifluoromethyl group was suc-
cessful in enhancing the antibacterial activity against S. aureus.
Thus, it may be concluded that the trifluoromethyl group is vital in
this series for obtaining good bioactivity against S. aureus.

10
N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
4387e4400.
4. Conclusions
[2] V.K. Tandon, S. Kumar, Recent development on naphthoquinone derivatives
and their therapeutic applications as anticancer agents, Expert Opin. Ther. Pat.
23 (9) (2013) 1087e1108.
Herein, thirteen BrPQ analogs (BrPQ1-13), based on the struc-
tural analogs of Plastoquinones, containing EDG or EWG group
were successfully designed and synthesized using two different
routes adopted from the literature: 1) dibromination followed by
oxidation and amination of dimethyl hydroquinone, respectively, 2)
oxidation of hydroquinone followed by amination and bromina-
tion, respectively. All of the obtained brominated PQ analogs were
structurally characterized by using spectroscopic methods (FTIR, 1H
and 13C NMR, and HRMS) with the additional single crystal of X-ray
structures of BrPQ2 and BrPQ3. In vitro antibacterial and antifungal
activity studies of all brominated PQ analogs were carried out
against a panel of microorganisms. It was shown that the bromi-
nated PQ analogs containing the electron-withdrawing group
(EWG) on the phenyl ring (-CF3, trifluoromethyl group) had better
activity than having electron-donating group (EDG) on the phenyl
ring (such as methyl and isopropyl group) for antibacterial activity
against S. aureus. Based on the results, additional studies, especially
for BrPQ1, BrPQ2, and BrPQ3, to improve their biological proper-
ties need to be studied as antibacterial agents against S. aureus and
S. epidermidis. Some of the brominated PQ analogs especially con-
taining trifluoromethyl group appear as promising antimicrobial
agents for further development studies. Besides, further investi-
gation of PQ analogs and their potential anticancer and antimi-
crobial activities is in progress.
[3] K. Mozaina, C.L. Cantrell, A.B. Mims, A.R. Lax, M.R. Tellez, W.L.A. Osbrink, Ac-
tivity of 1,4-benzoquinones against Formosan subterranean termites (Copto-
termes formosanus), J. Agric. Food Chem. 56 (11) (2008) 4021e4026.
[4] E.C. Cerqueira, P.A. Netz, C. Diniz, V.P. do Canto, C. Follmer, Molecular insights
into human monoamine oxidase (MAO) inhibition by 1,4-naphthoquinone:
evidences for menadione (vitamin K3) acting as a competitive and reversible
inhibitor of MAO, Bioorg. Med. Chem. 19 (24) (2011) 7416e7424.
[5] B. Blauenburg, T. Oja, K.D. Kika, M. Metsa-Ketela, Chemoenzymatic synthesis
of novel C-ribosylated naphthoquinones, ACS Chem. Biol.
8 (11) (2013)
2377e2382.
[6] A. Alfadhli, A. Mack, L. Harper, S. Berk, C. Ritchie, E. Barklis, Analysis of qui-
nolinequinone reactivity, cytotoxicity, and anti-HIV-1 properties, Bioorg. Med.
Chem. 24 (21) (2016) 5618e5625.
[7] S. Mostert, A. Petzer, J.P. Petzer, The evaluation of 1,4-benzoquinones as in-
hibitors of human monoamine oxidase, Eur. J. Med. Chem. 135 (2017)
196e203.
[8] J.C. Lien, L.J. Huang, J.P. Wang, C.M. Teng, K.H. Lee, S.C. Kuo, Synthesis and
antiplatelet, antiinflammatory, and antiallergic activities of 2-substituted 3-
chloro-1,4-naphthoquinone derivatives, Bioorg. Med. Chem. 5 (12) (1997)
2111e2120.
[9] M.H. Khraiwesh, C.M. Lee, Y. Brandy, E.S. Akinboye, S. Berhe, G. Gittens,
M.M. Abbas, F.R. Ampy, M. Ashraf, O. Bakare, Antitrypanosomal activities and
cytotoxicity of some novel imido-substituted 1,4-naphthoquinone derivatives,
Arch Pharm. Res. (Seoul) 35 (1) (2012) 27e33.
[10] D. Belorgey, D.A. Lanfranchi, E. Davioud-Charvet, 1,4-Naphthoquinones and
other NADPH-dependent glutathione reductase-catalyzed redox cyclers as
antimalarial agents, Curr. Pharmaceut. Des. 19 (14) (2013) 2512e2528.
[11] A. Sendl, J.L. Chen, S.D. Jolad, C. Stoddart, E. Rozhon, M. Kernan, W. Nanakorn,
M. Balick, Two new naphthoquinones with antiviral activity from Rhinacan-
thus nasutus, J. Nat. Prod. 59 (8) (1996) 808e811.
[12] A.K. Jordao, J. Novais, B. Leal, A.C. Escobar, H.M. dos Santos, H.C. Castro,
V.F. Ferreira, Synthesis using microwave irradiation and antibacterial evalu-
ation of new N,O-acetals and N,S-acetals derived from 2-amino-1,4-
naphthoquinones, Eur. J. Med. Chem. 63 (2013) 196e201.
Credit author statement
[13] A. Kacmaz, E.T. Acar, G. Atun, K. Kaya, B.D. Sigirci, F. Bagcigil, Synthesis,
electrochemistry, DFT calculations, antimicrobial properties and X-ray crystal
structures of some NH- and/or S- substituted-1,4-quinones, Chemistry 3 (30)
(2018) 8615e8623.
[14] C.K. Ryu, S.Y. Oh, S.J. Choi, D.Y. Kang, Synthesis of antifungal evaluation of 2H-
[1,2,3]Triazolo[4,5-g]isoquinoline-4,9-diones, Chem. Pharm. Bull. 62 (11)
(2014) 1119e1124.
[15] Y. Brandy, I. Ononiwu, D. Adedeji, V. Williams, C. Mouamba, Y. Kanaan,
R.L. Copeland, D.A. Wright, R.J. Butcher, S.R. Denmeade, O. Bakare, Synthesis
and cytotoxic activities of some 2-Arylnaphtho[2,3-d]oxazole-4,9-dione de-
rivatives on androgen-dependent (LNCaP) and androgen-independent (PC3)
human prostate cancer cell lines, Invest. N. Drugs 30 (4) (2012) 1709e1714.
[16] K.W. Wellington, N.I. Kolesnikova, N.B.P. Nyoka, L.J. McGaw, Investigation of
the antimicrobial and anticancer activity of aminonaphthoquinones, Drug
Develop Res, 2018, pp. 1e9.
Nilüfer Bayrak, performed the both synthetic work and crys-
tallographic studies. Mahmut Yıldız, performed the both synthetic
work and crystallographic studies. Hatice Yıldırım, performed the
both synthetic work and crystallographic studies. Emel Mataracı
Kara, coordinated the biological research, undertook the main
biological experiments, was also responsible for the correspon-
dence of the manuscript. All authors discussed, edited, and
approved the final version. Berna Ozbek Celik, coordinated the
biological research. Amaç Fatih Tuyun, designed the research, co-
ordinated the biological research, mainly wrote the manuscript.
[17] D. Dey, R. Ray, B. Hazra, Antitubercular and antibacterial activity of quinonoid
natural products against multi-drug resistant clinical isolates, Phytother Res.
28 (7) (2014) 1014e1021.
[18] A.B. Pardee, Y.Z. Li, C.J. Li, Cancer therapy with beta-lapachone, Curr. Cancer
Drug Targets 2 (3) (2002) 227e242.
Declaration of competing interest
The authors declare no conflict of interest.
[19] A.D. Bolzan, M.S. Bianchi, Genotoxicity of streptonigrin: a review, Mutat Res-
Rev Mutat 488 (1) (2001) 25e37.
Acknowledgments
[20] I. Wilson, P. Wardman, T.S. Lin, A.C. Sartorelli, One-electron reduction of 2-
methyl-1,4-naphthoquinone
reductive alkylating-agents, J. Med. Chem. 29 (8) (1986) 1381e1384.
and
6-methyl-1,4-naphthoquinone
bio-
This work was financially supported by the Scientific Research
Projects Coordination Unit of Istanbul University-Cerrahpasa,
Turkey (Project number: FBA-2018-29424) for supplying the
equipment and materials. The authors thank both the Central
Laboratory of the Middle-East Technical University and Advanced
Technology Laboratory of the Kütahya Dumlupınar University for
High-Resolution Mass Spectroscopy measurements for mass
analyses.
[21] N. El-Najjar, H. Gali-Muhtasib, R.A. Ketola, P. Vuorela, A. Urtti, H. Vuorela, The
chemical and biological activities of quinones: overview and implications in
analytical detection, Phytochemistry Rev. 10 (3) (2011) 353e370.
[22] C. Asche, Antitumour quinones, Mini Rev. Med. Chem. 5 (5) (2005) 449e467.
[23] M.M. Liu, S.F. Lu, Plastoquinone and ubiquinone in plants: biosynthesis,
physiological function and metabolic engineering, Front. Plant Sci. 7 (2016).
[24] S.S. Parmar, A. Jaiwal, O.P. Dhankher, P.K. Jaiwal, Coenzyme Q10 production in
plants: current status and future prospects, Crit. Rev. Biotechnol. 35 (2) (2015)
152e164.
[25] T. Meier, G. Buyse, Idebenone: an emerging therapy for Friedreich ataxia,
J. Neurol. 256 (2009) 25e30.
Appendix A. Supplementary data
[26] L.O. Klotz, X.Q. Hou, C. Jacob, 1,4-Naphthoquinones: from oxidative damage to
cellular and inter-cellular signaling, Molecules 19 (9) (2014) 14902e14918.
[27] T.J. Donohoe, C.R. Jones, L.C.A. Barbosa, Total synthesis of (þ/-)-Streptonigrin:
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2020.128560.
de novo construction of
a pentasubstituted pyridine using ring-closing
metathesis, J. Am. Chem. Soc. 133 (41) (2011) 16418e16421.
[28] G.R. Pettit, J.C. Knight, J.C. Collins, D.L. Herald, R.K. Pettit, M.R. Boyd,
V.G. Young, Antineoplastic agents 430. Isolation and structure of cribrostatins
3, 4, and 5 from the Republic of Maldives Cribrochalina species, J. Nat. Prod. 63
(6) (2000) 793e798.
References
[1] N. Chinchilla, G.A. Guerrero-Vasquez, R.M. Varela, J.M.G. Molinillo, F.A. Macias,
Phytotoxic studies of naphthoquinone intermediates from the synthesis of the
natural product Naphthotectone, Res. Chem. Intermed. 43 (8) (2017)
[29] M.T. Hoyt, R. Palchaudhuri, P.J. Hergenrother, Cribrostatin 6 induces death in
cancer cells through a reactive oxygen species (ROS)-mediated mechanism,

N. Bayrak et al. / Journal of Molecular Structure 1219 (2020) 128560
11
Invest. N. Drugs 29 (4) (2011) 562e573.
plastoquinone analogs for antimicrobial evaluation, Drug Dev. Res. 80 (8)
(2019) 1098e1109.
[47] S.G. Bodige, M. Mendez-Rojas, W.H. Watson, 2-amino-1,2,3-triazole de-
rivatives, J. Chem. Crystallogr. 29 (8) (1999) 931e942.
[30] J.P. Shrestha, Y.P. Subedi, L.H. Chen, C.W.T. Chang, A mode of action study of
cationic anthraquinone analogs: a new class of highly potent anticancer
agents, MedChemComm 6 (11) (2015) 2012e2022.
[31] D. Schulz, P. Beese, B. Ohlendorf, A. Erhard, H. Zinecker, C. Dorador, J.F. Imhoff,
A.-D. Abenquines, Aminoquinone derivatives produced by Streptomyces sp
strain DB634, J. Antibiot. 64 (12) (2011) 763e768.
[32] T. Tsuchida, M. Umekita, N. Kinoshita, H. Iinuma, H. Nakamura, K. Nakamura,
H. Naganawa, T. Sawa, M. Hamada, T. Takeuchi, A. and B. Epoxyquinomicins,
New antibiotics from Amycolatopsis, J. Antibiot. (Tokyo) 49 (3) (1996)
326e328.
[33] H.R. Lawrence, A. Kazi, Y.T. Luo, R. Kendig, Y.Y. Ge, S. Jain, K. Daniel,
D. Santiago, W.C. Guida, S.M. Sebti, Synthesis and biological evaluation of
naphthoquinone analogs as a novel class of proteasome inhibitors, Bioorg.
Med. Chem. 18 (15) (2010) 5576e5592.
[48] N. Bayrak, H. Yildirim, M. Yildiz, M.O. Radwan, M. Otsuka, M. Fujita,
A.F. Tuyun, H.I. Ciftci, Design, synthesis, and biological activity of Plastoqui-
none analogs as a new class of anticancer agents, Bioorg. Chem. 92 (2019)
103255.
[49] A.L. Spek, Structure validation in chemical crystallography, Acta Crystallogr. D
65 (2009) 148e155.
[50] C.F. Macrae, P.R. Edgington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor,
M. Towler, J. van De Streek, Mercury: visualization and analysis of crystal
structures, J. Appl. Crystallogr. 39 (2006) 453e457.
[51] SHELXTL, Version 6.14, Bruker, Bruker AXS Inc., Madison, WI, 2000.
[52] APEX2, Version 2014.1-1, Bruker, Bruker AXS Inc., Madison, WI, 2014.
[53] SAINT, Version 8.34A, Bruker, Bruker AXS Inc., Madison, WI, 2013.
[54] SADABS, Version 2012/2, Bruker, Bruker AXS Inc., Madison, WI, 2012.
[55] B. Wladislaw, L. Marzorati, S. Lima Netto, Some sulfur- and nitrogen-
substituted xyloquinones, Phosphorus, Sulfur, and Silicon 33 (3e4) (1987)
173e177.
[34] L.M. Gornostaev, T.A. Rukovets, T.I. Lavrikova, Y.G. Khalyavina, G.A. Stashina,
Isomerization of 4-arylamino-1,2-naphthoquinones to 2-arylamino-1,4-
naphthoquinones, Russ Chem Bþ 66 (6) (2017) 1007e1010.
[35] R. Pingaew, V. Prachayasittikul, A. Worachartcheewan, C. Nantasenamat,
S. Prachayasittikul, S. Ruchirawat, V. Prachayasittikul, Novel 1,4-
naphthoquinone-based sulfonamides: synthesis, QSAR, anticancer and anti-
malarial studies, Eur. J. Med. Chem. 103 (2015) 446e459.
[56] Clinical and Laboratory Standards Institute (CLSI), Performance Standards for
Antimicrobial Susceptibility Testing, Clinical and Laboratory Standards Insti-
tute, Wayne, Pennsylvania 19087, USA, 2020, 950 West Valley Road, Suite
2500.
[36] V. Prachayasittikul, R. Pingaew, A. Worachartcheewan, C. Nantasenamat,
S. Prachayasittikul, S. Ruchirawat, V. Prachayasittikul, Synthesis, anticancer
activity and QSAR study of 1,4-naphthoquinone derivatives, Eur. J. Med.
Chem. 84 (2014) 247e263.
[57] Clinical and Laboratory Standards Institute (CLSI), Reference Method for Broth
Dilution
Antifungal Susceptibility
Testing
of
Yeasts,
Approved
[37] J.E. Egleton, C.C. Thinnes, P.T. Seden, N. Laurieri, S.P. Lee, K.S. Hadavizadeh,
A.R. Measures, A.M. Jones, S. Thompson, A. Varney, G.M. Wynne, A. Ryan,
E. Sim, A.J. Russell, Structure-activity relationships and colorimetric properties
of specific probes for the putative cancer biomarker human arylamine N-
acetyltransferase 1, Bioorg. Med. Chem. 22 (11) (2014) 3030e3054.
[38] A. Kacmaz, Z. Hamurcu, New NH-substituted 1,4-naphtho- and 1,4-benzo-
Quinones: Synthesis, Characterization and Potential Antiproliferative Effect
against MDA-MB-231 Cells, Phosphorus, Sulfur, and Silicon, 2018.
[39] C. Parthiban, S. Ciattini, L. Chelazzi, K.P. Elango, Selective colorimetric sensing
of fluoride in an aqueous solution by amino-naphthoquinone and its Co(II),
Ni(II), Cu(II) and Zn(II) complexes - effect of complex formation on sensing
behaviour, RSC Adv. 6 (94) (2016) 91265e91274.
StandardeSecond Edition, Wayne, PA, USA, 1997.
[58] V.K. Tandon, H.K. Maurya, M.K. Verma, R. Kumar, P.K. Shukla, On water’
assisted synthesis and biological evaluation of nitrogen and sulfur containing
hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents,
Eur. J. Med. Chem. 45 (6) (2010) 2418e2426.
[59] J.A. Valderrama, V. Delgado, S. Sepulveda, J. Benites, C. Theoduloz,
P.B. Calderon, G.G. Muccioli, Synthesis and cytotoxic activity on human cancer
cells of novel isoquinolinequinone-amino acid derivatives, Molecules 21 (9)
(2016).
[60] C.K. Ryu, S.K. Lee, J.Y. Han, O.J. Jung, J.Y. Lee, S.H. Jeong, Synthesis and anti-
fungal activity of 5-arylamino-4,7-dioxobenzo[b]thiophenes, Bioorg. Med.
Chem. Lett 15 (10) (2005) 2617e2620.
[40] C. Parthiban, K.P. Elango, Selective and sensitive colorimetric detection of
Hg(II) in aqueous solution by quinone-diimidazole ensemble with mimicking
YES-OR-INHIBIT logic gate operation, Sensor. Actuator. B Chem. 237 (2016)
284e290.
[41] T. Ikeda, H. Wakabayashi, M. Nakane, Benzoquinone antiallergy and antiin-
flammatory agents, CA 115 (1991) 255808. Patent, Aug 28 EP 443710, A1.
[42] C.K. Ryu, K.H. Shin, J.H. Seo, H.J. Kim, 6-Arylamino-5,8-quinazolinediones as
potent inhibitors of endothelium-dependent vasorelaxation, Eur. J. Med.
Chem. 37 (1) (2002) 77e82.
[43] K. Li, B.T. Wang, L.F. Zheng, K. Yang, Y.Y. Li, M.M. Hu, D. He, Target ROS to
induce apoptosis and cell cycle arrest by 5,7-dimethoxy-1,4-naphthoquinone
derivative, Bioorg. Med. Chem. Lett 28 (3) (2018) 273e277.
[44] C.K. Ryu, H.Y. Kang, Y.J. Yi, C.O. Lee, Cytotoxic activities of 6-aylamino-7-halo-
5,8-quinolinediones against human tumor cell lines, Arch Pharm. Res. (Seoul)
23 (1) (2000) 42e45.
[61] T.H.J. Niedermeyer, A. Mikolasch, M. Lalk, Nuclear Amination catalyzed by
fungal laccases: reaction products of p-hydroquinones and primary aromatic
amines, J. Org. Chem. 70 (6) (2005) 2002e2008.
[62] V.K. Tandon, S. Kumar, N.N. Mishra, P.K. Shukla, Micelles catalyzed chemo-
and regio-selective one pot and one step synthesis of 2,3,5,6-tetrakis(alkyl
and arylsulfanyl)-1,4-benzoquinones and 2,5-diaminosubstituted-1,4-
benzoquinones "In-Water" and their biological evaluation as antibacterial
and antifungal agents, Eur. J. Med. Chem. 56 (2012) 375e386.
[63] V.K. Tandon, H.K. Maurya, ’, On water’: unprecedented nucleophilic substi-
tution and addition reactions with 1,4-quinones in aqueous suspension, Tet-
rahedron Lett. 50 (43) (2009) 5896e5902.
[64] M. Delarmelina, R.D. Daltoe, M.F. Cerri, K.P. Madeira, L.B.A. Rangel, V. Lacerda,
W. Romao, A.G. Taranto, S.J. Greco, Synthesis, Antitumor activity and docking
of 2,3-(substituted)-1,4-naphthoquinone derivatives containing nitrogen,
oxygen and sulfur, J. Braz. Chem. Soc. 26 (9) (2015) 1804e1816.
[65] H. Buff, U. Kucklander, Reaction of N-methyl-hydrazones as azaenamines with
quinones, Tetrahedron 56 (29) (2000) 5137e5145.
[45] H.I. Ciftci, N. Bayrak, H. Yildirim, M. Yildiz, M.O. Radwan, M. Otsuka, M. Fujita,
A.F. Tuyun, Discovery and structure-activity relationship of plastoquinone
analogs as anticancer agents against chronic myelogenous leukemia cells,
Arch. Pharm. (Weinheim) 352 (12) (2019), e1900170.
[66] J.A. Ibacache, J.A. Valderrama, V. Arancibia, C. Theoduloz, G.G. Muccioli,
J. Benites, Antiproliferative activity of new 6-bromine derivatives of 7-anilino-
1-arylisoquinolinequinones, J. Chil. Chem. Soc. 61 (4) (2016) 3191e3194.
[46] A.F. Tuyun, M. Yildiz, N. Bayrak, H. Yildirim, E. Mataraci Kara, A.T. Jannuzzi,
B. Ozbek Celik, Discovery of
a new family of heterocyclic amine linked