Synthesis and in vitro anticancer evaluation of 1,4-phenylene-bis-pyrimidine-2-amine derivatives

Article abstract of DOI:10.3906/kim-1603-112

A series of 1,4-phenylene-bis-chalcones 3a{3h were synthesized by the reaction of terephthalaldehyde with substituted arylketones in this study. The novel 1,4-phenylene-bis-pyrimidine-2-amine derivatives 5a{5h were obtained by the addition of guanidine hy

Full text of DOI:10.3906/kim-1603-112

Turk J Chem
Turkish Journal of Chemistry
(2017) 41: 263 – 271
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http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1603-112
Research Article
Synthesis and in vitro anticancer evaluation of
1,4-phenylene-bis-pyrimidine-2-amine derivatives
1,∗
1
2
¨
˙
˘
˘
Meliha Burcu GURDERE , Erdo˘gan KAMO , Ay¸se S¸AHIN YAGLIOGLU ,
Yakup BUDAK1, Mustafa CEYLAN1
1Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpa¸sa University, Tokat, Turkey
2Department of Chemistry, Faculty of Sciences, C¸ankırı Karatekin University, C¸ankırı, Turkey
Received: 25.03.2016
•
Accepted/Published Online: 06.10.2016
•
Final Version: 19.04.2017
Abstract: A series of 1,4-phenylene-bis-chalcones 3a–3h were synthesized by the reaction of terephthalaldehyde with
substituted arylketones in this study. The novel 1,4-phenylene-bis-pyrimidine-2-amine derivatives 5a–5h were obtained
by the addition of guanidine hydrochloride to 1,4-phenylene-bis-chalcone 3a–3h in ethanolic KOH under reflux conditions.
The structure of the compounds was explained by means of IR, 1 H NMR, 13 C NMR, and elemental analyses. The
anticancer activities of 3a–3h and 5a–5h were investigated against rat brain tumor cells and human uterus carcinoma
in vitro. Activity tests were performed as dose-dependent assays at eight concentrations. The positive control was 5-
fluorouracil (5-FU). Compounds 3c and 3d were examined and they showed high activities as compared to 5-FU against
C6 (rat brain tumor) and HeLa (human uterus carcinoma) cells. The anticancer activity of 5h was better than that of
5-FU at high concentrations cell-selectively against C6 cells.
Key words: 1,4-Phenylene-bis-chalcone, 1,4-phenylene-bis-pyrimidine, HeLa, C6, anticancer activity, 5-fluorouracil
1. Introduction
Cancer is a very dangerous disease and it is the second most common cause of death after heart disease in the
world.1 Numerous anticancer agents that can be used for cancer treatment have been developed, but most of
them have high toxicity rates.2 Therefore, the need to discover some new anticancer agents that are very effica-
cious in the treatment of cancer, but at the same time have very minimal toxicity rates, is one of the main ob-
jectives of organic and medicinal chemistry.3 Pyrimidines attract great attention on account of their wide range
of biological and pharmaceutical properties, such as anticancer,4−7 antibacterial,8,9 antiinflammatory,10−13
antiviral,14 antituberculosis,15,16 antihypertensive,17,18 and anticonvulsant19 properties. For this reason, the
design and synthesis of pyrimidine derivatives as potential cancer agents have been extensively studied20 and
hundreds of pyrimidine derivatives have been synthesized and evaluated for their anticancer activity.21−23 More-
over, various drugs containing a pyrimidine nucleus like 5-fluorouracil (5-FU), tegafur, and thioguanine were
prepared and used as anticancer agents.24,25 Chalcones are known to show different biological activities, such as
antioxidant,26 antiinflammatory,27 antimalarial,28 antileishmanial,29 anticancer,30 and antitumor31 activities.
Besides their biological activities, chalcones are very useful in starting materials for the preparation of bioactive
heterocycles such as pyridine, pyrimidine, pyrazoline, and isoxazoline derivatives.32−35
∗Correspondence: burcugurdere@gmail.com
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As a follow-up to these results, we aim at the synthesis of novel 1,4-phenylene-bis-pyrimidine-2-amine
derivatives from 1,4-phenylene-bis-chalcones, and we also investigate their anticancer activities against the C6
and HeLa cell lines.
2. Results and discussion
2.1. Chemistry
The synthetic approach to the desired compounds is given in the Scheme. The starting materials, 1,4-phenylene-
bis-chalcones (3a–3h), were prepared by Claisen–Schmidt condensation of terephthalaldehyde (2) and related
arylketones (1a–h) in the presence of NaOH in EtOH (Scheme; Table 1). 1,4-Phenylene-bis-chalcones are known
as 3a,36 3b,37 3c,38 and 3e–3h.39
Scheme. The synthetic approach to the desired compounds.
Synthesized 1,4-phenylene-bis-chalcones were submitted to reaction with guanidine hydrochloride (4)
to get 1,4-phenylene-bis-pyrimidine-2-amine derivatives. The 1,4-phenylene-bis-pyrimidine-2-amine derivatives
(5a–5h) were synthesized by literature procedures.40 Reaction of 1,4-phenylene-bis-chalcones (3a–3h) (1
equiv.) with guanidine hydrochloride (4) (8 equiv.) and KOH (2 equiv., 2.5 M) was started in dry ethanol
under reflux conditions. After 2 h of reaction, the mixture was added to H2 O2 (35%, 20 equiv.) dropwise for
2 h. The mixture was then cooled to r.t. and transferred to HCl/ice. The precipitated solid products were
filtered off, washed with methanol several times, and dried to yield the 1,4-phenylene-bis-pyrimidine-2-amine
derivatives (5a–5h) (Scheme; Table 1).
The structures of 5a–5h were explained by spectral data (IR and NMR) and elemental analysis. All
spectral data are in good agreement with the expected structures.
2.2. Anticancer activity results against C6 and HeLa cells
Anticancer activities against C6 and HeLa cells of 3a–3h and 5a–5h were investigated. The results were
compared with 5-FU, which was used as a positive control.
The anticancer activities of 3a–3h were shown to increase dose-dependently against C6 cells (Figure
1A). Most of compounds 3a–3h exhibited significant activity compared to the 5-FU as the reference drug.
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Table 1. Synthesized compounds.
Entry
Reagent
Project
Yield (%)
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Compounds 3c, 3d, and 3g showed almost the same activity as 5-FU, particularly at 75–100 µM concentrations.
While compounds 3a and 3e showed considerable activity, compounds 3b, 3f, and 3h exhibited moderate
anticancer activities when compared to 5-FU. Inhibitory effects of the compounds on HeLa cells at 100 µM
revealed the following potency order: 5-FU > 3d ∼ 3g ∼ 3c > 3e ∼ 3a > 3b > 3h > 3f.
B
A
Figure 1. The anticancer activities of 3a–3h (A) and 5a–5h (B) against C6 cells. *Each substance was tested twice
in triplicate against the cell line. Data show the average of two individual experiments (P < 0.01).
The anticancer activities of 5a–5h were also determined by the increase in dose-dependent activity
against C6 cells (Figure 1B). The anticancer activity of 5h was better than that of 5-FU at high concentrations.
Compound 5e exhibited a moderate anticancer effect, while compounds 5a–5d and 5f and 5g did not show
any significant activity when compared to 5-FU. Inhibitory effects of the compounds on C6 cells at 100 µM
revealed the following potency order: 5h > 5-FU > 5e > 5c > 5b > 5f > 5g > 5a > 5d.
Anticancer activities of 3a–3h and 5a–5h were also determined against HeLa cells. The anticancer
activities of 3a–3h and 5a–5h were shown to increase dose-dependently against HeLa cells (Figures 2A and
2B, respectively). The anticancer activity of compounds 3c and 3d was better than that of 5-FU at high
concentrations (30–100 µM). Moreover, the others (except 3h) showed moderate activity when compared to
5-FU. Inhibitory effects of the compounds against HeLa cells at 100 µM revealed the following potency order:
3c > 3d > 5-FU > 3g > 3a > 3b > 3f > 3e > 3h (Figure 2A). The anticancer activities of compounds
5a–5h are given in Figure 2B. Compound 5h exhibited moderate activity, whereas the others did not show any
significant activity when compared to 5-FU (Figure 2B). Inhibitory effects of the compounds on HeLa cells at
100 µM revealed the following potency order: 5-FU > 5h > 5b > 5e > 5a > 5d > 5c > 5f > 5g.
When comparing 1,4-phenylene-bis-chalcones 3a–3h with 1,4-phenylene-bis-pyrimidines 5a–5h, it was
seen that 1,4-phenylene-bis-chalcones 3a–3h were more effective against both cell lines (C6 and HeLa) than
1,4-phenylene-bis-pyrimidines 5a–5h.
Among all tested compounds, the most active compounds against both cell lines were compounds 3c and
3d, followed by compounds 3e and 3h against C6 and 5h against C6 (at 75–100 µM concentrations), when
compared with 5-FU. This result indicated that the thiophene and furan ring and the p-chloro substituent
enhanced anticancer activity.
Additionally, IC50 values were calculated by using ED50 Plus v1.0 and are given in Table 2.
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5a 5b 5c 5d 5e 5f
5g 5h 5-FU
against HeLa cell
against HeLa cell
3a 3b 3c 3d 3e 3f 3g 3h 5-FU
100
80
60
40
20
0
90
70
50
30
10
-20
100
-10
75
50
40
30
20
10
5
100
75
50
40
30
20
10
5
B
A
Concentration ( M)
Concentration ( M)
Figure 2. The anticancer activities of 3a–3h (A) and 5a–5h (B) against HeLa cells. *Each substance was tested twice
in triplicate against the cell line. Data show the average of two individual experiments (P < 0.01).
Table 2. The IC50 values of 3a–3h and 5a–5h against C6 and HeLa cells.
IC50
Sample codes
HeLa C6
3a
3b
3c
3d
3e
< 5
< 5
< 5
< 5
< 5
< 5
< 5
< 5
< 5
< 5
3f
39.48 41.86
38.65 < 5
44.71 31.43
34.39 55.31
60.66 < 5
> 100 73.75
> 100 > 100
89.18 58.38
3g
3h
5a
5b
5c
5d
5e
5f
< 5
71.39
5g
5h
5-FU
> 100 82.09
62.62 57.64
16.32 5.8
3. Experimental
3.1. General
IR spectra (KBr disks) were measured on a JASCO FT/IR-430 spectrometer. 1 H and 13 C NMR spectra were
recorded on a Bruker Avance DPX-400 instrument. As internal standards TMS (δ 0.00) was used for 1 H NMR
and CDCl3 (δ 77.0) for 13 C NMR spectroscopy; J values are given in Hz. The multiplicities of the signals
in the 1 H NMR spectra were abbreviated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
br (broad), and combinations thereof. Melting points were measured on an Electrothermal 9100 apparatus.
Elemental analyses were obtained from a LECO CHNS 932 Elemental Analyzer.
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3.1.1. General procedure for the synthesis of bis-pyrimidine derivatives (5a–5h)
A solution of bis-chalcone (3a–3h) (1 mmol), guanidine hydrochloride (4) (8 mmol), and KOH (2 mmol, 2.5
M) in ethanol was refluxed for 2 h. Continuing the reflux operation, to the reaction medium H2 O2 (20 mmol,
35%) was added dropwise within 2 h. After reflux, the reaction mixture was cooled to r.t. and the product was
precipitated by the addition of dilute HCl. The precipitate was filtered and washed with methanol and dried.
6,6’-(1,4-Phenylene)bis(4-(naphthalen-1-yl)pyrimidin-2-amine) (5a): Orange solid (433 mg,
84% yield); mp 290–292 ◦ C. IR (KCl, cm−1): 3471, 3288, 3143, 1627, 1567, 1538, 1454, 1400, 1353, 1220,
831, 808, 777. 1 H NMR (400 MHz, DMSO, ppm): δ 8.33 (s, 4H), 8.27–8.24 (m, 2H), 8.07–8.02 (m, 4H), 7.75
(d, J = 6.8 Hz 2H), 7.64 (t, J = 7.6 Hz 2H), 7.60–7.54 (m, 4H), 7.49 (s, 2H), 6.95 (s, 4H). 13 C NMR (100
MHz, DMSO, ppm): δ 168.5 (2C), 164.2 (2C), 164.0 (2C), 139.4 (2C), 137.3 (2C), 133.8 (2C), 130.6 (2C), 129.8
(2C), 128.7 (2C), 127.7 (4C), 127.5 (2C), 127.0 (2C), 126.5 (2C), 125.9 (2C), 125.8 (2C), 107.3 (2C). Anal. calc.
for C34 H24 N6 : C, 79.05; H, 4.68; N, 16.27. Found: C, 78.88; H, 4.49; N, 16.21.
6,6’-(1,4-Phenylene)bis(4-(thiophen-3-yl)pyrimidin-2-amine) (5b): Orange solid (334 mg, 78%
yield); mp 296–297 ◦ C. IR (KCl, cm−1): 3316, 3195, 1631, 1573, 1513, 1454, 1411, 1334, 1228, 829, 784, 742.
1 H NMR (400 MHz, DMSO, ppm): δ 8.41 (s, 2H), 8.33 (s, 4H), 7.87 (d, J = 4.0 Hz 2H), 7.71 (s, 2H), 7.67 (s,
2H), 6.67 (s, 4H). 13 C NMR (100 MHz, DMSO, ppm): δ 164.4 (2C), 164.3(2C), 164.1 (2C), 141.3 (2C), 139.4
(2C), 127.5 (6C), 127.3 (2C), 126.9 (2C), 102.7 (2C). Anal. calc. for C22 H16 N6 S2 : C, 61.66; H, 3.76; N, 19.61.
Found: C, 61.54; H, 3.61; N, 19.41.
6,6’-(1,4-Phenylene)bis(4-(thiophen-2-yl)pyrimidin-2-amine) (5c): Orange solid (355 mg, 83%
yield); mp 324–325 ◦ C. IR (KCl, cm−1): 3326, 3201, 1639, 1565, 1509, 1444, 1415, 1365, 1243, 1216, 813, 771,
715. 1 H NMR (400 MHz, DMSO, ppm): δ 8.35 (s, 4H), 8.17 (d, J = 4.0 Hz 2H), 7.80 (s, 2H), 7.76 (d, J =
5.2 Hz 2H), 7.26–7.24 (m, 2H), 6.81 (s, 4H). 13 C NMR (100 MHz, DMSO, ppm): δ 164.8 (2C), 164.7 (2C),
161.2 (2C), 144.1 (2C), 139.9 (2C), 131.0 (2C), 129.4 (2C), 129.1 (2C), 128.1 (4C), 101.5 (2C). Anal. calc. for
C22 H16 N6 S2 : C, 61.66; H, 3.76; N, 19.61. Found: C, 61.58; H, 3.56; N, 19.49.
6,6’-(1,4-Phenylene)bis(4-(furan-2-yl)pyrimidin-2-amine) (5d): Orange solid (289 mg, 73% yield);
mp 292–296 ◦ C. IR (KCl, cm−1): 3486, 3309, 3183, 1600, 1562, 1486, 1448, 1349, 1236, 1018, 991, 954, 885,
819, 779,757, 595. 1 H NMR (400 MHz, DMSO, ppm): δ 8.30 (s, 4H), 7.94 (s, 2H), 7.56 (s, 2H), 7.33 (d,J =
3.2 Hz 2H), 6.87 (s, 4H), 6.74–6.72 (dd, J = 3.2, 1.6 Hz 2H). 13 C NMR (100 MHz, DMSO, ppm): δ 164.3
(4C), 157.1 (2C), 152.4 (2C), 145.8 (2C), 139.3 (2C), 127.5 (4C), 112.9 (2C), 112.2 (2C), 100.5 (2C). Anal. calc.
for C22 H16 N6 O2 : C, 66.66; H, 4.07; N, 21.20. Found: C, 66.54; H, 4.00; N, 21.12.
6,6’-(1,4-Phenylene)bis(4-phenylpyrimidin-2-amine) (5e): Orange solid (375 mg, 90% yield); mp
294–298 ◦ C. IR (KCl, cm−1): 3330, 3203, 1644, 1565, 1496, 1455, 1359, 1216, 827, 969, 694, 649. 1 H NMR
(400 MHz, DMSO, ppm): δ 8.39 (s, 4H), 8.27–8.24 (m, 4H), 7.82 (s, 2H), 7.55–7.54 (m, 6H), 6.82 (s, 4H). 13 C
NMR (100 MHz, DMSO, ppm): δ 165.5 (2C), 164.6 (2C), 164.4 (2C), 139.5 (2C), 137.6 (2C), 131.0 (2C), 129.1
(4C), 127.7 (4C), 127.4 (4C), 102.6 (2C). Anal. calc. for C26 H20 N6 : C, 74.98; H, 4.84; N, 20.18. Found: C,
74.87; H, 4.79; N, 20.14.
6,6’-(1,4-Phenylene)bis(4-(p-tolyl)pyrimidin-2-amine) (5f): Orange solid (333 mg, 75% yield);
mp 311–312 ◦ C. IR (KCl, cm−1): 3484, 3313, 3193, 1625, 1573, 1533, 1508, 1448, 1361, 1220, 1148, 811, 790,
773. 1 H-NMR (400 MHz, DMSO, ppm): δ 8.38 (s, 4H), 8.17 (d, J = 8.0 Hz 4H), 7.79 (s, 2H), 7.35 (d,J = 8.0
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Hz 4H), 6.80 (s, 4H), 2.39 (s, 6H). 13 C NMR (100 MHz, DMSO, ppm): δ 165.3 (2C), 164.4 (4C), 140.7 (2C),
139.5 (2C), 134.9 (2C), 129.6 (4C), 127.6 (4C), 127.4 (4C), 102.1 (2C), 21.4 (2C). Anal. calc. for C28 H24 N6 :
C, 75.65; H, 5.44; N, 18.91. Found: C, 75.58; H, 5.39; N, 18.82.
6,6’-(1,4-Phenylene)bis(4-(4-methoxyphenyl)pyrimidin-2-amine) (5g): Orange solid (390 mg,
82% yield); mp 320–323 ◦ C. IR (KCl, cm−1): 3451, 3309, 3193, 1606, 1573, 1535, 1509, 1438, 1361, 1238, 1176,
1027, 823, 580. 1 H-NMR (400 MHz, DMSO, ppm): δ 8.37 (s, 4H), 8.25 (d, J = 8.4 Hz 4H), 7.77 (s, 2H), 7.09
(d,J = 8.8 Hz 4H), 6.76 (s, 4H), 3.85 (s, 6H). 13 C NMR (100 MHz, DMSO, ppm): δ 165.0 (2C), 164.4 (2C),
164.2 (2C), 161.7 (2C), 139.6 (2C), 130.0 (2C), 129.0 (4C), 127.5 (4C), 114.4 (4C), 101.7 (2C), 55.7 (2C). Anal.
calc. for C28 H24 N6 O2 : C, 70.57; H, 5.08; N, 17.64. Found: C, 70.54; H, 4.99; N, 17.59.
6,6’-(1,4-Phenylene)bis(4-(4-chlorophenyl)pyrimidin-2-amine) (5h): Orange solid (416 mg, 86%
yield); mp 308–310 ◦ C. IR (KCl, cm−1): 3490, 3332, 3201, 1631, 1567, 1492, 1359, 1218, 1091, 1012, 809, 485.
1 H NMR (400 MHz, DMSO, ppm): δ 8.39 (s, 4H), 8.30 (d, J = 8.4 Hz 4H), 7.86 (s, 2H), 7.62 (d,J = 8.4 Hz
4H), 6.89 (s, 4H). 13 C-NMR (100 MHz, DMSO, ppm): δ 164.8 (2C), 164.4 (2C), 164.2 (2C), 139.5 (2C), 136.5
(2C), 135.7 (2C), 129.3 (4C), 129.1 (4C), 127.7 (4C), 102.4 (2C). Anal. calc. for C26 H18 Cl2 N6 : C, 64.34; H,
3.74; N, 17.31. Found: C, 64.29; H, 3.67; N, 17.26.
3.2. Biological part
3.2.1. Preparation of stock solution
The compounds and 5-FU were solved by sterile dimethyl sulfoxide (DMSO) and were diluted with Dulbecco’s
modified Eagle’s medium. The final concentration of DMSO was kept below 0.1% in all tests.
3.2.2. Cell culture and cell proliferation assay
The anticancer activity tests and cell culture studies were performed according to the literature.41,42 HeLa and
C6 cells were used for the anticancer tests. The experiments were carried out at eight concentrations (5, 10, 20,
30, 40, 50, 75, and 100 µM).
3.2.3. Statistical analysis
The results are means ꢀ SDs of nine values. Differences between groups were determined by the ANOVA
method (P < 0.01). Statistical analysis was performed with SPSS 13.5.
4. Conclusion
A series of 1,4-phenylene-bis-chalcone derivatives (3a–3h) and new 1,4-phenylene-bis-pyrimidine derivatives
(5a–5h) were designed, synthesized, and evaluated for their anticancer activity against the C6 (rat brain tumor)
and HeLa (human uterus carcinoma) cell lines. Among all the compounds that were tested, compounds 3c and
3d were found to be the most promising agents due to their significant antiproliferative effects against both cell
lines. In addition, compounds 3e and 3h showed very high activity against C6. The pyrimidine series 5a–5h
(except 5h) demonstrated very low activity against both cell lines, while compound 5h exhibited very high
activity against C6 (at 75–100 µM concentrations) when compared to 5-FU. These results are encouraging, but
further studies are required to evaluate the mechanism of action for the anticancer activity of compounds 3c,
3d, 3e, 3h, and 5h.
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Acknowledgment
The authors are grateful to the Gaziosmanpa¸sa University Scientific Research Projects Commission (Project
No: BAP2011/95) for financial support.
References
1. Siegel, R. L.; Miller, K. D.; Jemal, A. Ca. Cancer. J. Clin. 2015, 65, 5-29.
2. Meenalosini, S.; Janet, J.; Kannan, E. Am. J. Applied. Sci. 2012, 9, 1020-1029.
3. Alfonse, M.; Aref, M. M.; Salem, A. B. M. International Journal of Information Engineering and Electronic
Business 2014, 6, 55-63.
4. Cordeu, L.; Cubedo, E.; Bandr´es, E.; Rebollo, A.; S´aenz, X.; Chozas, H.; Dom´ınguez, M. V.; Echeverr´ıa, M.;
Mendivil, B.; Sanmartin, C. et al. Bioorg. Med. Chem. 2007, 15, 1659-1669.
5. Mohammed, A. M.; Abdel, G. E.; Alsharai, M. A. Am. J. Biochem. Biotech. 2011, 7, 43-54.
6. Abdel Mohsen, H. T.; Ragab, F. A. F.; Ramla, M. M.; El Diwani, H. I. Eur. J. Med. Chem. 2010, 45, 2336-2344.
7. Xie, F.; Zhao, H. B.; Zhao, L.; Luo, L.; Hu, Y. Bioorg. Med. Chem. Lett. 2009, 19, 275-278.
8. Deshmukh, M. B.; Salunkhe, S. M.; Patil, D. R.; Anbhule, P. V. J. Med. Chem. 2009, 44, 2651-2654.
9. Chandrashekaran, S.; Nagarajan, S. Il Farmaco 2005, 60, 279-282.
10. Sondhi, S. M.; Singh, N.; Johar, M.; Kumar, A. Bioorg. Med. Chem. 2005, 13, 6158-6166.
11. Amin, K. M.; Hanna, M. M.; Abo-Youssef, H. E.; George, R. F. Eur. J. Med. Chem. 2009, 30, 1-13.
12. Kota, R. K.; Kompelly, K. K.; Surampudi, R.; Kulkarni, R. J. Chem. Pharm. Res. 2011, 3, 848-853.
13. Gupta, J. K.; Sharma, P. K.; Dudhe, R.; Chaudhary, A. Acta. Pol. Pharm. 2011, 68, 785-793.
14. Huckova, D.; Holy, A.; Masojidkova, M.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Bioorg. Med. Chem.
2004, 12, 3197-3202.
15. Chitre, T. S.; Kathiravan, M. K.; Chothe, A. S.; Rakholiya, V. K.; Asgaonkar, K. D.; Shital, M. M. J. Pharm.
Res. 2011, 4, 1882-1883.
16. Mohamed, Y. A.; Mohamed, S. F.; Abdullah, M. M. J. Chem. Sci. 2012, 124, 693-702.
17. Amin, K. M.; Awadalla, F. M.; Eissa, A. A. M.; Abou-Seri, S. M.; Hassan, G. S. Bioorg. Med. Chem. 2011, 19,
6087-6097.
18. Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W.; Verma, S. P.; Gilani, S. J. Eur. J. Med. Chem. 2010, 45, 5113-5119.
19. Naik, T. A.; Chikhalia, K. H. E. J. Chem. 2007, 4, 60-66.
20. Kandeel, M. M.; Mounir, A. A.; Refaat, H. M.; Kassab, A. E. Int. J. Pharm. Pharm. Sci. 2012, 4, 438-448.
21. Jennings, L. D.; Kincaid, S. L.; Wang, Y. D.; Krishnamurthy, G.; Beyer, C. F.; McGinnis, J. P. Bioorg. Med. Chem.
Lett. 2005, 15, 4731-4735.
22. Horiuchi, T.; Chiba, J.; Uoto, K.; Soga, T. Bioorg. Med. Chem. Lett. 2009, 19, 305-308.
23. Wang, Y. D.; Johnson, S.; Powell, D.; McGinnis, J. P.; Miranda, M.; Rabindran, S. K. Bioorg. Med. Chem. Lett.
2005, 15, 3763-3766.
24. Salman, A. A.; Tamara, S. N.; Farooq I. M. Journal of Al-Nahrain University - Science 2013, 16, 84-92.
25. Jain, K. S.; Chitre, T. S.; Miniyar, P. B.; Kathiravan, M. K.; Bendre, V. S.; Veer, V. S.; Shahane, S. R.; Shishooe,
C. J. Curr. Sci. 2006, 90, 793-803.
26. Miranda, C. L.; Stevens, J. F.; Ivanov, V.; McCall, M.; Frei, B.; Deinzer, M. L. J. Agric. Food. Chem. 2000, 48,
3876-3884.
27. Hsieh, H. K.; Tsao, L. T.; Wang, J. P.; Lin, C. N. J. Pharm. Pharmacol. 2000, 52, 163-170.
28. Liu, M.; Wilairat, P.; Go, M. L. J. Med. Chem. 2001, 44, 4443-4452.
270

¨
GURDERE et al./Turk J Chem
29. Nielsen, S. F.; Chen, M.; Theander, T. G.; Kharazmi, A.; Christensen, S. B. Bioorg. Med. Chem. Lett. 1995, 5,
449-452.
30. Pati, H. N.; Holt, H. L.; Blanc, R. L.; Dickson, J.; Stewart, M.; Brown, T. Med. Chem. Res. 2005, 14, 19-25.
31. Wu, J.; Li, J.; Cai, Y.; Pan, Y.; Ye, F.; Zhang, Y.; Zhao, Y.; Yang, S.; Li, X.; Liang, G. J. Med. Chem. 2011, 54,
8110-8123.
32. Abdelhafez, O. M.; Abdel-Latif, N. A.; Badria, F. A. Arch. Pharm. Res. 2011, 34, 1623-1632.
33. Abdel-Latif, N. A. Sci. Pharm. 2005, 74, 173-216.
34. Gomha, S.; Abdallah, M.; Abd El-Azız, M.; Serag, N. Turk. J. Chem. 2016, 40, 484-498.
35. Abbas, I.; Gomha, S.; Elaasser, M.; Bauomi, M. Turk. J. Chem. 2015, 39, 334-346.
36. Winter, E.; Neuenfeldt, P. D.; Chiaradia-Delatorre, L. D.; Gauthier, C.; Yunes, R. A.; Nunes, R. J.; Creczynski-
Pasa, T. B.; Pietro, A. D. J. Med. Chem. 2014, 57, 2930-2941.
¨
37. Gu¨rdere, M. B.; Ozbek, O.; Ceylan, M. Synth. Commun. 2016, 46, 322-331.
38. El-Rayyes, N.; Ai-Johary, A. J. Chem. Eng. Data. 1985, 30, 500-502.
39. Kanagarajana, V.; Ezhilarasi, M. R.; Gopalakrishnanb, M. Spectrochim. Acta. A. 2011, 78, 635-639.
40. Kachroo, M.; Panda, R.; Yadav, Y. Der Pharma Chemica 2014, 6, 352-359.
41. Sahin Yaglioglu, A.; Demirtas, I.; Goren, N. Phytochem. Lett. 2014, 8, 213-219.
42. Demirtas, I.; Sahin Yaglioglu, A. J. Chem. 2013, 2013,1-6.
271