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Synthesis of Novel Benzothiazolo[3,2- a ]pyridimidin-4-ones with Potential

Cytotoxic and Pro-Apoptotic Potential

Article  in  ChemistrySelect · November 2018

DOI: 10.1002/slct.201802426

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 DOI: 10.1002/slct.201802426 Full Papers

1
2 z Organic & Supramolecular Chemistry
3
4
5
Synthesis of Novel Benzothiazolo[3,2-a]pyridimidin-4-ones
6 with Potential Cytotoxic and Pro-Apoptotic Potential
7
8 Behzad Jafari,[a] Faisal Rashid,[d] Sayfidin Safarov,[b] Meirambek Ospanov,[a, c]
9 Nazym Yelibayeva,[a, c] Zharylkasyn A. Abilov,[c] Mirgul Z. Turmukhanova,[c]
10
Sergey N. Kalugin,[c] Peter Ehlers,[a, f] Muhammad Ihtisham Umar,[e] Sumera Zaib,[d]
11
12
Jamshed Iqbal,[d] and Peter Langer*[a, f]
13
14
15 The combination of cyclocondensation with palladium cata- the test derivatives exhibited the strongest cytotoxicity in HeLa
16 lysed cross-coupling reactions, afforded a variety of 8-function- cells with the median inhibitory concentration (IC50) of 0.93,
17 alized benzothiazolo[3,2-a]pyridimidin-4-ones in good to ex- 1.55 and 1.84 μM, respectively. Moreover, their anti-proliferative
18 cellent yields. The anti-proliferative potential of the synthetic effect was three times less strong in normal fibroblasts,
19 compounds was evaluated in human cervical adenocarcinoma asserting their possible anti-cancer potential.
20 cells (HeLa) and hamster normal fibroblasts (BHK-21). Three of
21
22 Introduction
repercussions of using cytotoxic drugs in cancer chemotherapy
23
In general, antimicrobial agents exert their cytolytic effects by could be far more jeopardous owing to the fact that these
24
targeting biomolecules that are exclusively pertaining to the aberrant cancer cells are themselves derived from normal
25
microbes. For instance, the anti-fungal drug amphotericin B human cells. Targeting a handful of nasty transformed cells
26
targets ergosterols in the fungal cell membranes.[1] Likewise, that are camouflaged with billions of the perfectly normal
27
penicillins and cephalosporins exhibit their bactericidal proper- human cells genuinely presents an immensely complex predic-
28
ties by blocking the synthesis of peptidoglycans in the bacterial ament with extremely narrow treatment options.[3]
29
cell wall. Since the ergosterols and peptidoglycans are absent Under normal physiological conditions, cells undergo a
30
from the human plasma membrane, the drugs, that selectively temporary cell cycle arrest, unless they are provided with
31
target these biomolecules, do not exert potential toxicity to the growing space, nutrients and growth factors. However, the
32
normal human cells. Tumors are not different from tissue- transformed cancer cells learn to survive under these extremely
33
invading bacteria in the sense that both act as opportunistic unfavorable conditions. Firstly, the uncontrolled cell division in
34
inhabitants of the living tissues.[2] However, it has never been these cells provokes hypoxic and ischemic conditions within
35
so easy for clinicians to combat with cancerous cells. The the tumor microenvironment that further induce tumor angio-
36
genesis and autophagy to support cancer cell survival.[4,5]
37
Secondly, the depletion of nutrients, such as glucose from the
38 [a] B. Jafari, Dr. M. Ospanov, Dr. N. Yelibayeva, Dr. P. Ehlers, Prof. Dr. P. Langer
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 extracellular fluid (ischemia) further mutilates the DNA repair
39
Rostock, Germany mechanism in the cancerous cells.[6] Consequently, these
40 Fax: + 49 381 4986412 extensively dividing cells, that are already vulnerable to DNA
41 Tel.: + 49 3814986410
damage, gradually acquire the ability to extricate from the in-
42 E-peter.langer@uni-rostock.de
[b] Dr. S. Safarov built apoptotic regulators. The anomalous angiogenesis and
43
Institute of Chemistry, Tajikistan Academy of Sciences, ul. Aini 299, autophagy along with the impaired DNA collectively strength-
44 Dushanbe, 734063 Tajikistan. ens tumor milieu and cancer cell survival. Interestingly, the cell
45 [c] Dr. M. Ospanov, Dr. N. Yelibayeva, Prof. Dr. Z. A. Abilov, Dr. M.
survival mechanism within these aberrant cells can be
46 Z. Turmukhanova, Prof. Dr. S. N. Kalugin
Al-Farabi Kazakh National University, Al-Farabi ave. 71, 050040 Almaty, efficiently countered by blocking tumor angiogenesis and
47
Kazakhstan. autophagy.[7,8] Alternatively, these self-invading cells can be
48 [d] F. Rashid, S. Zaib, Prof. Dr. J. Iqbal selectively silenced by stimulate apoptosis within these cells.
49 Centre for Advanced Drug Research, COMSATS University Islamabad,
Over the years, a higher and higher number of novel
50 Abbottabad Campus, Abbottabad-22060, Pakistan.
[e] Dr. M. I. Umar synthetic compounds have been reported with potential
51
Department of Pharmacy, COMSATS University Islamabad, Lahore Cam- cytotoxicity against human cancer cell lines. However, the
52 pus, Defence Road, Lahore-54000, Pakistan clinical success of all such cytotoxic drugs could not be
53 [f] Dr. P. Ehlers, Prof. Dr. P. Langer
guaranteed because of their narrow therapeutic window.
54 Leibniz Institut für Katalyse an der Universität Rostock e.V. (LIKAT), Albert-
Einstein-Str. 29a, 18059 Rostock, Germany. Among all such drugs, the pro-apoptotic compounds play a
55
Supporting information for this article is available on the WWW under special role because of their ability to selectively induce
56
https://doi.org/10.1002/slct.201802426 apoptosis within the cancer cells without harming normal cells.
57

ChemistrySelect 2018, 3, 12213 – 12218 12213 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Papers
Benzothiazoles are among many such synthetic derivatives that
1
have been reported so far for their pro-apoptic properties. For
2
instance, imidazolo[2,1-b]benzothiazole derivatives were previ-
3
ously reported to induce apoptosis within cancer cells by
4
modulating p53 function.[9] Moreover, 2-acetyl-3-(6-methoxy-
5
benzothiazo)-2-yl-amino-acrylonitrile derivatives are previously
6
reported to induce apoptosis within human leukemia cells
7 Scheme 1. Synthesis of 1 (PPA = polyphosphoric acid)
through the activation of p38 mitogen activated protein kinase
8
(MAPK) pathway.[10]
9
Among the many different series of benzothiazoles,
10
benzothiazolo[3,2-a]pyrimidin-4-ones are important heterocy-
11
clic core structures with tremendous pharmacological potential.
12
These derivatives are reported for their anti-leishmanial,
13
sedative, antifungal, and antibacterial properties.[11–17] However,
14
only a few synthetic strategies for the synthesis and functional-
15 Figure 1. Pharmacologically relevant benzothiazolo[3,2-a]pyrimidin-4-ones[5,6]
ization of these heterocyclic scaffolds have been reported to
16
date.[18] Moreover, cytotoxic and pro-apoptotic effects of these
17
derivatives has not been reported so far. Owing to our interest
18
in the functionalization of heterocycles by palladium catalyzed
19
cross coupling reactions and the broad spectrum of pharma-
20
ceutical properties of this substance class, we decided to
21
synthesize novel 8-chloro substituted benzothiazolo[3,2-a]pyr-
22
imidin-4-one and and studied its employment in the synthesis
23
of a variety of related derivatives by palladium catalyzed cross-
24
coupling reactions and analyze their cytotoxic and pro-
25
apoptotic potential.
26
27 Figure 2. Employed ligands during optimization
28 Results and Discussion
29
For our investigation, we chose chloro-functionalized benzo-
30
thiazolo[3,2-a]pyrimidin-4-one 1 as a readily available starting It became apparent that the choice of solvent and base has
31
material.[19–24] Compound 1 was synthesized by condensation of great impact on the reaction outcome. While K3PO4, applied in
32
commercially available 2-amino-6-chlorobenzothiazole with an alcoholic solvent, did not give any product, the application
33
ethyl acetoacetate (Scheme 1).[19–30] of a solvent mixture based on 1,4-dioxane and water furnished
34
We started our investigation by optimizing the conditions the product in very good yield, using XPhos as ligand. Reducing
35
of the Suzuki-Miyaura reaction of 1. Various catalysts, ligands the amount of catalyst and ligand decreased the yield
36
(figure 2), bases and solvents have been tested (Table 1). drastically.
37
38
39
40
41 Table 1. Optimization of the Suzuki reaction of 1
42
43
44
45
46
47
48 Reaction Catalyst [mol%] Ligand [mol%] Base [equiv.] Solvent [ml] Yield [%]a
49
1 Pd2(dba)3, 1 XPhos, 4 K3PO4 , 2 n-Butanol, 2 0
50 2 Pd2(dba)3, 1 XPhos, 4 K3PO4, 2 Ethanol, 2 0
51 3 Pd2(dba)3, 1 XPhos, 4 K3PO4, 2 n-Butanol, 2 0
52 4 Pd(PPh3)4, 4 DavePhos, 8 Na2CO3, 2.4 Dioxane/H2O, 4:1 47
5 Pd(PPh3)4 , 4 XPhos, 8 Na2CO3, 2.4 Dioxane/H2O, 4:1 34
53
6 Pd2(dba)3, 4 DavePhos, 8 Na2CO3, 2.4 Dioxane/H2O, 4:1 52
54 7 Pd2(dba)3, 4 Xphos, 8 Na2CO3, 2.4 Dioxane/H2O, 4:1 85
55 8 Pd2(dba)3, 2 Xphos, 4 Na2CO3, 2.4 Dioxane/H2O, 4:1 42
56 a
Isolated yields
57

ChemistrySelect 2018, 3, 12213 – 12218 12214 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Papers

1 Table 2. Suzuki-Miyaura reactions of 1a

2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Conditions: boronic acid (1.5 equiv.), Pd2(dba)3 (0.04 equiv.), XPhos (0.08 equiv.), K2CO3 (2.4 equiv.), dioxane/water = 4:1, 100 °C, 16 h. a isolated yields
30
31
32
33
After having developed appropriate conditions for the and electron withdrawing substituents were successfully
34
Suzuki-Miyaura reaction, we evaluated the scope of this employed.
35
reaction by using various boronic acids. The optimized In the last part of our synthetic investigations, we studied
36
conditions tolerate several functional groups, including N- and Sonogashira reactions of substrate 1. During the optimization,
37
S-heterocycles as well as ester and formyl functionalities. we have found that the use of Pd(OAc)2 and XPhos gave the
38
Arylboronic acids, containing electron donating or electron best results (Table 5). After several test reactions, we found that
39
withdrawing groups, gave equally good yields. However, steri- the use of DMF as solvent and K2CO3 as base allows the
40
cally hindered ortho-substituted arylboronic acids gave lower synthesis of desired products in high yields.
41
yields than para-substituted derivatives (comparing yields of Following our optimized conditions, products 4a-e were
42
derivatives 2b, 2c and 2d as well as 2 m with 2 l). synthesized in moderate to good yields (Table 6). In this
43
The second part of our study was devoted to the context, arylated acetylenes with electron-rich and electron-
44
Buchwald-Hartwig amination of substrates 1, due to the poor substituents were successfully employed.
45
importance of amino functions in medicinal chemistry and
46
pharmacology. The best results were obtained using
47 MTT Assay
Pd2(dba)3⋅CHCl3 as the catalyst, XPhos as the ligand and
48
NaOtBu as the base in toluene. To our delight, the reaction of 1 The synthetic compounds were initially tested for the evalua-
49
with morpholine gave the desired product 3a in up to 85% tion of the anticancer effects using MTT assay against cervical
50
yield (Table 3). It is important to note that simple nucleo- cancer cells (HeLa). All compounds were active and represent
51
philic aromatic substitution (SNAr), in the absence of a Pd more than 50% growth inhibition at 100 μM concentration.
52
catalyst, did not give the desired product (Table 3, en- Afterwards, the compounds were serially diluted up to 8
53
try 8).[21] different concentrations and inhibitory concentrations were
54
The preparative scope was next studied. The reaction of 1 obtained using graph pad prism. Cytotoxic effects of all the
55
with morpholine and various anilines afforded products 3a-e in derivatives were additionally observed against normal baby
56
good yields (Table 4). Anilines containing electron donating hamster kidney cells (BHK–21). The obtained results are
57

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 Full Papers

1 Table 3. Optimization of the synthesis of 3a

2
3
4
5
6
7 Reaction Catalyst [mol%] Ligand [mol%] Base [equiv.] Solvent [ml] Yield [%]a
8
9 1 Pd2(dba)3⋅CHCl3, 2 XPhos, 8 NaOtBu, 1.4 Toluene, 2 45
2 Pd2(dba)3⋅CHCl3, 1 DavePhos, 1.5 NaOtBu, 1.4 Toluene, 3 0
10 3 Pd(PPh3)4, 1 XPhos, 1.5 NaOtBu, 1.4 Toluene, 3 0
11 4 Pd2(dba)3⋅CHCl3, 2 DavePhos, 8 NaOtBu, 1.4 Toluene, 2 30
12 5 Pd2(dba)3⋅CHCl3, 4 XPhos, 8 NaOtBu, 1.4 Toluene, 2 85
13 6 Pd2(dba)3⋅CHCl3, 1 XPhos, 2 NaOtBu, 1.4 Toluene, 2 0
7 Pd2(dba)3, 2 XPhos, 8 NaOtBu, 1.4 Toluene, 2 0
14 8 - - - Methanol 0
15 a
Isolated yields
16
17
18
Table 4. Synthesis of products 3a-ea
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Conditions: Amine (1.2 equiv.), Pd2(dba)3⋅CHCl3 (0.04 equiv.), XPhos (0.08 equiv.), NaOtBu (1.4 equiv.), toluene, 100 °C, 16 h; a isolated yields.
37
38
39
presented in Table 7. The synthetic derivatives were found to methoxy-5-fluorophenyl derivative 2 k, with an inhibitory
40
exhibit significant inhibition of growth of cancer cell lines. concentration of 1.55 � 0.08 μM against HeLa cell lines. Other
41
Among all the derivatives, compounds 4 d, 2 k and 2 b were derivatives exhibiting strong inhibition were 2 b (4-tolyl) and
42
identified as most active and resulted in more than 70% growth 2 e (3,5-dimethylphenyl), with an inhibitory concentration of
43
reduction in HeLa cells. Similar results were obtained after 1.84 � 0.06 and 2.09 � 0.13 μM, respectively. All other com-
44
dilution and potent inhibition was found. Similarly, these pounds showed inhibitions ranging from 3.23 - 20.7 μM. How-
45
derivatives show less than 30% cytotoxic effects against normal ever, compound 2 j (4-methoxyphenyl) showed the lowest
46
cells. inhibition with an IC50 value of 43.3 � 0.16 μM. Compounds 2 b
47
and 2 e, containing methyl substituents, show a higher activity
48
than methoxy-substituted derivative 2 j. It was observed that
49 Structure activity relationship
the presence of a fluoro group along with a methoxy
50
Compound 4 d was found to be the most potent inhibitor substituent, as in the case of compound 2 k, results in a
51
among the three series with an IC50 value of 0.93 � 0.01 μM significant increase of activity.
52
against HeLa cell lines. The same derivative showed 25.5 � When amino-substituted derivatives 3 a-e were studied, the
53
8.82% inhibition against BHK-21, the cells used as normal best inhibition was observed for 3 d (containing a 3-trifluor-
54
control in the assay to check the cytotoxicity of the synthesized omethylphenylamino group) having an IC50 value of 2.65 �
55
compounds. Among 8-aryl-2-methyl-benzo[4,5]thiazolo[3,2-a] 0.20 μM. However, 3 a (morpholino group) and 3 c (4-fluorophe-
56
pyrimidin-4-ones 2 a-o, the most active compound was 2- nylamino group) also exhibited excellent IC50 values of 2.99 �
57

ChemistrySelect 2018, 3, 12213 – 12218 12216 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Papers

1 Table 5. Optimization of the synthesis of 4a

2
3
4
5
6
7
8 Reaction Catalyst [mol%] Ligand [mol%] Base [equiv.] Additive [mol-%] Solvent Yield [%]a

9 1 Pd(PPh3)2Cl2, 1.2 - Et3N, 2 CuI, 4 DMF 30

10 2 Pd (PPh3)2Cl2, 1.2 - Et3N, 2 CuI, 4 Dioxane 0
11 3 Pd (PPh3)2Cl2, 4 PtBu3⋅HBF4, 8 Cs2CO3, 2 DBU, 20 DMF 0
4 Pd(CH3CN)2Cl2, 3 XPhos, 9 Cs2CO3, 2.1 - CH3CN 0
12 5 Pd/C, 10 XPhos, 8 K2CO3, 2.1 - DMA 25
13 6 Pd(OAc)2, 4 XPhos, 8 Et3N, 2.1 CuI, 4 DMF, 2 10
14 7 Pd(OAc)2, 5 XPhos, 10 Cs2CO3, 2.1 - DMSO, 2 0
15 8 Pd(OAc)2, 4 XPhos, 8 Cs2CO3, 2.1 - DMF, 2 0
9 Pd(OAc)2, 4 XPhos, 8 K2CO3, 2.1 - DMA, 2 35
16 10 Pd(OAc)2, 4 XPhos, 8 K2CO3, 2.1 CuI, 4 DMA, 2 0
17 11 Pd(OAc)2, 4 XPhos, 8 Et3N, 2.1 - DMA, 2 40
18 12 Pd(OAc)2, 4 PtBu3⋅HBF4, 8 Cs2CO3, 2.1 DBU, 20 DMA, 2 0
19 13 Pd(OAc)2, 4 Xantphos, 8 Et3N, 2.1 - DMA, 2 15
14 Pd(OAc)2, 4 XPhos, 8 K2CO3, 2.1 - DMF, 2 77
20
21 a Isolated yields
22
23
24 Table 6. Synthesis of products 4a-ea

25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41 Conditions: alkyne (1.5 equiv.), Pd(OAc)2 (0.04 equiv.), XPhos (0.08 equiv.), K2CO3 (2.1 equiv.), DMF, 100 °C, 16 h; a isolated yields
42
43
44
0.09 and 5.04 � 0.11 μM, respectively. In this series, the having an IC50 values of 49.7 � 1.67 μM, was the least active
45
addition of a fluoro group resulted in a decrease of activity, derivative among this series. These results indicate that the
46
while the presence of a 3-trifluoromethylphenylamino group addition of a halogen group may be the reason for decreased
47
induced a strong inhibition of the HeLa cell line. However, a inhibition potential of this derivative. However, 4-methoxy
48
significant inhibition was noticed in the presence of a substituent 4 d showed a remarkable inhibition. Hence, it was
49
morpholino group as substituent. used for further investigations on the mechanism of inhibition
50
Among the alkynylated series 4 a-e, the best activity was along with positive control (carboplatin) against HeLa cell lines
51
observed for compound 4 a having a phenylethynyl substituent (see supporting information).
52
(the inhibitory concentration was found to be 2.95 � 0.13 μM).
53
A decrease of the inhibition was noticed for compounds 4 b (4-
54 Conclusion
tolylethynyl derivative) and 4 c (4-tert-butyl)phenylethynyl de-
55
rivative) with IC50 values of 4.17 � 0.25 and 4.25 � 0.34 μM, In conclusion, we studied the functionalization of readily
56
respectively. Compound 4 e (4-fluorophenylethynyl derivative), available 8-chloro-2-methyl-benzothiazolopyrimidin-4-one by
57

ChemistrySelect 2018, 3, 12213 – 12218 12217 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Full Papers

Table 7. Anticancer potential of synthetic compounds and standard Conflict of Interest

1
carboplatin against cervical cancer cells (HeLa) and normal baby hamster
2
kidney cells (BHK–21) cell lines The authors declare no conflict of interest.
3
Compound Code HeLa BHK-21
4
IC50 [μM] � SEM %age inhibition
5 Keywords: anticancer agents · cross-coupling · cyclization ·
6 2a 6.58 � 0.23 40.1 � 1.11 heterocycles · Palladium
2b 1.84 � 0.06 29.6 � 3.33
7
2c 20.7 � 0.15 38.8 � 8.90
8 2d 3.30 � 0.08 38.2 � 3.53 [1] K. C. Gray, D. S. Palacios, I. Dailey, M. M. Endo, B. E. Uno, B. C. Wilcock,
9 2e 2.09 � 0.13 36.3 � 3.93 M. D. Burke, Proc. Natl. Acad. Sci. U S A 2012, 109, 2234–2239.
10 2f 3.40 � 0.07 39.6 � 6.67 [2] J. Cummins, M. Tangney, Infect. Agent Cancer 2013, 8, 11.
2g 3.47 � 0.08 36.6 � 6.72 [3] W. G. Kaelin Jr., Nat. Rev. Cancer 2005, 5, 689–698.
11
2h 9.87 � 0.11 29.4 � 4.74 [4] C. C. Zhu, C. Chen, Z. Q. Xu, J. K. Zhao, B. C. Ou, J. Sun, M. H. Zheng, Y. P.
12 2i -NT -NT Zong, A. G. Lu, Biochim. Biophys. Acta, Mol. Basis Dis. 2018, 1864, 387–
13 2j 43.3 � 0.16 36.3 � 3.33 397.
14 2k 1.55 � 0.08 24.5 � 3.10 [5] M. Russo, G. L. Russo, Biochem. Pharmacol. 2018, 153, 51–61.
2l 19.4 � 1.03 32.6 � 4.79 [6] R. Ampferl, H. P. Rodemann, C. Mayer, T. T. A. Höfling, K. Dittmann,
15
2m 4.67 � 0.41 40.5 � 3.36 Radiother. Oncol. 2018, 126, 465–470.
16 2n 8.80 � 0.10 27.3 � 5.23 [7] E. C. Hayden, Nature 2009, 458, 686–687.
17 2o 3.23 � 0.25 36.7 � 7.84 [8] A. Thorburn, D. H. Thamm, D. L. Gustafson, Mol. Pharmacol. 2014, 85,
18 3a 2.99 � 0.09 30.8 � 8.89 830–838.
3b -NT -NT [9] M. S. Christodoulou, F. Colombo, D. Passarella, G. Ieronimo, V. Zuco, M.
19
3c 5.04 � 0.11 39.4 � 4.65 De Cesare, F. Zunino, Bioorg. Med. Chem. 2011, 19, 1649–1657.
20 3d 2.65 � 0.20 33.1 � 1.41 [10] A. Repicky, S. Jantova, L. Cipak, Cancer Lett. 2009, 277, 55–63.
21 3e -NT -NT [11] V. J. Ram, U. K. Singha, P. Y. Guru, ChemInform 1990, 21
22 4a 2.95 � 0.13 36.1 � 7.64 [12] M. S. Chaitanya, G. Nagendrappa, V. P. Vaidya, J. Chem. Pharm. Res. 2010,
4b 4.17 � 0.25 26.7 � 6.47 2, 206–213.
23
4c 4.25 � 0.34 21.1 � 7.64 [13] E. D. Jones, N. Vandegraaff, G. Le, N. Choi, W. Issa, K. Macfarlane, N.
24 4d 0.93 � 0.01 25.5 � 8.82 Thienthong, L. J. Winfield, J. A. Coates, L. Lu, X. Li, X. Feng, C. Yu, D. I.
25 4e 49.7 � 1.67 24.4 � 1.17 Rhodes, J. J. Deadman, Bioorg. Med. Chem. Lett. 2010, 20, 5913–5917.
26 Carboplatin 5.13 � 0.45 19.3 � 1.12 [14] S. V. Gupta, K. G. Baheti, S. B. Ganorkar, D. Dekhane, S. Pawar, S. N. Thore,
Med. Chem. Res. 2013, 22, 1065–1072.
27 NT = Not tested [15] G. Shukla, A. K. Tiwari, V. K. Singh, A. Bajpai, H. Chandra, A. K. Mishra,
28 Chem. Biol. Drug Des. 2008, 72, 533–539.
29 [16] H. S. Hilal, M. S. Ali-Shtayeh, R. Arafat, T. Al-Tel, W. Voelter, A. Barakat,
30 Eur. J. Med. Chem. 2006, 41, 1017–1024.
palladium catalyzed cross-coupling reactions. These reactions [17] M. M. Kandeel, J. Chin. Chem. Soc. 2001, 48, 37–43.
31
allow the synthesis of a variety of benzothiazolopyrimidin-4- [18] H. T. Abdel-Mohsen, J. Conrad, U. Beifuss, J. Org. Chem. 2013, 78, 7986–
32 8003.
one derivatives. Three of the test derivatives, 4d, 2k and 2b,
33 [19] B. Jafari, N. Yelibayeva, M. Ospanov, S. A. Ejaz, S. Afzal, S. U. Khan, Z. A.
showed promising anti-proliferative potential in HeLa cells with Abilov, M. Z. Turmukhanova, S. N. Kalugin, S. Safarov, J. Lecka, J. Sevigny,
34
relatively lesser inhibition of normal fibroblasts (selective index Q. Rahman, P. Ehlers, J. Iqbal, P. Langer, RSC Adv. 2016, 6, 107556–
35
> 3). Cell death analysis asserted the induction of S-phase 107571.
36 [20] Z. G. Sangov, Z. J. Ashurova, Z. D. Khalikova, M. A. Kukaniev, T. M.
apoptosis in HeLa cells.
37 Salimov, J. N. Dzhamshedov, Pharm. Chem. J. 2012, 45, 721–722.
38 [21] M. A. Kukaniev, C. Párkányi, J. Heterocycl. Chem. 2011, 48, 1308–1311.
[22] M. A. Kukaniev, M. M. Akbarova, Z. G. Sangov, S. S. Safarov, D. M. Osimov,
39 Supporting Information Summary
Chem. Heterocycl. Compd. 2010, 46, 605–607.
40 [23] M. A. Kukaniev, M. D. Osimov, Z. G. Sangov, S. S. Safarov, M. B. Karimov,
Supporting Information contains results from cell viability-, cell
41 T. R. Radjabov, Chem. Heterocycl. Compd. 2008, 44, 882–885.
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by the DAAD (scholarship for B. Jafari) is gratefully acknowledged. [30] N. B. Vijay, P. V. Sambhaji, N. K. Sarla, S. J. Jagannath, V. K. Sharad, Asian
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J. Iqbal is grateful to the Organization for the Prohibition of J. Res. Chem. 2010, 3, 161–165.
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Chemical Weapons (OPCW), The Hague, The Netherlands and
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Higher Education Commission of Pakistan for the financial Submitted: August 3, 2018
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support through Project No. 20-3733/NRPU/R&D/ 14/520. Accepted: November 8, 2018
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