Synthesis and colon anticancer activity of some novel thiazole/-2-quinolone derivatives

Article abstract of DOI:10.1016/j.molstruc.2020.127798

We direct for the synthesis of 1,6,7-trisubstituted-4-phenylthiazol-2(3H)-ylidene)hydrazono)methyl)quinolin-2-one derivatives by the reaction of corresponding thiosemicarbazone derived by 2-quinolone derivatives with 2-bromoacetophenones in presence of triethylamine at room temperature. The mechanism of the formed products was discussed. The structure of the obtained products was fully characterized using different spectral techniques including infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) together with elemental analyses. The new synthesized compounds showed a moderate colon anticancer activity.

Full text of DOI:10.1016/j.molstruc.2020.127798

Journal Pre-proof
Synthesis and colon anticancer activity of some novel thiazole/quinolone derivatives
Ashraf A. Aly, Asmaa H. Mohamed, Mohamed Ramadan
PII:
S0022-2860(20)30122-8
DOI:
https://doi.org/10.1016/j.molstruc.2020.127798
MOLSTR 127798
Reference:
To appear in: Journal of Molecular Structure
Received Date: 13 December 2019
Revised Date: 8 January 2020
Accepted Date: 24 January 2020
Please cite this article as: A.A. Aly, A.H. Mohamed, M. Ramadan, Synthesis and colon anticancer
activity of some novel thiazole/quinolone derivatives, Journal of Molecular Structure (2020), doi: https://
doi.org/10.1016/j.molstruc.2020.127798.
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Graphical abstract
Synthesis and colon anticancer activity of some novel
thiazole/quinolone derivatives
Ashraf A. Aly, Asmaa H. Mohamed, Mohamed Ramadan
1 Chemistry Department, Faculty of Science, Minia University, 61519-El-Minia, Egypt.
2
Department of Organic Pharmacy, Faculty of Pharmacy, Al-Azhar University,
Assiut Branch, Egypt.

Synthesis and colon anticancer activity of some novel
thiazole/quinolone derivatives
Ashraf A. Aly,1*Asmaa H. Mohamed,1 and Mohamed Ramadan2
1 Chemistry Department, Faculty of Science, Minia University, 61519-El-Minia, Egypt.
2
Department of Organic Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut
Branch, Egypt.
ꢀ
Corresponding
Authors:
e-mail:
ashrafaly63@yahoo.com
and
ashraf.shehata@mu.edu.eg; Tel./fax: +20 1006268742.
Abstract. We direct for the synthesis of 1,6,7-trisubstituted-4-phenylthiazol-2(3H)-
ylidene)hydrazono)-methyl)quinolin-2-one derivatives by the reaction of corresponding
thiosemicarbazones with 2-bromoacetophenones in presence of triethylamine at room
temperature. The mechanism of the products was discussed. The structure of the obtained
products was fully characterized using different spectral techniques including infrared (IR),
nuclear magnetic resonance (NMR), and mass spectrometry (MS) together with elemental
analyses. The new synthesized compounds showed a moderate colon anticancer activity
Keywords: 2-Bromoacetophenones; thiosemicarbazones, thiazoles; colon anticancer
activity.
1. Introduction
The cytotoxic activity of quinolone derivatives has become the source of new anticancer
agents, which might also help addressing side-toxicity and resistance [1]. Moreover, the
quinolone ring is considered an important structural unit in many anti-oxidant agents [2].
Synthesized 4-arylchalcogenyl-7-chloroquinolines were screened in vitro for antioxidant
activity by previous publication which demonstrated that compound presented a potent
antioxidant effect [3]. Thiosemicarbazones are a class of compounds which have enjoyed
significant attention due to their broad-spectrum of biological activities, including
antibacterial, antiprotozoal, antifungal, antiviral and antitumour activity [4]. Quinoline and
related derivatives, on the other hand, are useful compounds with diverse pharmaceutical
1

applications, and some have even reached markets for treatment of various ailments [5].
The 2-oxoquinoline (2-OCQ), which belongs to a quinoline family, is an interesting
naturally occurring scaffold to attach new moieties or bioactive groups. It has been widely
used as a ‘parental’ framework to synthesize a variety of molecules with a wide range of
biological activities such as antitubercular, antiinflammatory, antifungal and
antileishmanial activity [6-9]. For example, oxoquinoline-derived thiosemicarbazone I and
II (Figure 1) were found to exhibit good antiproliferative activity against the HCT116 cell
line [10].
Figure 1. Chemical structures of biologically active quinoline-derived thiosemicarbazone
derivatives (I and II) based on 2-oxo-quinoline structural motif.
Heterocycles bearing nitrogen, sulphur and thiazole moieties constitute the core for a
number of biological interesting compounds [11,12]. The applications of thiazoles have
found in drug development for the treatment of allergies [13], hypertension [14],
inflammation [15], schizophrenia [16], bacterial [17], HIV infections [18], and hypnotics
[19]. Moreover, thiazoles have been used for the treatment of pain [20], as fibrinogen
receptor antagonists with antithrombotic activity [21] and as new inhibitors of bacterial
DNA gyrase B [22]. A number of thiazole derivatives have been reported to possess
significant and diverse biological activities such as antimicrobial [23], analgesic [24], anti-
inflammatory [25], antioxidant [26], anti-HIV [27], antiallergic [28] and anticancer
activities [28].
2

Our research program has also dealt with the synthesis of various thiazoles via donor-
acceptor interactions [30-35]. Recently, we synthesized analogous derivatives of
LY293111, a potent antagonist of the leukotriene B4 (LTB4) receptor, based on the
synthesis of an amidinothiazole ring, connected with phenoxy group [36]. The
combination in a single molecule of the quinolone and thiazole (active in relation to 36
many microorganisms) caused a significant retardation in the growth of Mycobacterium
Tuberculosis H37Rv ATCC 27294 [37]. In addition it proved to be slightly active towards
the main forms of malignant tumors in man: leukemia, lung cancer, large intestine, CNS
cancer, melanoma, ovarian cancer, kidney, prostate, and mammary gland [38].
In continuation to these efforts and with an objective to develop novel and potent
therapeutic agents of synthetic origin, it was decided to synthesize certain thiazole
derivatives and evaluate them for their anticancer potential. Most indicative is to design
compounds having a combined of two structures; both as bioactive scaffolds; 2-quinolones
and other contains azothiazoloidinone groups as bio active scaffolds (Figure 2). Activity
against anticancer cell lines would expect to show remarkable activity.
Figure 2. Design of the target compounds 7a-g
2. Experimental
2.1.
Instrumentation
3

Melting points were determined on Stuart electrothermal melting point apparatus and were
uncorrected. TLC analysis was performed on analytical Merck 9385 silica aluminum
sheets (Kiselgel 60) with PF254 indicator. The IR spectra were recorded as KBr disks on
Shimadzu-408 infrared spectrophotometer, Faculty of Science, Minia University. The
NMR spectra were measured using a Bruker AV-400 spectrometer at the Karlsruhe
Institut für Technologie (KIT), Institute of Organic Chemistry, Karlsruhe, Germany.
Chemical shifts were expressed as δ (ppm) with tetramethylsilane as internal reference.
The samples were dissolved in DMSO-d6, s = singlet, d = doublet, dd = doublet of doublet
and t = triplet. Mass spectrometry were recorded on a Varian MAT 312 instrument in EI
mode (70 eV), at the Karlsruhe Institut für Technologie (KIT), Institute of Organic
Chemistry, Karlsruhe, Germany.
2.2.
Chemicals
2.2.1. Starting materials
Carbaldehydes (3a [39], 3b [40], 3c [41]) and thiosemicarbazones (5a [42], 5b [10], 5c
[41]) were prepared according to literature methods. 2-Bromoacetophenones 2 was
prepared according to literature [43].
2.2.2. Synthesis of substituted 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-
carbaldehydes 3a-g.
To a stirred solution of 2-quinolone derivatives (10 mmol) in chloroform (15 mL), a
solution of 20 mL sodium hydroxide (15 %) was added dropwise during 30 min. The
mixture was heated on water bath for 4 h. Chloroform was evaporated on vacuum and 100
mL of methanol was then added. The formed solid was filtered and recrystallized.
2.2.2.1.
4-Hydroxy-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (3d)
1
Yellow crystals (DMF); yield 1.59 g (80%); Mp. > 360°C; H NMR (400 MHz, DMSO-
4

d6): δH 3.83 (s, 3H, OCH3), 7.07-7.09 (d, 1H, J = 8.0 Hz, Ar-H), 7.38-7.41 (m, 2H, Ar-H),
7.80 (s, 1H, NH), 9.90 (s, 1H, HC=O), 10.19 (s,1H, OH) ppm; 13C NMR (100 MHz,
DMSO-d6): δC 55.44 (OCH3), 107.56 (C-3), 116.88, 123.52, 124.10 (Ar-CH), 124.53,
131.00, 139.42 (Ar-C), 165.58 (C=O), 176.35 (C4), 188.17 (HC=O) ppm; IR (KBr): ν
3345 (OH), 3267 (NH), 1656 (C=O), 1625 (C=O), 1596 cm−1; Anal. Calcd for C11H9NO4
(219.19): C 60.27, H 4.14, N 6.39; Found: C 60.38, H 4.18, N 16.40.
2.2.2.2.
7-Chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (3e)
Yellow crystals (DMF/methanol); yield 1.56 g (78%); Mp. > 360°C; 1H NMR (400 MHz,
DMSO-d6): δH 7.07-7.10 (d, 1H, J = 10.0 Hz, Ar-H), 7.38-7.41 (m, 2H, Ar-H), 7.80 (s,
1H, NH), 9.89 (s, 1H, CHO), 10.31 (s,1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): δC
108.14 (C-3), 116.94, 123.50, 124.54 (Ar-CH), 125.54, 131.09, 139.41 (Ar-C), 165.18
(C=O), 176.31 (C4), 188.26 (HC=O) ppm; IR (KBr): ν 3335 (OH), 3267 (NH), 1661
(C=O), 1624 (C=O) cm−1; MS (70 eV): m/z (%) = 224 (M+1, 31), 223 (28), 169 (5), 155
(39), 137 (70), 107 (20); Anal. Calcd for C10H6ClNO3 (223.61): C 53.71, H 2.70, N 6.26;
Found: C 53.82, H 2.73, N 6.35.
2.2.2.3.
6-Chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (3f)
1
Yellow crystals (DMF/ethanol); yield 1.50 g (76%); Mp. > 360°C; H NMR (400 MHz,
DMSO-d6): δH 7.07-7.09 (d, 1H, J = 8.0 Hz, Ar-H), 7.38-7.42 (m, 2H, Ar-H), 7.80 (s, 1H,
NH), 9.88 (s, 1H, CHO), 10.32 (s,1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): δC
108.20 (C-3), 116.22, 123.54, 124.15 (Ar-CH), 124.53, 131.10, 139.39 (Ar-C), 163.10
(C=O), 174.20 (C4), 186.09 (HC=O) ppm; IR (KBr): ν 3329 (OH), 3254 (NH), 1656
(C=O), 1624 (C=O) cm−1; MS (70 eV): m/z (%) = 224 (M+1, 35), 223 (31), 169 (5), 155
(39), 137 (72), 107 (30); Anal. Calcd for C10H6ClNO3 (223.61): C 53.71, H 2.70, N 6.26;
Found: C 53.82, H 2.73, N 6.35.
5

2.2.2.4.
7-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (3g)
1
Yellow crystals (DMF); yield 1.71 g (79%); Mp. >360 °C; H NMR (400 MHz, DMSO-
d6): δH 7.08-7.10 (d, 2H, J = 7.6 Hz, Ar-H,), 7.26 (d, 1H, J = 2.1 Hz, Ar-H,), 7.80 (s, 1H,
NH), 9.90 (s, 1H, CHO), 10.17 (s,1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): δC
108.35 (C3), 117.47, 123.23, 127.50 (Ar-CH), 128.18, 131.93, 142.33 (Ar-C), 166.27
(C=O), 177.61 (C4), 188.83 (HC=O) ppm; IR (KBr): ν 3308 (OH), 3189 (NH), 1639
(C=O), 1615 (C=O) cm−1; Anal. Calcd for C10H6BrNO3 (268.06): C 44.81, H 2.26, N 5.23;
Found: C 44.94, H 2.30, N 5.30.
2.2.3. Synthesis of substituted hydrazinecarbothioamide 5a-g
A mixture of thiosemicarbazide 4 (0.83 g, 9.1 mmol) and aldehyde 3a-g (9.1 mmol) in 100
mL of a mixture of ethanol 50 mL together with few drops of glacial acid was heated
under reflux with stirring for 4 h. The yellow precipitate was allowed to stand, filtered,
washed with ethanol, dried and recrystallized from the stated solvents.
2.2.3.1.
2-((4-Hydroxy-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-
hydrazinecarbothioamide (5d)
1
Pale yellow crystals (DMF/ethanol); yield 2.39 g (82%); MP. 252-254 °C; H NMR (400
MHz, DMSO-d6): δH 3.81 (s, 3H, OCH3), 7.24-7.30 (m, 3H, Ar-H), 8.11 (bs, 2H, NH2),
13
8.55 (s, 1H, HC=N), 11.49 (bs, 1H, NH), 11.52 (bs, 1H, NH), 11.95 (bs, 1H, OH); C
NMR (100 MHz, DMSO-d6): δC 55.86 (OCH3), 103.11 (C3), 104.53, 114.99, 117.53 (Ar-
CH), 122.65, 134.00 (Ar-C), 144.42 (HC=N), 154.74 (C6), 161.64 (C=O), 172.48 (C4),
176.80 (C=S); IR (KBr): ν 3364 (NH2), 3010 (NH), 2838 (Ar-CH), 1688 (C=O), 1659
(C=N) cm−1; MS (70 eV): m/z (%) = 293 (M+1, 10), 292 (M+, 8); Anal. calcd. for
C12H12N4O3S (292.31): C 49.31, H 4.14, N 19.17, S 10.97; Found: C 49.43, H 4.19, N
19.29, S 11.08.
6

2.2.3.2.
2-((7-Chloro-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-
hydrazinecarbothioamide (5e).
1
Pale yellow crystals (DMF/methanol); yield 2.39 g (81%); Mp. > 360 °C; H NMR (400
MHz, DMSO-d6): δH 7.45-7.38 (m, 2H, Ar-H), 7.81 (d, 1H, J = 8 Hz, Ar-H), 8.14 (bs, 2H,
NH2), 8.51 (bs, 1H, HC=N), 11.51 (bs, 1H, NH), 11.65 (bs, 1H, NH), 11.95 (s, 1H, OH);
IR (KBr) ν 3350 (NH2), 3020 (NH), 2989 (Ar-CH), 1656 (C=O), 1590 (C=N) cm−1; MS
(70 eV): 297 (M+1, 6), 296 (M+, 6 ), 289 (15), 239 (5), 195 (5). Anal. calcd. for
C11H9ClN4O2S (296.73): C 44.52; H 3.06; N 18.88; S 10.81 Found: C, 44.67; H, 3.10; N,
18.99; S 10.97.
2.2.3.3.
2-((6-Chloro-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-
hydrazinecarbothioamide (5f).
1
Pale yellow crystals (DMF/ethanol); yield 2.39 g ( 81%); Mp. > 330 °C; H NMR (400
MHz, DMSO-d6): δH 7.23-7.27 (m, 1H, ArH), 7.47-7.51 (m, 2H, Ar-H), 8.14 (bs, 2H,
NH2), 8.53 (bs, 1H, HC=N), 11.53 (bs, 1H, NH), 11.64 (bs, 1H, NH), 11.69 (bs, 1H, OH);
13C NMR (100 MHz, DMSO-d6): δC 103.21 (C-3), 110.15, 114.99, 117.53 (Ar-CH),
123.70, 134.05, 136.14 (Ar-C), 145.68 (HC=N), 159.55 (C6), 161.60 (C=O), 168.19 (C-
4), 176.25 (C=S); IR (KBr) ν 3345 (NH2), 3110 (NH), 2889 (Ar-CH), 1665 (C=O), 1610
(C=N) cm−1; Anal. calcd. for C11H9ClN4O2S (296.73): C 44.52; H 3.06; N 18.88; S 10.81
Found: C 44.68; H 3.11; N 18.99; S 10.95.
2.2.3.4.
2-((6-Bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-
hydrazinecarbothioamide (5g).
1
Pale yellow crystals (DMF); yield 2.65 g (76%); Mp. > 360 °C; H NMR (400 MHz,
DMSO-d6): δH 7.36-7.38 (dd, J = 7.38, 4.6 Hz, 1H, Ar-H), 7.44-7.46 (d, 1H, J = 8.6 Hz,
Ar-H), 7.80-7.83 (d, 1H, J = 8.6 Hz, Ar-H), 8.14 (bs, 2H, NH2), 8.52 (bs, 1H, HC=N),
7

11.51 (bs, 1H, NH), 11.52 (bs, 1H, NH), 11.65 (bs, 1H, OH); 13C NMR (100 MHz,
DMSO-d6): δC 103.27 (C3), 116.25 (C5), 118.73, 125.95, 129.49 (CH-Ar), 132.99, 140.26
(C-Ar), 145.88 (HC=N), 161.42 (C=O), 162.06 (C4), 172.49 (C=S); IR (KBr) ν 3356
(NH2), 3200 (NH), 2988 (Ar-CH), 1656 (C=O), 1590 (C=N) cm−1; MS (70 eV): 343
(M+2, 25), 343 (M+1, 90), 341 (M+, 100), 340 (M-1, 18 ); Anal. Calcd for C11H9BrN4O2S
(341.18): C 38.72, H 2.66, N 16.42, S 9.40; Found: C 38.89, H 2.71, N 16.60, S 9.51.
2.2.4. Synthesis of substituted thiazoles 7a-g
A mixture of hydrazinecarbothioamides 5a-g (1.0 mmol) and 2-bromoacetophenone (7)
(0.198 mg, 1.0 mmol) in 50 ml dry ethanol together 0.5 mL of triethylamine were stirred
at room temperature for 3-7 h (the reaction was followed up by TLC analysis). The
precipitate was filtered, washed with 10 mL ethanol, dried and recrystallized from
DMF/EtOH to give the title products 7a-f.
2.2.4.1.
4-Hydroxy-3-((E)-((Z)-(4-phenylthiazol-2(3H)-ylidene)hydrazono)-
methyl)quinolin-2(1H)-one (7a)
Yellow crystals; yield 0.304 g (84%); Mp. 298–300 °C; NMR (DMSO-d6): see Table 1; IR
(KBr): ν 3198 (OH), 3150 (NH), 2966 (Ar–H), 1659 (C=O), 1572 (C=N) cm-1; MS (70
eV): m/z (%) = 363 (M+1, 30), 362 (M+, 19), 307 (40), 289 (15); 154 (100); Anal. Calcd
for C19H14N4O2S (362.41): C 62.97, H 3.89, N 15.46, S 8.85; Found: C 63.11, H 3.92, N
15.56, S 8.98.
2.2.4.2.
1-Ethyl-4-hydroxy-3-((E)-((Z)-(4-phenylthiazol-2(3H)-ylidene)hydrazono)-
methyl)quinolin-2(1H)-one (7b).
o
1
Yellow crystals; yield: 0.331 g (85%); Mp. 250-252 C; H NMR (400 MHz, DMSO-d6):
δH 1.22 (t, 3H, J = 7.0 Hz, CH3), 4.30 (q, 2H, J = 7.0 Hz, CH2), 7.34 (m, 2H, Ar-H), 7.44
(t, 3H, J = 7.5, Ar-H), 7.62 (d, 1H, J = 8.5 Hz, Ar-H), 7.72 (ddd, 1H, J = 8.5, 7.2, 1.3 Hz,
8

Ar-H), 7.88 (bd, 2H, J = 6.7 Hz, Ar-H), 8.09 (dd, 1H, J = 8.0, 1.3 Hz Ar-H), 8.60 (s, 1H,
13
HC=N), 12.51 (bs, 1H, OH), 12.66 (bs, 1H, NH) ppm; C NMR (100 MHz, DMSO-d6):
δC 12.76 (CH3), 36.54 (CH2), 102.31 (C-3), 103.43 (C-5'), 114.80 (C8), 115.11 (C-4a),
122.05 (C-6), 123.79 (C-5), 125.59 (C-o), 127.82 (C-p), 128.65 (C-m), 132.59 (C-7),
134.49 (C-i), 138.43 (C-8a), 142.33 (C-3a), 151.18 (C-4'), 160.17 (C=O), 161.76 (C-OH),
166.25 (C=N) ppm; IR (KBr): ν 3200 (OH), 3151 (NH), 3021 (Ar-CH), 1659 (C=O), 1572
(C=N), 1442 (CH2) cm-1; MS (70 eV): m/z (%) = 390 (M+, 7), 307 (40), 289 (20), 154
(100), 137 (65); Anal. Calcd for C21H18N4O2S (390.46): C 64.60, H 4.65, N 14.35, S 8.21;
Found: C 64.75, H 4.68, N 14.49, S 8.36.
2.2.4.3. 4-Hydroxy-6-methyl-3-((4-phenylthiazol-2(3H)-ylidene)hydrazono-
methyl)quinolin-2(1H)-one (7c)
Yellow crystals; yield 0.312 g (83%); Mp. 276-278 ºC; NMR (DMSO-d6): see Table 2; IR
(KBr): ν 3210 (OH), 3150 (NH), 3021 (Ar–H), 1659 (C=O), 1572 (C=N) cm-1; MS (70
eV): m/z (%) = 376 (M+, 20), 307 (42), 289 (17), 154 (100), 137 (62); Anal. Calcd for
C20H16N4O2S (376.43): C 63.81, H 4.28, N 14.88, S 8.52; Found: C 63.96; H, 4.32; N,
14.99, S 8.61.
2.2.4.4.
4-Hydroxy-6-methoxy-3-(4-phenylthiazol-2(3H)-ylidene)-hydrazono)-
methyl)quinolin-2(1H)-one (7d)
o
1
Yellow crystals; yield: 0.313 g (81%); Mp. 284-286 C; H NMR (400 MHz, DMSO-d6):
δH 3.84 (s, 3H, OCH3), 7.22-7.26 (m, 2H, Ar-H + CH-thiazol), 7.32-7.36 (m, 2H, Ar-H),
7.39-7.45 (m, 3H, Ar-H), 7.86-7.88 (m, 2H, Ar-H), 8.53 (s, 1H, HC=N), 11.58 (s, 1H,
13
NH), 12.49 (bs, 1H, OH), 12.60 (bs, 1H, NH) ppm; C NMR (100 MHz, DMSO-d6): δC
55.44 (OCH3), 102.91 (C-3), 103.62 (C-5'), 114.39 (C-8), 117.06 (C-4a), 121.81 (C-6),
123.40 (C-5), 125.55 (C-o), 127.85 (C-p), 128.67 (C-m), 133.27 (C-7, C-8a), 140.00 (C-
9

i), 150.10 (C-3a), 154.30 (C-4'), 160.77 (C=O), 161.88 (C-OH), 165.01 (C=N), ppm; IR
(KBr): ν 3200 (OH), 3150 (NH), 3066 (Ar-CH), 1652 (C=O), 1604 (C=N), 1566 (CH3)
cm-1; MS (70 eV): m/z (%) = 393 (M+1, 30), 392 (M+, 20), 307 (35), 289 (17), 154 (100),
137 (67), 107 (18); Anal. Calcd for C20H16N4O3S (392.43): C 61.21, H 4.11, N 14.28, S
8.17; Found: C 61.38, H 4.16, N 14.41, S 8.29.
2.2.4.5.
7-Chloro-4-hydroxy-3-(4-phenylthiazol-2(3H)-ylidene)-hydrazono)-
methyl)quinolin-2(1H)-one (7e).
1
Yellow crystals; yield: 0.312 g (79%); Mp. 270 -772oC; H NMR (400 MHz, DMSO-d6):
δH 7.21-7.27 (m, 2H, Ar-H+C5H-thiazol), 7.32-7.39 (m, 2H, Ar-H), 7.40-7.52 (m, 3H, Ar-
H), 7.91-7.95 (m, 2H, Ar-H), 8.32 (s, 1H, HC=N), 10.97 (s, 1H, NH), 11.11 (bs, 1H, NH),
11.95 (bs, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): δC 109.14 (C-3), 110.37 (C-5'),
115.24 (C-8), 115.76 (C-4a), 123.40 (C-6), 124.89 (C-5), 125.87 (C-o), 129.80 (C-p),
130.82 (C-m), 135.33 (C7), 137.35 (C-8a), 139.27 (C-i), 143.50 (C3a), 160.62 (C-4'),
161.74 (C=O), 165.18 (C-OH), 166.25 (C=N) ppm; IR (KBr): ν 3670 (OH), 3200 (NH),
2943 (Ar-CH), 1647 (C=O), 1568 (C=N) cm-1; MS (70 eV): m/z (%) = 397 (M+1, 35),
396 (M+, 20), 307 (30), 289 (15), 223 (10), 176 (15), 154 (100), 137 (67), 107 (20); Anal.
Calcd for C19H13ClN4O2S (396.85): Calcd. C 57.50, H 3.30, N 14.12, S 8.08; Found: C
57.68, H 3.35, N 14.27; S 8.20.
2.2.4.6.
6-Chloro-4-hydroxy-3-(4-phenylthiazol-2(3H)-ylidene)hydrazono)-
methyl)quinolin-2(1H)-one (7f)
1
Yellow crystals; yield: 0.312 g (79%); Mp. 274 -776oC; H NMR (400 MHz, DMSO-d6):
δH 7.23-7.27 (m, 2H, Ar-H + CH-5-thiazol), 7.31-7.39 (m, 2H, Ar-H), 7.40-7.45 (m, 3H,
Ar-H), 7.85-7.89 (m, 2H, Ar-H), 8.55 (s, 1H, HC=N), 11.72 (s, 1H, NH), 11.79 (bs, 1H,
NH), 12.43 (bs, 1H, OH) ppm; IR (KBr): ν 3435 (OH), 3185 (NH), 2943 (Ar-CH), 1648
10

(C=O), 1590 (C=N) cm-1; MS (70 eV, Fab, %): m/z = 397 (M+1, 35), 396 (M+, 22), 307
(30), 289 (15), 223 (10), 176 (15), 154 (100), 137 (67), 107 (20); Anal. Calcd for
C19H13ClN4O2S (396.85): C, 57.50; H, 3.30; N, 14.12; S, 8.08; Found: C 57.68, H 3.35, N
14.27; S 8.20.
2.2.4.7 7-Bromo-4-hydroxy-3-(4-phenylthiazol-2(3H)-ylidene)hydrazono)-methyl)-
quinolin-2(1H)-one (7g)
Yellow crystals; yield: 0.352 g (80%); Mp. 280 -282 oC; 1H NMR (400 MHz, DMSO-d6):
δH 7.20-7.22 (d, 2H, J = 8.4 Hz, Ar-H+C5H-thiazol), 7.31-7.39 (m, 2H, Ar-H), 7.40-7.45
(m, 3H, Ar-H), 7.74-7.75 (d, 1H, J = 2.0 Hz, Ar-H), 7.86-7.88 (d, 1H, J = 7.6 Hz, Ar-H),
8.52 (s, 1H, HC=N), 11.58 (s, 1H, NH), 12.50 (bs, 1H, NH), 12.66 (bs, 1H, OH) ppm; 13C
NMR (100 MHz, DMSO-d6): δC 102.64 (C-3), 113.89 (C-5'), 115.44 (C-8), 122.39 (C-4a),
125.55 (C-6), 127.83 (C-5), 128.66 (C-o), 131.07 (C-p), 133.39 (C-m), 136.72 (C7, C-8a),
138.14 (C-i), 142.65 (C-3a), 154.34 (C-4'), 160.20 (C=O), 161.90 (C-OH), 164.20 (C=N)
ppm; IR (KBr): ν 3200 (OH), 3150 (NH), 3066 (Ar-CH), 1652 (C=O), 1604 (C=N), 1566
(CH3) cm-1; MS (70 eV): m/z (%) = 443 (M+2, 10), 441 (M+, 10). Anal. Calcd for
C19H13BrN4O2S (441.30): Calcd. C 51.71; H 2.97; N 12.70; S 7.27; Found: C 51.89, H
3.01, N 12.85, S 7.40.
3. Results and Discussion
For the preparation of the target compounds, it was important at the beginning to
synthesize the key thiosemicarbazones 5a-g. It was successfully synthesized as illustrated
in Scheme 1.
11

Scheme 1. Synthesis of 2-quinlonylthiosemicarbazones 5a-g
Upon refluxing of aniline derivatives 1a-g with phosphorous pentaoxide, phosphoric acid
and diethyl malonate at 220 ºC, cyclization to quinolones 2a-g occurred [44]. Heating
gently of 2a-g with chloroform and 15% NaOH afforded the corresponding 4-hydroxy-2-
oxo-1,2-dihydroquinoline-3-carbaldehydes
thiosemicarbazide 4 in presence of few drops of glacial acetic acid as a catalyst gave the
corresponding thiosemicarbazones 5a-g (Scheme 1) The target compounds 1,6,7-
3a-g.
Refluxing
of
3a-g
with
.
trisubstituted-4-hydroxy-3-((E)-((Z)-(4-phenylthiazol-2(3H)-ylidene)hydrazono)methyl)-
quinolin-2(1H)-ones 7a-g were synthesized in 82-85 % yield by treatment of different
thiosemicarbazones 5a-g with 2-bromoacetophenones (6) at room temperature in the
presence of triethylamine (Scheme 2).
12

OH
H
O
R2
R1
N
NH2
+
N
Br
OH
S
H
R2
R1
N
N
R
O
N
EtOH, Et3N
r.t., 4-6 h
N
S
6
N
R
O
5a-g
7a-g
a, R = R1 = R2 = H
b, R = CH2CH3; R1, R2 = H
c, R = R1 = H; R2 = CH3
d, R = R1 = H; R2 = OCH3
e, R=R2= H; R1 = Cl
f, R=R1= H; R2 = Cl
g, R=R2= H; R1 = Br
Scheme 2. Synthesis of 1,6,7-trisubstituted-4-hydroxy-3-(4-phenylthiazol-2(3H)-
ylidene)hydrazono)methyl)quinolin-2(1H)-ones 7a-g
The suggested mechanism for the formation of thiazoles 7a-g was based upon attacking of
the thione-lone pair to the α-bromo-C in 6 (Scheme 3). That was followed by salt
formation as in intermediates 8a-g. Subsequently, H transfer in 8a-g followed by internal
nucleophilic attack of nitrogen lone-pair on the carbonyl carbon to form intermediates
9a-g. Which upon elimination of a water molecule afford the thiazoles 7a-g (Scheme 3).
Scheme 3. Suggested mechanism showed the formation of compounds 7a-g
The fragmentation pattern of mass spectrum of 7a is in full agreement with the structure,
where it gave the molecular ion peak at m/z = 362 which is in accordance with the
molecular weight of 7a. In addition to two fragmentations at m/z = 288 and 273 which are
2·
related to both (M+- C6H4 ) and (M+- C6H5N2·), respectively (Figure 3)
.
13

Figure 3. Fragmentation patterns in mass spectroscopy for compound 7a
The structure of the target compounds 7a-g was confirmed by elemental analyses, IR,
NMR (1H, 13C, 2D NMR, 15N) and mass spectra were performed; these and elemental
analyses were in good agreement with the assigned structures. The structure of the target
compounds 7a-g was confirmed by elemental analyses, IR, NMR (1H, 13C, 2D NMR, 15N)
and mass spectra were performed; these and elemental analyses were in good agreement
with the assigned structures.
3.1.
1H NMR of compound 5a-g
The 1H NMR spectra of compounds 5a-g showed three δ values for NH and NH2 protons.
For example, the 1H NMR of compound 5e revealed δH 11.65 for NH-quinolone, 11.51 for
NH-thioamide and 8.14 for NH2-thioamide. It was previously reported that there is an
intramolecular hydrogen bond in case of compounds having thiosemitcarbazones
structures [45]. In our case, the presence of E- and Z-configuration is found (Figure 4) and
that was confirmed by the appearance of the azomethine protons as a broad singlet (see
the experimental section).
14

Figure 4. Proposed intramolecular hydrogen bond in compound 5e
Figure 5. 1H NMR spectrum of compound 5e as an example
3.2.
Infrared spectroscopy of 7a-g.
All compounds 7a-g exhibit yellow colors: The IR spectrum of 7a showed absorption
bands at ν = 3198, 3150 cm-1 for the OH and NH groups (Figure 6). The C=O and C=N
stretching bands at 1659, 1572 cm-1.
15

Figure 6. IR spectrum of compound 7a
3.3.
NMR spectra of 7a-g.
The NMR spectra (1H and 13C) of compound 7a were recorded using DMSO as a solvent
1
1
(Figure 7). H NMR spectra of 7a (Table 1) showed three broad H singlet at δ = 12.65,
12.50 and 11.66 ppm, assigned as thiazol-NH, OH, quinolone-NH, respectively. In
addition, a singlet signal at 8.53 ppm for the HC=N (Figures 7 and 8).
Figure 7. 1 H NMR spectrum of compound 7a
16

Figure 8. 1H NMR expanded spectrum of compound 7a
13
The C NMR spectrum (Figure 9) also supported the structure of 7a and showed signals
at δ = 166.49, 162.53, 161.25 and 141.99 ppm which were assigned to C=O, thiazol C=N,
C-OH, imine C=N, respectively. The monosubstituted phenyl ring in 7a is assigned
straightforwardly.
Figure 9. 13C NMR spectrum of compound 7a
17

The C-i gives HMBC correlation with H-m, as usual; C-4’ is assigned on chemical-shift
grounds. Carbons 3, 4, and 4a all give HMBC correlation with the singlet at δH 8.53,
leading to assignment of this signal as H-3a not H-5’ (Figure 10). The distinctive carbons
were shown in Figure 11.
Figure 10. HMBC spectrum of compound 7a
OH
4
3'
3c
N
m
o
3a
O
H
5
4a
8a
N
i
N
3b
p
3
6
7
4'
S
2'
N
2
5'
1
8
H
Figure 11. The distinctive carbons in compound 7a
The nitrogen atom of 7a appeared at δN = 142.9 ppm and gives HSQC correlation with the
1H broadened singlet at δH = 11.66 ppm (Figure 12) and gives HMBC correlation with an
aromatic proton at δH = 7.34 ppm. The nitrogen at 150.3 gives HMBC correlation with H-
3a at 8.53 ppm, this nitrogen is assigned as N-3b (Figure 13).
18

Figure 12. 1H-15NHSQC spectrum of compound 7a
Figure 13. Another section of 1H-15NHSQC spectrum of compound 7a
Table 1. NMR spectroscopy of compound 7a
1H NMR (DMSO-d6):
12.65 (b; 1H), 12.50 (b; 1H)
11.66 (bs; 1H)
1H-1H COSY:
Assignment:
NH-3', OH
NH-1
8.53 (s; 1H)
H-3a
7.96 (d, J = 7.8; 1H)
7.58, 7.25
H-5
19

7.87 (bd; J = 7.1; 2H)
7.58 ("t"d; J = 7.2, 0.8; 2H)
7.43 ("t", J = 7.6; 2H)
7.43 (s,; 1H)
7.34 (d, J = 7.4; 1H)
7.32 (t, J = 8.2; 1H)
7.25 (t, J = 7.6; 1H)
13C NMR (DMSO-d6): HSQC:
166.49 (b); 162.53 (b)
161.25
7.43, 7.32
7.96, 7.34, 7.25
7.87, 7.32
H-o
H-7
H-m
H-5'
H-8
H-p
H-6
Assignment
C-2, 2'
C-4
7.58
7.87, 7.43
7.96, 7.58
HMBC:
8.53, 7.96, 7.34
151.11 (b)
141.99 (b)
138.70
134.34 (b)
132.08
128.65
127.81
125.58
123.07
121.96
C-4'
C-3a
C-8a
C-i
C-7
C-m
C-8
C-o
C-5
C-6
C-p
8.53
8.53
7.96, 7.58
7.43
7.96, 7.25
7.43
7.87
7.58
7.43
7.34
7.87
7.96
7.25
7.32
7.87, 7.43, 7.34
7.58, 7.32
115.49
7.32, 7.25
114.10
103.30 (b)
102.73
15N NMR (DMSO-d6): HSQC:
11.66, 8.53, 7.58
C-4a
C-5'
C-3
Assignment
N-3b
11.66, 8.53, 7.58
HMBC:
8.53
150.3
142.9
11.66
7.34
N-1
Another representative example, 4-hydroxy-6-methyl-3-((E)-((Z)-(4-phenylthiazol-2(3H)-
ylidene)hydrazono)methyl)quinolin-2(1H)-one (7c) was distinguished and its distinctive
pattern was shown in Figure 14. According to elemental analysis and mass spectrometry,
compound 7c has the gross formula C20H16N4O2S.
Figure 14. The distinctive carbons in compound 7c
13
In Table 2, the C spectrum showed 18 lines. The nitrogen atom of 7c appeared at δN =
1
142.1 ppm and gives HSQC correlation with the H broadened singlet at δH = 11.58 ppm
and gives HMBC correlation with an aromatic proton at δH = 7.22 ppm. The nitrogen at
20

150.2 gives HMBC correlation with H-3a at 8.52 ppm, this nitrogen is assigned as N-3c.
The carbon at 162.30 ppm gives HMBC correlation with H-3a, H-5 and H-8, and is
assigned as C-4. The carbon C-6a appears at 20.46 and gives HMBC correlation with H-5
and H-7. The fragmentation pattern of mass spectrum of 7c is in full agreement with
structure where it gave the molecular ion peak at m/z = 376.
Table 2. NMR spectroscopy of compound 7c
1H NMR (DMSO-d6):
12.64 (b; 1H), 12.49 (b; 1H)
11.58 (bs; 1H)
8.52 (s; 1H)
7.88 (bd; J = 7.0; 2H)
7.75 (bs; 1H)
1H-1H COSY:
Assignment:
NH-3', OH
NH-1
H-3a
H-o
H-5
H-m
H-5', 7
H-p
H-8
7.44
7.41, 2.39
7.88, 7.34
7.75, 7.22, 2.39
7.44
7.41
7.75, 7.41
7.44 ("t", J = 7.5; 2H)
7.41 (m,; 2H)
7.34 (d, J = 7.2; 1H)
7.22 (d, J = 8.4; 1H)
2.39 (s, 3H)
H-6a
Assignment
C-2'
13C NMR (DMSO-d6): HSQC:
166.28 (b)
HMBC:
162.30 (b)
8.52, 7.75, 7.22
C-4
161.13
C-2
151.11 (b)
C-4'
142.03 (b)
136.77
134.38 (b)
133.38
131.06
128.64
127.81 (b)
125.58
122.41
115.45
113.94
8.52
7.41
C-3a
C-8a
C-i
C-7
C-6
C-m
C-p
C-o
C-5
C-8
C-4a
C-5'
C-3
C-6a
Assignment
N-3c
7.75, 7.41
7.44
7.75, 2.39
7.22, 2.39
7.44
7.44
7.34
7.88
7.75
7.22
7.34
7.41, 2.39
11.58
7.22
103.41 (b)
102.67
20.46
15N NMR (DMSO-d6): HSQC:
7.41
2.39
7.75, 7.41
HMBC:
8.52
150.2
142.1
11.58
7.22
N-1
4. Biology
21

4.1. The NCI-60 anticancer drug screen
The methodology of the NCI for primary anticancer assay was performed at 60 human
tumor cell lines panel derived from nine neoplastic diseases, according to the protocol of
the Drug Evaluation Branch, National Cancer Institute, Bethesda.
The antiproliferative activity of quinolin nitrones 7a-g was evaluated according to the
protocol of the drug evaluation branch of the national cancer institute (NCI), Bethesda,
USA, for in vitro anticancer activity (http://www.dtp.nci.nih.gov). Results for each tested
compound were reported as the percentage of growth of the treated cells when compared to
the untreated control cells.
Thiazoloquinolone derivatives 7b,c,e,g exhibited weak to moderate antiproliferative activity.
Moreover, the 6-methoxy analogue 7d showed remarkable activity against colon cancer
HCT-15 and lung cancer NCI-H322M. Also, compound 7a exhibited good antiproliferative
activity against colon carcinoma HCT-15.
Table 3. Sixty cell line in vitro anticancer screening data of compounds 7a-e,g.
Subpanel tumor cell
lines
Growth % (G%)
7a
7b
7c
7d
7e
7g
NSC 818868
NSC 818869 NSC 818871 NSC 818870 NSC 818872 NSC 818873
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
96.92
102.27
101.24
108.09
104.37
105.38
92.17
102.01
95.50
103.06
106.59
106.33
35.24
87.66
74.33
42.19
75.67
65.65
45.83
105.08
99.24
80.24
83.80
82.64
28.99
87.19
55.69
39.41
67.41
45.32
26.52
83.89
71.30
35.23
70.58
56.19
Non-Small Cell
Lung Cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Colon Cancer
COLO 205
61.30
46.84
47.78
94.10
70.61
84.03
71.58
49.03
74.33
102.82
98.14
101.20
117.43
99.39
106.06
101.47
100.35
94.94
103.54
86.93
89.03
57.34
53.79
43.02
94.74
66.60
89.72
18.22
46.61
80.13
86.97
69.90
61.94
92.94
83.61
97.00
85.24
91.46
90.47
29.49
61.84
42.97
81.74
81.68
95.44
79.78
76.58
72.69
97.98
103.28
108.53
100.53
100.95
92.07
97.50
107.01
108.78
106.03
95.40
105.04
22

74.15
43.28
19.41
60.88
69.30
68.54
115.10
93.93
102.95
103.51
100.76
101.82
111.00
101.19
93.56
105.70
100.06
98.24
77.59
50.83
20.51
70.25
69.34
67.20
100.57
62.75
28.05
44.07
87.24
80.61
110.37
75.39
40.82
81.79
97.25
89.37
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
CNS Cancer
SF-268
68.87
68.56
75.99
73.33
45.05
93.22
101.80
101.37
103.88
99.64
96.97
98.14
101.86
100.56
97.29
56.43
69.33
84.11
75.41
44.28
67.57
82.85
90.31
82.51
33.82
78.47
90.24
92.48
85.65
68.51
SF-295
SF-539
SNB-19
U251
Melanoma
LOX IMVI
MALME-3M
M14
58.94
80.85
55.48
83.17
89.47
76.93
70.22
107.17
54.38
96.70
107.17
98.77
91.44
105.78
100.32
99.90
101.13
104.02
100.33
105.00
98.78
59.95
84.48
75.24
79.32
83.07
75.99
65.25
98.78
62.66
74.44
96.52
73.30
91.06
76.67
88.26
87.47
98.23
75.44
83.15
98.79
78.65
96.55
88.83
92.92
83.21
106.45
82.12
99.12
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
Ovarian Cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
Renal Cancer
A498
103.17
105.69
100.83
103.63
101.95
64.03
43.35
52.22
82.56
66.51
46.69
73.65
101.60
107.16
103.30
105.35
107.67
104.04
101.02
95.87
105.74
91.89
102.09
103.16
105.50
102.21
70.35
24.16
47.88
85.58
55.10
37.74
76.79
79.80
68.00
56.84
94.90
61.26
72.05
71.98
78.32
84.66
65.72
98.88
82.53
77.93
89.20
87.11
30.92
37.03
86.07
77.05
64.77
35.85
106.07
107.61
91.98
110.16
100.11
126.91
91.46
108.77
101.76
74.68
134.39
97.83
94.89
48.64
43.68
97.06
73.78
90.20
42.53
102.84
68.35
38.47
98.49
80.50
74.74
51.11
109.52
73.49
70.75
101.40
83.87
119.72
49.44
ACHN
CAKI-1
RXF 393
SN12C
TK-10
127.74
71.14
UO-31
Prostate Cancer
PC-3
61.90
73.05
96.85
106.59
95.08
110.11
58.94
63.71
69.76
84.47
78.96
95.05
DU-145
Breast Cancer
MCF7
MDA-MB-
231/ATCC
HS 578T
BT-549
74.73
60.93
107.09
99.79
93.89
91.09
67.16
57.53
89.24
70.58
93.72
63.58
115.62
65.48
70.97
90.42
109.49
87.39
95.82
116.46
85.81
98.87
111.71
60.84
72.59
87.61
108.82
76.22
68.46
114.14
69.37
85.17
T-47D
MDA-MB-468
112.92
112.12
100.62
103.06
5. Conclusions
This study reports facile synthesis of novel thiazole derivatives with a good yields through
the reaction of 2-((4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-hydrazine-
23

carbothioamides 5a-g with 2-bromoacetophenone 6. The structure of the isolated compounds
was proved by spectral data and elemental analyses. The antiproliferative activity of the
thiazoloquinolone derivatives 7a-e,g exhibited weak to moderate activity against 60 panel
cancer cell line, while compounds 7a,d revealed remarkable activity against colon
carcinoma HCT-15 and compound 7d against lung cancer NCI-H322M.
6. References
[1] C. Sissi, M. Palumbo, "The quinolone family: from antibacterial to anticancer agents".
Curr. Med. Chem. Anticancer agents
10.2174/1568011033482279
3
(2003) 439-450. doi:
[2] P.M. Orhan, B. Tekiner, S. Suzen, "Recent studies of antioxidant quinolone
derivatives". Mini. Rev. Med. Chem. 13(2013) 365-372. doi:
org/10.2174/138955713804999793.
[3] S. Lucielli, I.V. Aline, S. Natália, S.G. Bruna, R.C. Micheli, "Synthesis and antioxidant
properties of novel quinoline-chalcogenium compounds". Tetrahedron Lett. 54
(2013) 40-44. doi: org/10.1016/j.tetlet.2012.10.067.
[4] A.C. Lima Leite, J.W. Pontes Espíndola, M.V. de Oliveira Cardoso, G.B. de Oliveira
Filho, "Privileged structures in the design of potential drug candidates for
neglected diseases". Curr. Med. Chem. 25 (2018) 1–30. doi:
10.2174/0929867324666171023163752.
[5] O. Afzal, S. Kumar, M.R. Haider, M.R. Ali, R. Kumar, M. Jaggi, S. Bawa, "A review
on atnicancer potential of bioactive heterocycle quinolone". Eur. J. Med. Chem.
97 (2015) 871–910. doi: 10.1016/j.ejmech.2014.07.044.
24

[6] S. Jain, V. Chandra, P.K. Jain, K. Pathak, D. Pathak, A. Vaidya, "Comprehensive
review on current developments of quinoline-based anticancer agents". Arab. J.
Chem. (2016). doi: org/10.1016/j.arabjc.2016.10.009.
[7] M.C. Mandewale, U.C. Patil, S.V. Shedge, U.R. Dappadwad, R.S. Yamgar, "A review
on quinoline hydrazone derivatives as a new class of potent antitubercular and
anticancer agents". J. Basic Appl. Sci. 6 (2017) 354–361.
[8] R.S. Keri, S.A. Patil, "Synthesis of hexahdrofuro[3,2-c]quinoline, a martinelline type
analogues and invesigation of its biological activity". BioMed. Pharmacother. 68
(2014) 1161–1175.
[9] S. Vandekerckhove, M. D’hooghe, "Quinoline-based antimalarial hybrid compounds".
Bioorg. Med. Chem. 23 (2015) 5098–5119. doi: 10.1016/j.bmc.2014.12.018.
[10] I.V. Ukrainets, L. Yangyang, A.A. Tkach, O.V. Gorokhova, A.V. Turov, "4-
Hydroxy-2-quinolones
165.
1-R-4-hydroxy-2-1,2-dihydroquinoline-3-
carbaldehydes and their thiosemicarbazones. Synthesis, structure and biological
properties". Chem. Heterocycl. Compd. 45 (2009) 705–714. e-mail:
uiv@kharkov.ua.
[11] A. Sharma, V. Kumar, S. Jain, P.C. Sharma, "Thiazolidin-4-one and hydrazone
derivatives of capric acid as possible anti-inflammatory, analgesic and hydrogen
peroxide-scavenging agents". J. Enzyme Inhib. Med. Chem. 26(2011) 546–552.
doi: 10.3109/14756366.2010.535796.
[12] V. Kumar, A. Sharma, P.C. Sharma, "Synthesis of some novel 2,5- disubstituted
thiazolidinones from a long chain fatty acid as possible anti-inflammatory,
analgesic and hydrogen peroxide scavenging agents". J. Enzyme Inhib. Med.
Chem. 26 (2011) 198–203. doi: 10.3109/14756366.2010.489897.
25

[13] K.D. Hargrave, F.K. Hess, J.T. Oliver, "N-(4-Substituted-thiazolyl)oxamic acid
derivatives, new series of potent, orally active antiallergy agents". J. Med. Chem.
26 (1983) 1158-1163. doi: org/10.1021/jm00362a014.
[14] W.C. Patt, H.M. Hamilton, M.D. Taylor, M.J. Ryan, Jr.D.G. Taylor, " Structure-
activity relationships of a series of 2-amino-4-thiazole-containing renin inhibitors".
J. Med. Chem. 35 (1992) 2562-2572. doi: org/10.1021/jm00092a006.
[15] R.N. Sharma, F.P. Xavier, K.K. Vasu, S.C. Chaturvedi, S.S. Pancholi, "Synthesis of
4-benzyl-1,3-thiazole derivatives as potential anti-inflammatory agents: An
analogue-based drug design approach". J. Enzyme Inhib. Med. Chem. 24 (2009)
890-897. doi: org/10.1080/14756360802519558.
[16] J.C. Jean, L.D. Wise, B.W. Caprathe, H. Tecle, S. Bergmeier, "4-(1,2,5,6-Tetrahydro-
1-alkyl-3-pyridinyl)-2-thiazolamines: a novel class of compounds with central
dopamine agonist properties". J. Med. Chem. 33 (1990) 311-317. doi:
org/0.1021/jm00163a051, PMID: 1967314.
[17] K. Tsuji, H. Ishikawa, "Synthesis and anti-pseudomonal activity of new 2-isocephems
with a dihydroxypyridone moiety at C-7". Bioorg. Med. Chem. Lett. 4 (1994)
1601-1606. doi: org/10.1016/S0960-894X(01)80574-6.
[18] F.W. Bell, A.S. Cantrell, M. Hogberg, S.R. Jaskunas, N.G. Johansson,
"Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse
transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship
studies of PETT analogs". J. Med. Chem.
10.1021/jm00025a010.
38 (1995) 4929-4936. doi:
[19] N. Ergenc, G. Capan, N.S. Gunay, S. Ozkirimli, M. Gungor, S. Ozbey, E. Kendi, "
New benzimidazoles and their antitumor effects with aurora a Kinase and KSP
26

inhibitory activities" Arch. Pharm. Pharm. Med. Chem. 332 (1990) 343-347.
doi:org/10.1002/ardp.201400441.
[20] J.S. Carter, S. Kramer, J.J. Talley, T. Penning, P. Collins, "Synthesis and activity of
sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2
inhibitors".
Bioorg. Med. Chem. Lett.
9 (1994) 1171-1174. doi:
org/10.1016/S0960-894X(99)00157-2.
[21] A. Badorc, M.F. Bordes, P. de Cointet, P. Savi, A. Bernat, " New orally active non-
peptide fibrinogen receptor (GpIIb-IIIa) antagonists: Identification of ethyl 3-[N-
[4-[4-[Amino[(ethoxycarbonyl)imino]methyl]phenyl]-
1,3-thiazol-2-yl]-N-[1-
[(ethoxycarbonyl)methyl]piperid-4-yl]amino]propionate (SR 121787) as a potent
and long-acting antithrombotic agent". J. Med. Chem. 40 (1997) 3393-3401. doi:
org/10.1021/jm970240y.
[22] J. Rudolph, H. Theis, R. Hanke, R. Endermann, L. Johannsen, F.U. Geschke, "seco-
Cyclothialidines: New Concise Synthesis, Inhibitory Activity toward Bacterial and
Human DNA Topoisomerases, and Antibacterial Properties". J. Med. Chem. 44
(2001) 619-626. doi: 10.1021/jm0010623.
[23] S. Huang, P.J. Collony, "Synthesis of 2-N-alkyl (aryl) amino-nitrobenzothiazoles".
Tetrahedron Lett. 45 (2004) 9373–9375. doi: org/10.1016/j.tetlet.2004.10.117.
[24] A. Geronikaki, I. Argyropoulou, P. Vicini, F. Zani, "Synthesis and biological
evaluation of sulfonamide thiazole and benzothiazole derivatives as antimicrobial
agents". Arkivoc 6 (2009) 89-102. ISSN: 1551-7012.
[25] A.K. Singh, G. Mishra, K. Jyoti, "Review on biological activities of 1,3,4-thiadiazole
derivatives". J. Applied Pharm. Sciences 1(5) (2011) 44-49. ISSN: 2231-3354.
27