- Email: [email protected]
-2-quinolone derivatives
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
Reference:
MOLSTR 127798
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. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
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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
2
Chemistry Department, Faculty of Science, Minia University, 61519-El-Minia, Egypt.
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 2
Chemistry Department, Faculty of Science, Minia University, 61519-El-Minia, Egypt. Department of Organic Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Egypt.
Corresponding Authors: e-mail: [email protected] [email protected]; Tel./fax: +20 1006268742.
and
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], antiinflammatory [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 donoracceptor 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.
3
Instrumentation
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-3carbaldehydes 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)
Yellow crystals (DMF); yield 1.59 g (80%); Mp. > 360°C; 1H 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;
13
C 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)
Yellow crystals (DMF/ethanol); yield 1.50 g (76%); Mp. > 360°C; 1H 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;
13
C 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)
Yellow crystals (DMF); yield 1.71 g (79%); Mp. >360 °C; 1H NMR (400 MHz, DMSOd6): 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;
13
C 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) Pale yellow crystals (DMF/ethanol); yield 2.39 g (82%); MP. 252-254 °C; 1H NMR (400 MHz, DMSO-d6): δH 3.81 (s, 3H, OCH3), 7.24-7.30 (m, 3H, Ar-H), 8.11 (bs, 2H, NH2), 8.55 (s, 1H, HC=N), 11.49 (bs, 1H, NH), 11.52 (bs, 1H, NH), 11.95 (bs, 1H, OH);
13
C
NMR (100 MHz, DMSO-d6): δC 55.86 (OCH3), 103.11 (C3), 104.53, 114.99, 117.53 (ArCH), 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). Pale yellow crystals (DMF/methanol); yield 2.39 g (81%); Mp. > 360 °C; 1H 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). Pale yellow crystals (DMF/ethanol); yield 2.39 g ( 81%); Mp. > 330 °C; 1H 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); 13
C 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 (C4), 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). Pale yellow crystals (DMF); yield 2.65 g (76%); Mp. > 360 °C; 1H 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);
13
C 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). Yellow crystals; yield: 0.331 g (85%); Mp. 250-252 oC; 1H 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, HC=N), 12.51 (bs, 1H, OH), 12.66 (bs, 1H, NH) ppm; 13C 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)hydrazonomethyl)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) Yellow crystals; yield: 0.313 g (81%); Mp. 284-286 oC; 1H 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, NH), 12.49 (bs, 1H, OH), 12.60 (bs, 1H, NH) ppm; 13C 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). Yellow crystals; yield: 0.312 g (79%); Mp. 270 -772oC; 1H 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, ArH), 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) Yellow crystals; yield: 0.312 g (79%); Mp. 274 -776oC; 1H 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-2oxo-1,2-dihydroquinoline-3-carbaldehydes
3a-g.
Refluxing
of
3a-g
with
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 1,6,7trisubstituted-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 R2 R1
N N R
O
H N
O
NH2 S
5a-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
Br
+
EtOH, Et3N 6
r.t., 4-6 h
OH R2 R1
N N R
H N
N
O
S
7a-g
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 related to both (M+- C6H42· ) 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,
13
C, 2D NMR,
15
N) 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.
1
H 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 (Figure 7). 1H NMR spectra of 7a (Table 1) showed three broad 1H 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 The 13C 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 5
4a
OH 3a 4 3
6 7 8
8a N 1 2 O H
N 3b
3c 3' H N N 2'
o m i
p
4'
S 5'
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 1
H 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 H3a 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 1 1 H NMR (DMSO-d6): H-1H COSY: 12.65 (b; 1H), 12.50 (b; 1H) 11.66 (bs; 1H) 8.53 (s; 1H) 7.96 (d, J = 7.8; 1H) 7.58, 7.25 19
Assignment: NH-3', OH NH-1 H-3a H-5
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) 13
C NMR (DMSO-d6): 166.49 (b); 162.53 (b) 161.25 151.11 (b) 141.99 (b) 138.70 134.34 (b) 132.08 128.65 127.81 125.58 123.07 121.96 115.49 114.10 103.30 (b) 102.73 15 N NMR (DMSO-d6): 150.3 142.9
HSQC:
7.43, 7.32 7.96, 7.34, 7.25 7.87, 7.32 7.58 7.87, 7.43 7.96, 7.58 HMBC: 8.53, 7.96, 7.34
8.53
7.58 7.43 7.34 7.87 7.96 7.25 7.32
HSQC: 11.66
8.53 7.96, 7.58 7.43 7.96, 7.25 7.43 7.87 7.87, 7.43, 7.34 7.58, 7.32 7.32, 7.25 11.66, 8.53, 7.58 11.66, 8.53, 7.58 HMBC: 8.53 7.34
H-o H-7 H-m H-5' H-8 H-p H-6 Assignment C-2, 2' C-4 C-4' C-3a C-8a C-i C-7 C-m C-8 C-o C-5 C-6 C-p C-4a C-5' C-3 Assignment N-3b 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 In Table 2, the
13
C spectrum showed 18 lines. The nitrogen atom of 7c appeared at δN =
142.1 ppm and gives HSQC correlation with the 1H 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 1 1 H NMR (DMSO-d6): H-1H COSY: 12.64 (b; 1H), 12.49 (b; 1H) 11.58 (bs; 1H) 8.52 (s; 1H) 7.88 (bd; J = 7.0; 2H) 7.44 7.75 (bs; 1H) 7.41, 2.39 7.44 ("t", J = 7.5; 2H) 7.88, 7.34 7.41 (m,; 2H) 7.75, 7.22, 2.39 7.34 (d, J = 7.2; 1H) 7.44 7.22 (d, J = 8.4; 1H) 7.41 2.39 (s, 3H) 7.75, 7.41 13 C NMR (DMSO-d6): HSQC: HMBC: 166.28 (b) 162.30 (b) 8.52, 7.75, 7.22 161.13 151.11 (b) 142.03 (b) 8.52 136.77 7.75, 7.41 134.38 (b) 7.44 133.38 7.41 7.75, 2.39 131.06 7.22, 2.39 128.64 7.44 7.44 127.81 (b) 7.34 125.58 7.88 7.34 122.41 7.75 7.41, 2.39 115.45 7.22 11.58 113.94 7.22 103.41 (b) 7.41 102.67 20.46 2.39 7.75, 7.41 15 N NMR (DMSO-d6): HSQC: HMBC: 150.2 8.52 142.1 11.58 7.22
4. Biology
21
Assignment: NH-3', OH NH-1 H-3a H-o H-5 H-m H-5', 7 H-p H-8 H-6a Assignment C-2' C-4 C-2 C-4' 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 N-1
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
Leukemia CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 SR 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
22
Growth % (G%) 7a
7b
7c
7d
7e
7g
NSC 818868
NSC 818869
NSC 818871
NSC 818870
NSC 818872
NSC 818873
28.99 87.19 55.69 39.41 67.41 45.32
96.92 102.27 101.24 108.09 104.37 105.38
92.17 102.01 95.50 103.06 106.59 106.33
26.52 83.89 71.30 35.23 70.58 56.19
35.24 87.66 74.33 42.19 75.67 65.65
45.83 105.08 99.24 80.24 83.80 82.64
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 97.98 103.28 108.53 100.53 100.95 92.07
57.34 53.79 43.02 94.74 66.60 89.72 18.22 46.61 80.13
29.49 61.84 42.97 81.74 81.68 95.44 79.78 76.58 72.69
86.97 69.90 61.94 92.94 83.61 97.00 85.24 91.46 90.47
97.50
107.01
108.78
106.03
95.40
105.04
HCC-2998 HCT-116 HCT-15 HT29 KM12 SW-620 CNS Cancer SF-268 SF-295 SF-539 SNB-19 U251 Melanoma LOX IMVI MALME-3M M14 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 ACHN CAKI-1 RXF 393 SN12C TK-10 UO-31 Prostate Cancer PC-3 DU-145 Breast Cancer MCF7 MDA-MB231/ATCC HS 578T BT-549 T-47D MDA-MB-468
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
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
58.94 80.85 55.48 83.17 89.47 76.93 70.22 107.17 54.38
96.70 107.17 98.77 99.12 103.17 105.69 100.83 103.63 101.95
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
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 97.83 127.74 71.14
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
61.90 73.05
96.85 106.59
95.08 110.11
58.94 63.71
69.76 84.47
78.96 95.05
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 95.82 112.92
116.46 85.81 98.87 112.12
111.71 60.84 72.59 87.61
108.82 76.22 68.46 100.62
114.14 69.37 85.17 103.06
5. Conclusions This study reports facile synthesis of novel thiazole derivatives with a good yields through the
23
reaction
of
2-((4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-hydrazine-
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.
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Figure captions: Figure 1. Chemical structures of biologically active quinoline-derived thiosemicarbazone derivatives (I and II) based on 2-oxo-quinoline structural motif. Figure 2. Design of the target compounds 7a-f 30
Figure 3. Fragmentation patterns in mass spectroscopy for compound 7a Figure 4: Proposed intramolecular hydrogen bond in compound 5e Figure 5. 1H NMR spectrum of compound 5e as an example Figure 6: IR spectrum of compound 7a. Figure 7: 1H NMR spectrum of compound 7a. Figure 8. 1H NMR expanded spectrum of compound 7a Figure 9: 13C NMR of compound 7a Figure 10. 1H-13C HMBC of compound 7a Figure 11. The distinctive carbons in compound 7a Figure 12. 1H-15N HSQC of compound 7a Figure 13. 1H-15N HSQC of compound 7a Figure 14. The distinctive carbons in compound 7c
31
Synthesis and colon anticancer activity of some novel thiazole/quinolone derivatives Asmaa H. Mohamed,1 Ashraf A. Aly,1* 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:
Tel./fax: +20 1006268742.
Highlights: -
Synthesis of thiosemicarbazones
-
Synthesis of 1,6,7-trisubstituted-4-phenylthiazol-2(3H)-ylidene)hydrazono)methyl)quinolin-2-one derivatives
-
NMR spectra were used to elucidate the proposed structures
-
The NCI-60 anticancer drug screen
-
The new synthesized compounds showed a moderate colon anticancer activity
Dear Editor Our recent interest has been directed towards the synthesis of quinolones and thiazoles. The main aim is, the synthesize heterocycles of biologically and pharmaceutically important. Therefore, we synthesized of 1,6,7-trisubstituted-4-phenylthiazol-2(3H)ylidene)hydrazono)-methyl)quinolin-2-one derivatives. The structure of the obtained products was proved using different spectral techniques including infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) together with elemental analyses. The anticancer activity of the new synthesized compounds was, then investigated.
S0022-2860(20)30122-8
DOI:
https://doi.org/10.1016/j.molstruc.2020.127798
Reference:
MOLSTR 127798
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. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Dear Editor CRediT offers authors the opportunity to share an accurate and detailed description of their diverse contributions to the published work. •
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•
The role(s) of all authors should be listed, using the relevant above categories. The second and third authors: writing and revising the MS
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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
2
Chemistry Department, Faculty of Science, Minia University, 61519-El-Minia, Egypt.
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 2
Chemistry Department, Faculty of Science, Minia University, 61519-El-Minia, Egypt. Department of Organic Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Egypt.
Corresponding Authors: e-mail: [email protected] [email protected]; Tel./fax: +20 1006268742.
and
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], antiinflammatory [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 donoracceptor 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.
3
Instrumentation
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-3carbaldehydes 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)
Yellow crystals (DMF); yield 1.59 g (80%); Mp. > 360°C; 1H 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;
13
C 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)
Yellow crystals (DMF/ethanol); yield 1.50 g (76%); Mp. > 360°C; 1H 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;
13
C 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)
Yellow crystals (DMF); yield 1.71 g (79%); Mp. >360 °C; 1H NMR (400 MHz, DMSOd6): 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;
13
C 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) Pale yellow crystals (DMF/ethanol); yield 2.39 g (82%); MP. 252-254 °C; 1H NMR (400 MHz, DMSO-d6): δH 3.81 (s, 3H, OCH3), 7.24-7.30 (m, 3H, Ar-H), 8.11 (bs, 2H, NH2), 8.55 (s, 1H, HC=N), 11.49 (bs, 1H, NH), 11.52 (bs, 1H, NH), 11.95 (bs, 1H, OH);
13
C
NMR (100 MHz, DMSO-d6): δC 55.86 (OCH3), 103.11 (C3), 104.53, 114.99, 117.53 (ArCH), 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). Pale yellow crystals (DMF/methanol); yield 2.39 g (81%); Mp. > 360 °C; 1H 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). Pale yellow crystals (DMF/ethanol); yield 2.39 g ( 81%); Mp. > 330 °C; 1H 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); 13
C 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 (C4), 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). Pale yellow crystals (DMF); yield 2.65 g (76%); Mp. > 360 °C; 1H 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);
13
C 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). Yellow crystals; yield: 0.331 g (85%); Mp. 250-252 oC; 1H 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, HC=N), 12.51 (bs, 1H, OH), 12.66 (bs, 1H, NH) ppm; 13C 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)hydrazonomethyl)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) Yellow crystals; yield: 0.313 g (81%); Mp. 284-286 oC; 1H 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, NH), 12.49 (bs, 1H, OH), 12.60 (bs, 1H, NH) ppm; 13C 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). Yellow crystals; yield: 0.312 g (79%); Mp. 270 -772oC; 1H 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, ArH), 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) Yellow crystals; yield: 0.312 g (79%); Mp. 274 -776oC; 1H 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-2oxo-1,2-dihydroquinoline-3-carbaldehydes
3a-g.
Refluxing
of
3a-g
with
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 1,6,7trisubstituted-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 R2 R1
N N R
O
H N
O
NH2 S
5a-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
Br
+
EtOH, Et3N 6
r.t., 4-6 h
OH R2 R1
N N R
H N
N
O
S
7a-g
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 related to both (M+- C6H42· ) 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,
13
C, 2D NMR,
15
N) 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.
1
H 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 (Figure 7). 1H NMR spectra of 7a (Table 1) showed three broad 1H 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 The 13C 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 5
4a
OH 3a 4 3
6 7 8
8a N 1 2 O H
N 3b
3c 3' H N N 2'
o m i
p
4'
S 5'
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 1
H 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 H3a 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 1 1 H NMR (DMSO-d6): H-1H COSY: 12.65 (b; 1H), 12.50 (b; 1H) 11.66 (bs; 1H) 8.53 (s; 1H) 7.96 (d, J = 7.8; 1H) 7.58, 7.25 19
Assignment: NH-3', OH NH-1 H-3a H-5
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) 13
C NMR (DMSO-d6): 166.49 (b); 162.53 (b) 161.25 151.11 (b) 141.99 (b) 138.70 134.34 (b) 132.08 128.65 127.81 125.58 123.07 121.96 115.49 114.10 103.30 (b) 102.73 15 N NMR (DMSO-d6): 150.3 142.9
HSQC:
7.43, 7.32 7.96, 7.34, 7.25 7.87, 7.32 7.58 7.87, 7.43 7.96, 7.58 HMBC: 8.53, 7.96, 7.34
8.53
7.58 7.43 7.34 7.87 7.96 7.25 7.32
HSQC: 11.66
8.53 7.96, 7.58 7.43 7.96, 7.25 7.43 7.87 7.87, 7.43, 7.34 7.58, 7.32 7.32, 7.25 11.66, 8.53, 7.58 11.66, 8.53, 7.58 HMBC: 8.53 7.34
H-o H-7 H-m H-5' H-8 H-p H-6 Assignment C-2, 2' C-4 C-4' C-3a C-8a C-i C-7 C-m C-8 C-o C-5 C-6 C-p C-4a C-5' C-3 Assignment N-3b 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 In Table 2, the
13
C spectrum showed 18 lines. The nitrogen atom of 7c appeared at δN =
142.1 ppm and gives HSQC correlation with the 1H 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 1 1 H NMR (DMSO-d6): H-1H COSY: 12.64 (b; 1H), 12.49 (b; 1H) 11.58 (bs; 1H) 8.52 (s; 1H) 7.88 (bd; J = 7.0; 2H) 7.44 7.75 (bs; 1H) 7.41, 2.39 7.44 ("t", J = 7.5; 2H) 7.88, 7.34 7.41 (m,; 2H) 7.75, 7.22, 2.39 7.34 (d, J = 7.2; 1H) 7.44 7.22 (d, J = 8.4; 1H) 7.41 2.39 (s, 3H) 7.75, 7.41 13 C NMR (DMSO-d6): HSQC: HMBC: 166.28 (b) 162.30 (b) 8.52, 7.75, 7.22 161.13 151.11 (b) 142.03 (b) 8.52 136.77 7.75, 7.41 134.38 (b) 7.44 133.38 7.41 7.75, 2.39 131.06 7.22, 2.39 128.64 7.44 7.44 127.81 (b) 7.34 125.58 7.88 7.34 122.41 7.75 7.41, 2.39 115.45 7.22 11.58 113.94 7.22 103.41 (b) 7.41 102.67 20.46 2.39 7.75, 7.41 15 N NMR (DMSO-d6): HSQC: HMBC: 150.2 8.52 142.1 11.58 7.22
4. Biology
21
Assignment: NH-3', OH NH-1 H-3a H-o H-5 H-m H-5', 7 H-p H-8 H-6a Assignment C-2' C-4 C-2 C-4' 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 N-1
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
Leukemia CCRF-CEM HL-60(TB) K-562 MOLT-4 RPMI-8226 SR 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
22
Growth % (G%) 7a
7b
7c
7d
7e
7g
NSC 818868
NSC 818869
NSC 818871
NSC 818870
NSC 818872
NSC 818873
28.99 87.19 55.69 39.41 67.41 45.32
96.92 102.27 101.24 108.09 104.37 105.38
92.17 102.01 95.50 103.06 106.59 106.33
26.52 83.89 71.30 35.23 70.58 56.19
35.24 87.66 74.33 42.19 75.67 65.65
45.83 105.08 99.24 80.24 83.80 82.64
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 97.98 103.28 108.53 100.53 100.95 92.07
57.34 53.79 43.02 94.74 66.60 89.72 18.22 46.61 80.13
29.49 61.84 42.97 81.74 81.68 95.44 79.78 76.58 72.69
86.97 69.90 61.94 92.94 83.61 97.00 85.24 91.46 90.47
97.50
107.01
108.78
106.03
95.40
105.04
HCC-2998 HCT-116 HCT-15 HT29 KM12 SW-620 CNS Cancer SF-268 SF-295 SF-539 SNB-19 U251 Melanoma LOX IMVI MALME-3M M14 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 ACHN CAKI-1 RXF 393 SN12C TK-10 UO-31 Prostate Cancer PC-3 DU-145 Breast Cancer MCF7 MDA-MB231/ATCC HS 578T BT-549 T-47D MDA-MB-468
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
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
58.94 80.85 55.48 83.17 89.47 76.93 70.22 107.17 54.38
96.70 107.17 98.77 99.12 103.17 105.69 100.83 103.63 101.95
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
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 97.83 127.74 71.14
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
61.90 73.05
96.85 106.59
95.08 110.11
58.94 63.71
69.76 84.47
78.96 95.05
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 95.82 112.92
116.46 85.81 98.87 112.12
111.71 60.84 72.59 87.61
108.82 76.22 68.46 100.62
114.14 69.37 85.17 103.06
5. Conclusions This study reports facile synthesis of novel thiazole derivatives with a good yields through the
23
reaction
of
2-((4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-hydrazine-
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.
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Figure captions: Figure 1. Chemical structures of biologically active quinoline-derived thiosemicarbazone derivatives (I and II) based on 2-oxo-quinoline structural motif. Figure 2. Design of the target compounds 7a-f 30
Figure 3. Fragmentation patterns in mass spectroscopy for compound 7a Figure 4: Proposed intramolecular hydrogen bond in compound 5e Figure 5. 1H NMR spectrum of compound 5e as an example Figure 6: IR spectrum of compound 7a. Figure 7: 1H NMR spectrum of compound 7a. Figure 8. 1H NMR expanded spectrum of compound 7a Figure 9: 13C NMR of compound 7a Figure 10. 1H-13C HMBC of compound 7a Figure 11. The distinctive carbons in compound 7a Figure 12. 1H-15N HSQC of compound 7a Figure 13. 1H-15N HSQC of compound 7a Figure 14. The distinctive carbons in compound 7c
31
Synthesis and colon anticancer activity of some novel thiazole/quinolone derivatives Asmaa H. Mohamed,1 Ashraf A. Aly,1* 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:
Tel./fax: +20 1006268742.
Highlights: -
Synthesis of thiosemicarbazones
-
Synthesis of 1,6,7-trisubstituted-4-phenylthiazol-2(3H)-ylidene)hydrazono)methyl)quinolin-2-one derivatives
-
NMR spectra were used to elucidate the proposed structures
-
The NCI-60 anticancer drug screen
-
The new synthesized compounds showed a moderate colon anticancer activity
Dear Editor Our recent interest has been directed towards the synthesis of quinolones and thiazoles. The main aim is, the synthesize heterocycles of biologically and pharmaceutically important. Therefore, we synthesized of 1,6,7-trisubstituted-4-phenylthiazol-2(3H)ylidene)hydrazono)-methyl)quinolin-2-one derivatives. The structure of the obtained products was proved using different spectral techniques including infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) together with elemental analyses. The anticancer activity of the new synthesized compounds was, then investigated.