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Article

An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents

by
Magda A. Abdallah
1,
Sobhi M. Gomha
1,*,
Ikhlass M. Abbas
1,
Mariam S. H. Kazem
2,
Seham S. Alterary
3 and
Yahia N. Mabkhot
3,*
1
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
2
Department of Chemistry, Faculty of Dentistry, October University for Modern Science & Arts, Giza 12613, Egypt
3
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2017, 7(8), 785; https://doi.org/10.3390/app7080785
Submission received: 22 July 2017 / Revised: 28 July 2017 / Accepted: 31 July 2017 / Published: 3 August 2017
(This article belongs to the Section Chemical and Molecular Sciences)
Browse Figures
Versions Notes

Abstract

:
A new series of pyrazolylpyridines was prepared by reaction of ethyl-3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate with the appropriate aldehyde, malononitrile, or ethyl acetoacetate and an excess of ammonium acetate under reflux in acetic acid. Similarly, two novel bipyridine derivatives were prepared by the above reaction using terephthaldehyde in lieu of benzaldehyde derivatives. In addition, a series of 1,2,4-triazolo[4,3-a]pyrimidines was synthesized by a reaction of 6-(pyrazol-3-yl)pyrimidine-2-thione with a number of hydrazonoyl chlorides in dioxane and in the presence of triethylamine. The structure of the produced compounds was established by elemental analyses and spectral methods, and the mechanisms of their formation was discussed. Furthermore, the pyrazolyl-pyridine derivatives were tested as anticancer agents and the results obtained showed that some of them revealed high activity against human hepatocellular carcinoma (HEPG2) cell lines.

1. Introduction

A literature survey revealed that compounds, including the pyrazole nucleus, are extensively used as a precursor for the synthesis of compounds presenting many applications, such as electrolyte additives in batteries [1], catalysis [2], photographic materials [3], agrochemicals [4], and dyes [5]. The chemical versatility of the pyrazole and its analogues has attracted interest because it allows a range of applications in the pharmaceutical industry. Many pyrazole-derived compounds are known to exhibit anticancer [6,7,8,9,10], antimicrobial [11,12], antiviral [13], antiparasitic [14], anti-inflammatory [15,16], antipyretic [17], analgesic [18], anticoagulant [19], and anti-obesity [20] biological activities. The pyridine nucleus is a key constituent, present in a range of bioactive compounds, occurring both synthetically and naturally with wide range of biological applications [21,22]. Among the successful examples as drug candidates possessing pyridine nuclei are streptonigrin, streptonigrone, and lavendamycin, which are described in the literature as anticancer drugs. Some pyridine derivatives were studied for their topoisomerase inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. As a result, it has been reported that various pyridine derivatives, as bioisosteres of α-terthiophene (potent protein kinase C inhibitor) [23], have significant topoisomerase I and/or II inhibitory activity, and cytotoxicity against several human cancer cell lines [24,25,26,27,28]. Early reports on the ability of α-terpyridine to form metal complexes [29] and to bind with DNA/RNA [30] have been the base for the study on pyridine derivatives as antitumor agents. On the other hand, multicomponent reactions (MCRs) are powerful tools in modern medicinal chemistry, facilitating the lead generation by providing access to drug-like compounds, helping in drug discovery [31,32,33]. Additionally, the utility of MCR under microwave irradiation in the synthesis of heterocyclic compounds enhanced the reaction rates and improved the regioselectivity [34,35]. Over the last decade, several research groups adopted a hybridization approach for the design of pyrazole-pyridine hybrid analogs and illuminated their synthetic and medicinal importance [36,37,38,39,40,41,42].
In light of the above findings and in continuation of our efforts to synthesize new anticancer compounds [43,44,45,46,47,48,49,50,51,52], the aim of presented report is to synthesize a new series of pyrazolyl-pyridines via multicomponent reactions which are expected to be active as antitumor agents.

2. Results and Discussion

2.1. Chemistry

Ethyl 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate (1) [53] was used as the starting compound for the preparation of a number of novel pyrazolyl-pyridine derivatives via one-pot multicomponent reactions. For example, a series of novel 2-amino-3-cyano-6-(pyrazol-3-yl)-pyridines 4a–f was prepared by a one-pot reaction of 3-acetylpyrazole derivative 1 with the appropriate aldehyde 2, malononitrile 3, and ammonium acetate under reflux in acetic acid (Scheme 1). Both elemental analyses and spectral data were used to elucidate the structures of the products 4a–f. The IR spectra of compounds 4a–f revealed in each case three absorption bands in the regions υ 3431–3211, 2218–2210, 1715–1709 cm−1 attributed to the NH2, CN and C=O groups. The 1HNMR spectrum of compound 4a taken as a typical example of the products 4, revealed two signals at δ = 6.93 (brs, 2H, NH2) and 8.11 (s, 1H, pyridine-H5), in addition to the expected signals for the aryl and ester protons. Moreover, the mass spectra of product 4 showed in each case the respective molecular ion peak which is consistent with the assigned structure.
In a similar manner, another series of pyrazolylpyridines 6a–f was synthesized using ethyl acetoacetate in lieu of malononitrile. Thus, the reaction of 3-acetylpyrazole derivative 1 with the appropriate aldehyde 2, ethyl acetoacetate 5, and ammonium acetate in refluxing acetic acid afforded the corresponding products 6a–f (Scheme 2). The structure 6 assigned for the obtained products was established by elemental analyses and spectral (IR, 1HNMR, and MS) data. For example, the IR spectra of products 6a–f revealed, in each case, four absorption bands assigned for the three carbonyl groups and the -NH group of the pyridinone ring (see Section 3). The 1HNMR spectra displayed three singlet signals near δ 2.58, 9.80 and 7.79 ppm attributed to the acetyl, NH and pyridinyl-5H protons, in addition to the expected signals due to the ester and aryl protons (see Section 3).
To account for the formation of products 4 and 6, it was suggested that the reaction proceeds by condensation of the acetyl group of Compound 1 with the aldehyde to give the corresponding chalcone which reacts with ammonium acetate to give the imino derivative, followed by tandem Michael addition of the active methylene group of 3 (or 5) to afford the non-isolable tetrahydropyridine intermediates A (or B). The latter undergo in situ auto-oxidation (followed by tautomerization in case of A) and formation of the final products 4 (or 6) (Scheme 3).
Our study was extended to prepare another new bipyridine derivatives including the pyrazole moiety via multi-component reaction. Thus, the reaction of 3-acetylpyrazole derivative 1 with terephthaldehyde 7, malononitrile 3, and ammonium acetate in acetic acid under reflux furnished the bipyridine derivative 8 (Scheme 4).
Similarly, the reaction of compound 1 with terephthaldehyde, ethyl acetoacetate 5, and ammonium acetate in acetic acid under reflux gave the respective bipyridinone 9 (Scheme 4). The structure of products 8 and 9 were confirmed by elemental analyses and spectral data (IR, 1HNMR, and MS) (see Section 3).
On the other hand, chalcone 10, prepared by the reaction of 1 with benzaldehyde in ethanol containing catalytic amounts of NaOH [54], was used for preparation of 6-(pyrazol-3-yl) pyrimidine-2-thione derivative 11 via its reaction with thiourea in ethanol containing a catalytic amount of sodium hydroxide [54]. Reaction of the latter compound 11 with a number of hydrazonoyl chlorides 12a–h [55] in dioxane in the presence of triethylamine afforded the respective products 15a–h through the non-isolated intermediates 13 and 14 (Scheme 5). The structure assigned for the products 15 was established via microanalytical and spectral data (see Section 3). For example, the IR spectra of product 15 revealed the absence of the pyrimidinyl-NH groups, and instead showed two absorption bands near υ 1706 and 1649 cm−1 assigned for the two carbonyl groups. Additionally, 1HNMR spectra of product 15 showed the absence of the signals attributed to the pyrimidinyl-NH protons and, instead, revealed the signals assigned for the acetyl protons (for 15a–d) or the ethoxycarbonyl protons (for 15e–h), in addition to the characteristic signals due to the ester and aromatic protons (see Section 3). The mass spectra of product 15 showed, in each case, the respective molecular ion peak, which is consistent with the assigned structure.

2.2. Antitumor Activity

The cytotoxicity of the synthesized pyridines 4a,b,e and 6a,b,e was evaluated against the human liver carcinoma cell line (HepG2-1) using doxorubicin as a reference drug (IC50 value of doxorubicin = 0.08 ± 0.07 nM) and MTT assay. The data generated were used to plot a dose response curve of which the concentration of the tested compounds required to kill 50% of cell population (IC50) was determined. Cytotoxic activity was expressed as the mean IC50 of three independent experiments. The results are depicted in Table 1 and Figure 1.
The results revealed that the descending order of the antitumor activity of the tested compounds against HEPG2-1cell line is as follow: 4b > 6b > 4a > 6a > 4e > 6e.
The pyridine derivatives 4b and 6b (IC50 = 1.9 ± 0.16 and 2.4 ± 0.29 nM, respectively) have promising antitumor activity against HEPG2-1. On the other hand, pyridine derivatives 4e and 6e have poor inhibitory activity (IC50 > 17 nM) compared with doxorubicin which used as reference drug.

Structural Activity Relationship SAR

Examination of the SAR led to the following conclusions:
The activity of the synthesized compounds 4 and 6 against hepatocellular carcinoma depends on the structural skeleton and electronic environment of the molecules. For example, the activity of the tested compounds 4a,b,e and 6a,b,e were found to be highly related to their structures since replacement of electron-donating groups in the two aryl groups in compounds 4b and 6b with electron-withdrawing groups in compounds 4e and 6e dramatically decreases their cytotoxicity against HEPG2-1. On the other hand, the cytotoxicity of compounds 4a and 6a whose structures contain two phenyl groups (no substituent), is intermediate between the highly-potent and the weakly-potent compounds (See Table 1).

3. Experimental

3.1. Chemistry

Melting points were measured on an Electrothermal IA 9000 series (Bibby Sci. Lim. Stone, Staffordshire, UK) digital melting point apparatus. The IR spectra were recorded in potassium bromide discs on a Pye Unicam SP 3300 (Cambridge, UK) and a Shimadzu FT IR 8101 PC infrared (Shimadzu, Tokyo, Japan) spectrophotometer. 1H-NMR spectra were recorded in deuterated dimethyl sulfoxide (DMSO-d6) using a Varian Gemini 300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany). Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analysis was carried out at the Microanalytical Centre of Cairo University, Giza, Egypt. All reactions were followed by TLC (Silica gel, Merck, Darmstadt, Germany).

3.1.1. Synthesis of Tetra-Substituted Pyridine Derivatives (4a–f and 6a–f)

General procedure: A mixture of ethyl 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate (1) (0.334 g, 1 mmol), the appropriate aldehyde 2a–f (1 mmol) and malononitrile (3), or ethyl acetoacetate (5) (1 mmol) in glacial acetic acid (20 mL) containing ammonium acetate (0.616 g, 8 mmol) was refluxed for 6–8 h (monitored by TLC). After complete reaction, the mixture was cooled and the precipitated products were filtered, washed with water, dried, and crystallized from ethanol to give the pyridine derivatives 4a–f and 6a–f, respectively. Compounds 4a–f and 6a–f together with their physical and spectral data are listed below:
Ethyl 3-(6-amino-5-cyano-4-phenylpyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4a). Brown solid, (70% yield), mp 169–171 °C; IR (KBr) νmax 3364, 3208 (NH2), 2218 (CN), 1715 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 4.13 (q, J = 7.2 Hz, 2H, CH2), 6.93 (s, br, 2H, NH2), 7.18–7.90 (m, 15H, Ar-H), 8.11 (s, 1H, Pyridine-H5); MS m/z (%) 485 (M+, 14), 322 (47), 252 (29), 167 (38), 77 (52), 43 (100). Anal. Calcd. for C30H23N5O2 (485.55): C, 74.21; H, 4.77; N, 14.42. Found: C, 74.05; H, 4.52; N, 14.26%.
Ethyl 3-(6-amino-5-cyano-4-(p-tolyl)pyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4b). Brown solid, (72% yield), mp 180–182 °C; IR (KBr) νmax 3379, 3211 (NH2), 2210 (CN), 1712 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.01 (t, J = 7.2 Hz, 3H, CH3), 2.36 (s, 3H, CH3), 4.12 (q, J = 7.2 Hz, 2H, CH2), 6.92 (s, br, 2H, NH2), 7.14–7.94 (m, 14H, Ar-H), 8.15 (s, 1H, Pyridine-H5); MS m/z (%) 499 (M+, 15), 468 (32), 364 (39), 209 (42), 104 (38), 78 (72), 43 (100). Anal. Calcd. for C31H25N5O2 (499.57): C, 74.53; H, 5.04; N, 14.02. Found: C, 74.37; H, 5.00; N, 13.85%.
Ethyl 3-(6-amino-5-cyano-4-(4-methoxyphenyl)pyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4c). Pale green solid, (68% yield), mp 154–156 °C; IR (KBr) νmax 3367, 3219 (NH2), 2210 (CN), 1714 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 3.78 (s, 3H, OCH3), 4.15 (q, J = 7.2 Hz, 2H, CH2), 6.93 (s, br, 2H, NH2), 7.18–7.80 (m, 14H, Ar-H), 8.12 (s, 1H, Pyridine-H5); MS m/z (%) 515 (M+, 9), 452 (42), 316 (100), 234 (51), 182 (37), 118 (50), 76 (66). Anal. Calcd. for C31H25N5O3 (515.57): C, 72.22; H, 4.89; N, 13.58. Found: C, 72.01; H, 4.77; N, 13.30%.
Ethyl 3-(6-amino-5-cyano-4-(4-(dimethylamino)phenyl)pyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4d). Dark yellow solid, (73% yield), mp 150–152 °C; IR (KBr) νmax 3431, 3212 (NH2), 2210 (CN), 1709 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.01 (t, J = 7.2 Hz, 3H, CH3), 2.97 (s, 6H, 2CH3), 4.11 (q, J = 7.2 Hz, 2H, CH2), 6.82 (s, br, 2H, NH2), 7.14–7.82 (m, 14H, Ar-H), 8.10 (s, 1H, Pyridine-H5); MS m/z (%) 528 (M+, 14), 416 (80), 212 (100), 170 (27), 105 (48), 76 (63). Anal. Calcd. for C32H28N6O2 (528.62): C, 72.71; H, 5.34; N, 15.90. Found: C, 72.59; H, 5.30; N, 15.73%.
Ethyl 3-(6-amino-4-(4-chlorophenyl)-5-cyanopyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4e). Dark yellow solid, (76% yield), mp 181–183 °C; IR (KBr) νmax 3362, 3218 (NH2), 2213 (CN), 1712 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 4.14 (q, J = 7.2 Hz, 2H, CH2), 6.98 (s, br, 2H, NH2), 7.17–7.84 (m, 14H, Ar-H), 8.17 (s, 1H, Pyridine-H5); MS m/z (%) 521 (M+, 23), 519 (M+, 8), 397 (32), 316 (60), 191 (55), 127 (51), 85 (47), 57 (100). Anal. Calcd. for C30H22ClN5O2 (519.99): C, 69.30; H, 4.26; N, 13.47. Found: C, 69.16; H, 4.18; N, 13.28%.
Ethyl 3-(6-amino-5-cyano-4-(2,4-dichlorophenyl)pyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4f). Yellow solid, (75% yield), mp 197–199 °C; IR (KBr) νmax 3367, 3215 (NH2), 2214 (CN), 1714 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 4.15 (q, J = 7.2 Hz, 2H, CH2), 7.06 (s, br, 2H, NH2), 7.28–7.85 (m, 13H, Ar-H), 8.14 (s, 1H, Pyridine-H5); MS m/z (%) 554 (M+, 100), 316 (77), 281 (41), 193 (71), 105 (33), 58 (72). Anal. Calcd. for C30H21Cl2N5O2 (554.43): C, 64.99; H, 3.82; N, 12.63. Found: C, 64.80; H, 3.61; N, 12.44%.
Ethyl 3-(5-acetyl-6-oxo-4-phenyl-1,6-dihydropyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6a). Brown solid, (68% yield), mp 186–188 °C; IR (KBr) νmax 3367 (NH), 1722, 1690, 1657 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.03 (t, J = 7.2 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 4.12 (q, J = 7.2 Hz, 2H, CH2), 7.24–7.49 (m, 15H, Ar-H), ), 7.77 (s, 1H, Pyridine-H5), 9.63 (s, br, 1H, NH); MS m/z (%) 503 (M+, 48), 458 (27), 334 (52), 232 (46), 99 (54), 57 (68), 43 (100). Anal. Calcd. for C31H25N3O4 (503.56): C, 73.94; H, 5.00; N, 8.34. Found: C, 73.73; H, 4.86; N, 8.17%.
Ethyl 3-(5-acetyl-6-oxo-4-(p-tolyl)-1,6-dihydropyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6b). Brown solid, (66% yield), mp 134–136 °C; IR (KBr) νmax 3409 (NH), 1718, 1681, 1662 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.56 (s, 3H, CH3), 4.11 (q, J = 7.2 Hz, 2H, CH2), 7.19–7.49 (m, 14H, Ar-H), ), 7.79 (s, 1H, Pyridine-H5), 9.81 (s, br, 1H, NH); MS m/z (%) 517(M+, 23), 385 (33), 294 (38), 147 (50), 120 (100), 76 (62). Anal. Calcd. for C32H27N3O4 (517.59): C, 74.26; H, 5.26; N, 8.12. Found: C, 74.20; H, 5.14; N, 8.03%.
Ethyl 3-(5-acetyl-4-(4-methoxyphenyl)-6-oxo-1,6-dihydropyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6c). Pale brown solid, (67% yield), mp 141–143 °C; IR (KBr) νmax 3423 (NH), 1715, 1687, 1660 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.00 (t, J = 7.2 Hz, 3H, CH3), 2.57 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.01 (q, J = 7.2 Hz, 2H, CH2), 7.16–7.54 (m, 14H, Ar-H), ), 7.74 (s, 1H, Pyridine-H5), 9.80 (s, br, 1H, NH); MS m/z (%) 533 (M+, 14), 423 (37), 313 (51), 279 (100), 105 (36), 76 (43). Anal. Calcd. for C32H27N3O5 (533.58): C, 72.03; H, 5.10; N, 7.88. Found: C, 71.85; H, 5.02; N, 7.63%.
Ethyl 3-(5-acetyl-4-(4-(dimethylamino)phenyl)-6-oxo-1,6-dihydropyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6d). Brown solid, (69% yield), mp 141–143 °C; IR (KBr) νmax 3425 (NH), 1721, 1682, 1657 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.00 (t, J = 7.2 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 2.99 (s, 6H, 2CH3), 4.11 (q, J = 7.2 Hz, 2H, CH2), 6.78–7.39 (m, 14H, Ar-H), 7.72 (s, 1H, Pyridine-H5), 9.73 (s, br, 1H, NH); MS m/z (%) 546 (M+, 14), 406 (36), 349 (55), 241 (49), 121 (36), 76 (30), 43 (100). Anal. Calcd. for C33H30N4O4 (546.63): C, 72.51; H, 5.53; N, 10.25. Found: C, 72.39; H, 5.38; N, 10.02%.
Ethyl 3-(5-acetyl-4-(4-chlorophenyl)-6-oxo-1,6-dihydropyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6e). Brown solid, (68% yield), mp 170–172 °C; IR (KBr) νmax 3366 (NH), 1720, 1680, 1663 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.06 (t, J = 7.2 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 4.14 (q, J = 7.2 Hz, 2H, CH2), 7.24–7.59 (m, 14H, Ar-H), 7.78 (s, 1H, Pyridine-H5), 10.06 (s, br, 1H, NH); MS m/z (%) 540 (M+ + 2, 1), 538 (M+, 3), 368 (53), 214 (100), 120 (55), 40 (79). Anal. Calcd. for C31H24ClN3O4 (538.00): C, 69.21; H, 4.50; N, 7.81. Found: C, 69.46; H, 4.35; N, 7.66%.
Ethyl 3-(5-acetyl-4-(2,4-dichlorophenyl)-6-oxo-1,6-dihydropyridin-2-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6f). Brown solid, (69% yield), mp 197–199 °C; IR (KBr) νmax 3414 (NH), 1720, 1683, 1659 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 4.15 (q, J = 7.2 Hz, 2H, CH2), 7.26–7.52 (m, 13H, Ar-H), 7.76 (s, 1H, Pyridine-H5), 10.24 (s, br, 1H, NH); MS m/z (%) 572 (M+, 12), 388 (64), 256 (44), 207 (67), 125 (50), 83 (42), 55 (100). Anal. Calcd. for C31H23Cl2N3O4 (572.44): C, 65.04; H, 4.05; N, 7.34. Found: C, 65.24; H, 4.02; N, 7.16%.

3.1.2. Synthesis of Bipyridine Derivatives 8 and 9

A mixture of 3-acetylpyrazole derivative 1 (0.668 g, 2 mmol), terephthalaldehyde 7 (0.134 g, 1 mmol), and malononitrile 3 or ethyl acetoacetate 5 (2 mmol) in acetic acid (30 mL) containing ammonium acetate (1.232 g, 16 mmol) was refluxed for 8 h. After cooling the reaction mixture it was poured into an ice-water mixture, the formed a precipitate that was collected by filtration, then crystallized from dioxane to give the bipyridine products 8 and 9, respectively.
Diethyl 3,3′-(1,4-phenylenebis(6-amino-5-cyanopyridine-4,2-diyl))bis(1,5-diphenyl-1H-pyrazole-4-carboxylate) (8). Brown solid, (68% yield), mp 187–189 °C; IR (KBr) νmax 3378, 3201 (NH2), 2211 (CN), 1709 (C=O) cm−1; 1H NMR (DMSO-d6) δ 1.03 (t, J = 7.2 Hz, 6H, 2CH3), 4.14 (q, J = 7.2 Hz, 4H, 2CH2), 6.93 (s, br, 4H, 2NH2), 7.18–7.49 (m, 20H, Ar-H), 7.85 (s, 4H, Ar-H), 8.10 (s, 2H, 2Pyridine-H3); MS m/z (%) 892 (M+, 39), 724 (48), 622 (63), 368 (39), 82 (60), 76 (57), 43 (100). Anal. Calcd. for C54H40N10O4 (892.98): C, 72.63; H, 4.52; N, 15.69. Found: C, 72.69; H, 4.36; N, 15.47%.
Diethyl 3,3′-(1,4-phenylenebis(5-acetyl-6-oxo-1,6-dihydropyridine-4,2-diyl))bis(1,5-diphenyl-1H-pyrazole-4-carboxylate) (9). Brown solid, (66% yield), mp 207–209 °C; IR (KBr) νmax 3423 (NH), 1723, 1677, 1653 (3C=O) cm−1; 1H NMR (DMSO-d6) δ 1.11 (t, J = 7.2 Hz, 6H, 2CH3), 2.58 (s, 6H, 2CH3), 4.14 (q, J = 7.2 Hz, 4H, 2CH2), 7.24–7.48 (m, 20H, Ar-H), ), 7.77 (s, 2H, 2Pyridine-H3), 7.81 (s, 4H, Ar-H), 10.06 (s, br, 2H, 2NH); MS m/z (%) 929 (M+, 17), 776 (41), 509 (37), 386 (55), 267 (40), 148 (32), 77 (100), 43 (68). Anal. Calcd. for C56H44N6O8 (929.00): C, 72.40; H, 4.77; N, 9.05. Found: C, 72.17; H, 4.62; N, 9.01%.

3.1.3. Synthesis of 1,5-Diphenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine derivatives 15a–h

General procedure: Triethylamine (0.14 mL, 1 mmol) was added to a mixture of equimolar amounts of thione 11 (0.480 g, 1 mmol) and the appropriate hydrazonoyl halides 12a–h (1 mmol) in dioxane (20 mL) at room temperature. The reaction mixture was then refluxed for 10–15 h until all hydrogen sulfide gas stopped evolving. The solid that formed after concentration of the reaction mixture was filtered and crystallized from the proper solvent to give the products 15a–h, respectively.
Ethyl 3-(3-acetyl-1,5-diphenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15a). Yellow solid, (74% yield), mp 233–235 °C (DMF); IR (KBr) νmax 3026, 2956 (C-H), 1706, 1649 (2C=O), 1595 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.15 (t, J = 7.2 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 4.19 (q, J = 7.2 Hz, 2H, CH2), 5.33 (d, J = 4 Hz, 1H, CH), 6.62 (d, J = 4Hz, 1H, CH), 7.03–7.80 (m, 20H, Ar-H); MS m/z (%) 606 (M+, 5),406 (36), 287 (29), 247 (75), 194 (37), 92 (71), 65 (60), 43 (100). Anal. Calcd. for C37H30N6O3 (606.69): C, 73.25; H, 4.98; N, 13.85. Found: C, 73.07; H, 4.84; N, 13.67%.
Ethyl 3-(3-acetyl-5-phenyl-1-(p-tolyl)-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15b). Yellow solid, (72% yield), mp 211–213 °C (DMF); IR (KBr) νmax 3030, 2951 (C-H), 1697, 1642 (2C=O), 1597 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 2.44 (s, 3H, CH3), 4.16 (q, J = 7.2 Hz, 2H, CH2), 5.32 (d, J = 4 Hz, 1H, CH), 6.61 (d, J = 4Hz, 1H, CH), 7.05–7.73 (m, 19H, Ar-H); MS m/z (%) 620 (M+, 7), 498 (27), 390 (35), 285 (60), 105 (41), 77 (100), 43 (92). Anal. Calcd. for C38H32N6O3 (620.71): C, 73.53; H, 5.20; N, 13.54. Found: C, 73.39; H, 5.38; N, 13.36%.
Ethyl 3-(3-acetyl-1-(4-chlorophenyl)-5-phenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15c). Yellow solid, (74% yield), mp 242–244 °C (DMF/EtOH); IR (KBr) νmax 3028, 2963 (C-H), 1707, 1641 (2C=O), 1597 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 2.44 (s, 3H, CH3), 4.15 (q, J = 7.2 Hz, 2H, CH2), 5.36 (d, J = 4 Hz, 1H, CH), 6.69 (d, J = 4Hz, 1H, CH), 7.27–7.70 (m, 19H, Ar-H); MS m/z (%) 643 (M+ + 2, 4), 641 (M+, 13), 499 (57), 322 (39), 180 (28), 105 (35), 77 (100). Anal. Calcd. for C37H29ClN6O3 (641.13): C, 69.32; H, 4.56; N, 13.11. Found: C, 69.19; H, 4.51; N, 13.00%.
Ethyl 3-(3-acetyl-1-(4-nitrophenyl)-5-phenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-yl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15d). Yellow solid, (75% yield), mp 204–206 °C (EtOH); IR (KBr) νmax 3031, 2950 (C-H), 1712, 1656 (2C=O), 1598 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 2.47 (s, 3H, CH3), 4.15 (q, J = 7.2 Hz, 2H, CH2), 5.39 (d, J = 4 Hz, 1H, CH), 6.72 (d, J = 4Hz, 1H, CH), 7.24–8.52 (m, 19H, Ar-H); MS m/z (%) 651 (M+, 26), 484 (48), 400 (71), 252 (39), 179 (42), 105 (100), 57 (83). Anal. Calcd. for C37H29N7O5 (651.68): C, 68.19; H, 4.49; N, 15.05. Found: C, 68.04; H, 4.33; N, 14.92%.
Ethyl 7-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)-1,5-diphenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (15e). Yellow solid, (72% yield), mp 180–182 °C (DMF/EtOH); IR (KBr) νmax 3056, 2973 (C-H), 1713, 1679 (2C=O), 1596 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 1.26 (t, J = 7.6 Hz, 3H, CH3), 4.14 (q, J = 7.2 Hz, 2H, CH2), 4.26 (q, J = 7.6 Hz, 2H, CH2), 5.46 (d, J = 4 Hz, 1H, CH), 6.47 (d, J = 4Hz, 1H, CH), 6.96–7.79 (m, 20H, Ar-H); MS m/z (%) 636 (M+, 9), 394 (51), 283 (33), 235 (49), 194 (62), 83 (53), 57 (100). Anal. Calcd. for C38H32N6O4 (636.71): C, 71.68; H, 5.07; N, 13.20. Found: C, 71.62; H, 5.01; N, 13.03%.
Ethyl 7-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)-5-phenyl-1-(p-tolyl)-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (15f). Yellow solid, (73% yield), mp 172–174 °C (EtOH); IR (KBr) νmax 3052, 2955 (C-H), 1710, 1699 (2C=O), 1595 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.02 (t, J = 7.2 Hz, 3H, CH3), 1.23 (t, J = 7.6 Hz, 3H, CH3), 2.30 (s, 3H, CH3), 4.10 (q, J = 7.2 Hz, 2H, CH2), 4.26 (q, J = 7.6 Hz, 2H, CH2), 5.39 (d, J = 4 Hz, 1H, CH), 6.45 (d, J = 4Hz, 1H, CH), 7.12–7.76 (m, 19H, Ar-H); MS m/z (%) 650 (M+, 6), 439 (44), 361 (30), 244 (57), 104 (100), 91 (48), 43 (60). Anal. Calcd. for C39H34N6O4 (650.74): C, 71.98; H, 5.27; N, 12.91. Found: C, 71.75; H, 5.19; N, 12.74%.
Ethyl 1-(4-chlorophenyl)-7-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)-5-phenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (15g). Yellow solid, (75% yield), mp 188–190 °C (DMF/EtOH); IR (KBr) νmax 3037, 2966 (C-H), 1713, 1667 (2C=O), 1597 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.05 (t, J = 7.2 Hz, 3H, CH3), 1.19 (t, J = 7.6 Hz, 3H, CH3), 4.13 (q, J = 7.2 Hz, 2H, CH2), 4.24 (q, J = 7.6 Hz, 2H, CH2), 5.42 (d, J = 4 Hz, 1H, CH), 6.47 (d, J = 4Hz, 1H, CH), 7.25–7.79 (m, 19H, Ar-H); MS m/z (%) 673 (M+ + 2, 11), 671 (M+, 36), 387 (100), 324 (68), 278 (50), 105 (42), 78 (83). Anal. Calcd. for C38H31ClN6O4 (671.15): C, 68.00; H, 4.66; N, 12.52. Found: C, 68.25; H, 4.40; N, 12.46%.
Ethyl 7-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)-1-(4-nitrophenyl)-5-phenyl-1,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate (15h). Brown solid, (71% yield), mp 206–208 °C (EtOH); IR (KBr) νmax 3030, 2948 (C-H), 1713, 1644 (2C=O), 1593 (C=N) cm−1; 1H NMR (DMSO-d6) δ 1.07 (t, J = 7.2 Hz, 3H, CH3), 1.25 (t, J = 7.6 Hz, 3H, CH3), 4.12 (q, J = 7.2 Hz, 2H, CH2), 4.27 (q, J = 7.6 Hz, 2H, CH2), 5.46 (d, J = 4 Hz, 1H, CH), 6.49 (d, J = 4Hz, 1H, CH), 7.25–8.42 (m, 19H, Ar-H); MS m/z (%) 681 (M+, 31), 577 (73), 390 (66), 327 (95), 115 (100), 83 (52). Anal. Calcd. for C38H31N7O6 (681.71): C, 66.95; H, 4.58; N, 14.38. Found: C, 66.77; H, 4.42; N, 14.23%.

3.2. Cytotoxic Activity

The cytotoxic evaluation of the synthesized compounds was carried out at the Regional Center for Mycology and Biotechnology at Al-Azhar University, Cairo, Egypt according to the reported method [56].

4. Conclusions

Two series of functionalized pyrazolyl-pyridines were prepared by multi-component reaction of 3-acetylpyrazole derivative with the appropriate aldehyde, malononitrile (or ethyl acetoacetate) in acetic acid in the presence of excess ammonium acetate. The mechanism of formation of the novel products was also discussed. Additionally, two novel bipyridine derivatives were synthesized by the above described reaction and under the same reaction conditions using terephthaldehyde in lieu of benzaldeyde derivatives. Another series of 1,2,4-triazole[4,3-a]pyrimidines, including a pyrazole moiety, was prepared by the reaction of a pyrazolylpyrimidine-2-thione derivative with a variety of hydrazonoyl chlorides under reflux in dioxane in the presence of triethylamine. The assigned structure for the products was elucidated based on elemental analyses and spectral data (IR, 1HNMR, MS). Moreover, the novel pyrazolyl-pyridines were tested for their reactivity as antitumor agents and the results obtained revealed high potency of some of them against HEPG2-1 compared with doxorubicin used as the reference drug.

Acknowledgments

The authors extend their sincere appreciation to the Deanship of Scientific Research at the King Saud University for its funding this Prolific Research group (PRG-1437-29).

Author Contributions

Magda A. Abdallah, Sobhi M. Gomha, and Ikhlass M. Abbas designed research; Mariam S. H. Kazem, Seham S. Alterary and Yahia N. Mabkhot performed the research, analyzed the data, wrote the paper, and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interests.

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Applsci 07 00785 sch001 550
Scheme 1. Synthesis of pyridine derivatives 4a–f.
Scheme 1. Synthesis of pyridine derivatives 4a–f.
Applsci 07 00785 sch001
Applsci 07 00785 sch002 550
Scheme 2. Synthesis of pyridine derivatives 6a–f.
Scheme 2. Synthesis of pyridine derivatives 6a–f.
Applsci 07 00785 sch002
Applsci 07 00785 sch003 550
Scheme 3. Mechanism of the synthesis of pyridine derivatives 4a–f and 6a–f.
Scheme 3. Mechanism of the synthesis of pyridine derivatives 4a–f and 6a–f.
Applsci 07 00785 sch003
Applsci 07 00785 sch004 550
Scheme 4. Synthesis of bipyridine derivatives 8 and 9.
Scheme 4. Synthesis of bipyridine derivatives 8 and 9.
Applsci 07 00785 sch004
Applsci 07 00785 sch005 550
Scheme 5. Synthesis of 1,2,4-triazolo[4,3-a]pyrimidines 15a–h.
Scheme 5. Synthesis of 1,2,4-triazolo[4,3-a]pyrimidines 15a–h.
Applsci 07 00785 sch005
Applsci 07 00785 g001 550
Figure 1. Cytotoxic activities of tested compounds against HEPG2-1.
Figure 1. Cytotoxic activities of tested compounds against HEPG2-1.
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Table
Table 1. IC50 values of tested compounds 4 and 6 ± standard deviation against HEPG2-1.
Table 1. IC50 values of tested compounds 4 and 6 ± standard deviation against HEPG2-1.
Compound No.XYZIC50 (nM)General Structure
Doxorubicin---0.08 ± 0.07Applsci 07 00785 i001
4aHCNNH29.7 ± 0.85
4bMeCNNH21.9 ± 0.16
4eClCNNH217.2 ± 0.83
6aHMeCOOH12.3 ± 0.37
6bMeMeCOOH2.4 ± 0.29
6eClMeCOOH22.3 ± 0.36

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MDPI and ACS Style

Abdallah, M.A.; Gomha, S.M.; Abbas, I.M.; Kazem, M.S.H.; Alterary, S.S.; Mabkhot, Y.N. An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents. Appl. Sci. 2017, 7, 785. https://doi.org/10.3390/app7080785

AMA Style

Abdallah MA, Gomha SM, Abbas IM, Kazem MSH, Alterary SS, Mabkhot YN. An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents. Applied Sciences. 2017; 7(8):785. https://doi.org/10.3390/app7080785

Chicago/Turabian Style

Abdallah, Magda A., Sobhi M. Gomha, Ikhlass M. Abbas, Mariam S. H. Kazem, Seham S. Alterary, and Yahia N. Mabkhot. 2017. "An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents" Applied Sciences 7, no. 8: 785. https://doi.org/10.3390/app7080785

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