Skip to main content
Download PDF
Download ePub

Microwave-assisted one pot three-component synthesis of some novel pyrazole scaffolds as potent anticancer agents

Chemistry Central Journal volume 11, Article number: 37 (2017) Cite this article

Abstract

Background

Pyrazoles, thiazoles and 1,3,4-thiadiazoles have been reported to possess various pharmacological activities.

Results

An efficient and a novel approach for the synthesis of some novel pyrazole based-azoles are described via multi-component reaction under controlled microwave heating conditions. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, 1H NMR and mass spectral data. All the synthesized compounds were tested for in vitro activities against two antitumor cell lines, human lung cancer and human hepatocellular carcinoma compared with the employed standard antitumor drug (cisplatin).

Conclusions

All the newly synthesized compounds were evaluated for their anticancer activity against human lung cancer and human hepatocellular carcinoma cell lines using MTT assay. The results obtained exploring the high potency of six of the tested compounds compared with cisplatin.

Microwave-assisted one pot three-component synthesis of some novel pyrazole scaffolds as potent anticancer agents

Background

Multi-component reactions (MCR) are one-pot processes with at least three components to form a single product, which incorporates most or even all of the starting materials [1,2,3,4,5,6]. The huge interest for such multi-component reactions during the last years has been oriented towards developing combinatorial chemistry procedures, because of their high efficiency and convenience of these reactions in comparison with multistage procedures. Also, the utility of MCR under microwave irradiation in synthesis of heterocyclic compounds enhanced the reaction rates and improve the regioselectivity [7,8,9,10,11,12].

On the other hand, pyrazole and its derivatives have drawn considerable attention of the researchers in the past few decades owing to their high therapeutic values. Some of the drugs, possessing pyrazole as basic moiety, like celecoxib [13], deracoxib [14], etoricoxib and atorivodine [15] are already booming in the market. Pyrazole derivatives possess an extensive range of pharmacological activities such as antiinflammatory, antipyretic, analgesic, antimicrobial, sodium channel blocker, antitubercular, antiviral, antihypertensive, antiglaucoma, antioxidant, antidepressant, anxiolytic, neuroprotective and antidiabetic activity [16,17,18,19,20,21,22,23]. Furthermore, pyrazole prodrugs have also been reported to possess significant anticancer activities [24,25,26,27,28,29,30]. Keeping this in mind, and in continuation of our previous work on the synthesis of new anticancer agents [31,32,33,34,35,36,37,38,39,40], we herein present an efficient regioselective synthesis of novel 4-heteroaryl-pyrazoles, which have not been reported hitherto in a multicomponent synthesis under microwave irradiation and to assess their anticarcinogenic effects against hepatocellular carcinoma (HepG-2) and human lung cancer (A-549) cell lines.

Results and discussion

Chemistry

Multi-component reaction of acetyl pyrazole 1 [41], dimethylformamide dimethylacetal (DMF–DMA) 2 and nitrileimine 4a–d (generated in situ from 3a–d with triethylamine) in toluene under conventional heating for 10–15 h or under microwave irradiation at 150 °C for 4–10 min. afforded compound 6a–d rather than its isomeric structure 8a–d in 66–70 and 84–90%, respectively (Scheme 1; Table 1). The structure of 6a–d was confirmed by their spectral data (IR, MS and 1H-NMR) and elemental analyses. For example, the IR spectra of products 6 revealed in each case two absorption bands in the regions υ 1638–1676 and 1682–1724 cm−1 due to the two carbonyl groups. The 1HNMR spectra showed, in addition to the expected signals for the aromatic protons, three singlet signals at δ ~2.34, 2.55 and 8.92 reveled to the two methyl groups and the pyrazole-H5, respectively. The mass spectra of products 6a–d revealed a molecular ion peak for each one which is consistent with the respective molecular weight. These data are much closer to those reported in literature on similar work [42,43,44].

Scheme 1
scheme 1

Synthesis of pyrazoles 6a–d

Full size image
Table 1 Comparative data of conventional (A) and MW (B) methods for the synthesis of compounds 6a–d, 13a, b, 18a–c, 21a, b and 23a, b
Full size table

Compound 6a was alternatively synthesized by reacting enaminone 9 (prepared separately via condensation of acetyl pyrazole 1 with DMF–DMF) with 2-oxo-N-phenylpropanehydrazonoyl chloride (3a) in toluene containing catalytic amount of TEA under MWI. The obtained product was found to be identical with 6a in all respects (TLC, mp and IR spectrum) which affords further evidence to all structures 6a–d. The latter products were assumed to be formed via initial 1,3-dipolar cycloaddition of the nitrileimines 4a–d to the activated double bond in enaminone 9 to afford the non-isolable cycloadducts 5 which underwent loss of dimethylamine yielding the final pyrazole derivatives 6a–d.

The results obtained Table 1 indicate that, unlike classical heating, microwave irradiation results in higher yields and shorter reaction times for all the carried reactions. Microwave irradiation facilitates the polarization of the molecules under irradiation causing rapid reaction to occur. This is consistent with the reaction mechanism, which involves a polar transition state [45].

By the same way reaction of acetyl pyrazole 1 with nitrile-oxide 11a, b (derived from reaction of hydroximoyl chloride 10a, b with TEA) and DMF–DMA in toluene under microwave irradiation at 150 °C gave isoxazoles 13a, b (Scheme 2; Table 1). The 1H NMR spectrum of the product revealed a singlet signal at 9.67 ppm assigned for isoxazole-5H proton not isoxazole-4H proton [42,43,44, 46] which consistent with the isomeric structure 13 rather than the isomeric structure 15. Moreover, the mass spectrum of 13a and 13b revealed a molecular ion peaks at m/z = 506 and 446, respectively, which is consistent with their molecular weights.

Scheme 2
scheme 2

Synthesis of isoxazoles 13a, b

Full size image

Furthermore, alternative synthesis of compound 13a was achieved via reaction enaminone 9 with N-hydroxy-2-naphthimidoyl chloride (10a) under the same reaction condition to yield authentic product 13a (Scheme 2).

Next, our study was extended to investigate the reactivity of compound 1 towards thiosemicarbazide and various hydrazonoyl halides aiming to synthesize new pyrazole based—1,3-thiazoles and 1,3,4-thiadiazoles. Thus, acetyl pyrrole 1, thiosemicarbazide 2 and α-keto hydrazonoyl halides 3a, b, e were allowed to react in a one-pot three-component reaction in dioxane containing catalytic amount of TEA under MWI to afford the arylazothiazole derivatives 18a–c, respectively (Scheme 3; Table 1). The reaction goes in parallel to literature [32, 35,36,37].

Scheme 3
scheme 3

Synthesis of thiazoles 18a–c

Full size image

The structure of the products 18a–c was assigned based on the spectral data and elemental analyses. For example mass spectrum of compound 18a revealed molecular ion peak at m/z 542 and its 1H NMR spectrum exhibited four characteristic singlet signals at 2.32, 2.36, 2.48 and 10.47 assignable to three CH3 groups and NH protons, respectively, in addition to an aromatic multiplet in the region 6.99–7.93 ppm equivalent to 12 protons. Its IR spectra showed one NH group band at 3396 cm−1.

The structure of products 18 was further confirmed by an alternative method. Thus, reaction of acetylpyrazole 1 with thiosemicarbazide 16 under MWI in ethanol containing drops of concentrated HCl led to the formation of product 19. Compound 19 was then react with 2-oxo-N-phenylpropanehydrazonoyl chloride (3a) in dioxane containing catalytic amount of TEA under MWI to give a product identical in all respects (IR, mp and mixed mp.) with 18a (Scheme 3).

In a similar manner, when acetyl pyrazole 1 was allowed to react with thiosemicarbazide 2 and ethyl (N-arylhydrazono)-chloroacetates 3c, f in dioxane in the presence of triethylamine under MWI, it afforded in each case a single isolable product, namely, 2-(2-(1-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazinyl)-5-(2-arylhydrazono) thiazol-4(5H)-one 21a, b (Scheme 4; Table 1). Structure 21 was confirmed by elemental analysis, spectral data (IR, 1H NMR, and mass), and alternative synthesis route. Thus, thiosemicarbazone 19 was reacted with ethyl)-2-chloro-2-(2-phenylhydrazono)acetate (3c) in dioxane in the presence of TEA under MWI afforded a product identical in all aspects (mp, mixed mp, and spectra) with 21a (Scheme 4).

Scheme 4
scheme 4

Synthesis of thiazolones 21a, b

Full size image

Finally, the reactivity of acetylpyrazole 1 towards hydrazonoyl halides, be bereft of a-keto group, was examined. In the present study, we have established that reaction of acetylpyrazole 1 with N-thiosemicarbazide 16 and aryl carbohydrazonoyl chlorides 3d, g gave the respective 1,3,4-thiadiazoles 23a, b as the end products (Scheme 5; Table 1). The structures of compounds 23a, b were confirmed on the bases of spectral data and elemental analyses (see Experimental part). The reaction proceeded via S-alkylation, with removal of hydrogen chloride, to give S-alkylated intermediates 22 followed by intramolecular Michael type addition under the employed reaction conditions, followed by elimination of ammonia, afforded the final product 23 [36, 47] (Scheme 5).

Scheme 5
scheme 5

Synthesis of thiadiazoles 23a, b

Full size image

Cytotoxic activity

The in vitro growth inhibitory activity of the synthesized compounds 6a–d, 9, 13a, b, 18a–c, 19, 21a, b and 23a, b was investigated against two carcinoma cell lines: human lung cancer (A-549) and human hepatocellular carcinoma(HepG-2) in comparison with the well-known anticancer standard drug (cisplatin) under the same conditions using colorimetric MTT assay. Data generated were used to plot a dose response curve of which the concentration of test compounds required to kill 50% of cell population (IC50) was determined. The results revealed that all the tested compounds showed inhibitory activity to the tumor cell lines in a concentration dependent manner. Interestingly, the results represented in Table 2 and Fig. 1 showed that compounds 13a, 13b and 21a were the most active compounds (IC50 value of 4.47 ± 0.3, 3.46 ± 0.6, 3.10 ± 0.8 μg/mL, respectively) against the lung carcinoma cell line (A549), compared with cisplatin reference drug with IC50 value of 0.95 ± 0.23 μg/mL. Moreover, the order of activity against A549 cell line was 18c > 18b > 19 > 9 > 6a > 6c > 23b > 6d > 18a > 21b > 6b.

Table 2 The in vitro inhibitory activity of tested compounds against tumor cell lines expressed as IC50 values (μg/mL) ±standard deviation from three replicates
Full size table
Fig. 1
figure 1

Cytotoxic activities of the most active compounds against HEPG2 and A-549 cell lines

Full size image

On the other hand, compounds 6a, 9, 13b, 23b were the most active compounds (IC50 value of 5.60 ± 0.8, 5.67 ± 1.2, 4.47 ± 0.9 and 5.67 ± 1.2 μg/mL, respectively) against liver carcinoma cell line (HepG2) cell line while the rest compounds have moderate activities.

Experimental

Chemistry

General

Melting points were measured on an Electrothermal IA 9000 series digital melting point apparatus (Bibby Sci. Lim. Stone, Staffordshire, UK). IR spectra were measured on PyeUnicam SP 3300 and Shimadzu FTIR 8101 PC infrared spectrophotometers (Shimadzu, Tokyo, Japan) in potassium bromide discs. NMR spectra were measured on a Varian Mercury VX-300 NMR spectrometer (Varian, Inc., Karlsruhe, Germany) operating at 300 MHz (1H-NMR) and run in deuterated dimethylsulfoxide (DMSO-d 6 ). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (Tokyo, Japan) at 70 eV. Elemental analyses were measured by using a German made Elementarvario LIII CHNS analyzer. Antitumor activity of the products was measured at the Regional Center for Mycology and Biotechnology at Al-Azhar University, Cairo, Egypt. Hydrazonoyl halides 3a–g were prepared following literature method [41, 48].

Synthetic procedures

Synthesis of trisubstituted pyrazoles 6a-d and isoxazoles 13a,b

Method A To a stirred solution of acetyl pyrazole 1 (0.327 g, 1 mmol), dimethylformamide dimethylacetal 2 (1 mmol) and the appropriate hydrazonoyl halides 3a–d or hyroximoyl chlorides 10a, b (1 mmol) in dry toluene (15 mL), an equivalent amount of triethylamine (0.5 mL) was added. The reaction mixture was heated under reflux for 10–15 h (monitored through TLC). The precipitated triethylamine hydrochloride was filtered off, and the filtrate was evaporated under reduced pressure. The residue was triturated with MeOH. The solid product, so formed in each case, was collected by filtration, washed with water, dried, and crystallized from the proper solvent to afford the corresponding pyrazole 6a–d and isoxazole derivatives 13a, b, respectively.

Method B

Repetition of the same reactions of method A with heating in microwave oven at 500 W and 150 °C for 4–10 min., gave products identical in all respects with those separated from method A. The products 6a–d and 13a, b together with their physical constants are listed below.

1-(4-(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carbonyl)-1-phenyl-1H-pyrazol-3-yl)ethanone (6a)

Brown solid, mp 208–210 °C; IR (KBr) νmax 1599 (C=N),1670, 1682 (2C=O), 2924, 3105 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.34 (s, 3H, CH3), 2.55 (s, 3H, CH3), 6.98–8.39 (m, 12H, Ar–H), 8.92 (s, 1H, pyrazole-H5); MS m/z (%) 497 (M+, 9), 342 (25), 252 (22), 174 (11), 145 (22), 115 (26), 103 (40), 76 (100), 63 (13), 50 (19). Anal. Calcd. for C26H19N5O4S (497.53): C, 62.77; H, 3.85; N, 14.08. Found: C, 63.08; H, 3.55; N, 13.70%.

1-(4-(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carbonyl)-1-(p-tolyl)-1H-pyrazol-3-yl)ethanone (6b)

Yellow solid, mp 222–224 °C; IR (KBr) νmax 1597 (C=N),1676, 1688 (2C=O), 2919, 3118 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.24 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.56 (s, 3H, CH3), 7.12 (t, J = 1.2 Hz, 1H, thiophene-H), 7.31 (d, J = 1.2 Hz, 1H, thiophene-H), 7.33 (d, J = 1.2 Hz, 1H, thiophene-H), 7.55 (d, J = 4.4 Hz, 2H, Ar–H), 7.63 (d, J = 4.4 Hz, 2H, Ar–H),7.88 (d, J = 8.8 Hz, 2H, Ar–H), 8.39 (d, J = 8.8 Hz, 2H, Ar–H), 10.58 (s, 1H, pyrazole-H5); 13C-NMR (DMSO-d 6): δ 13.3, 20.8, 25.7 (CH3), 115.3, 117.6, 118.9, 121.37, 122.7, 125.2, 126.7, 128.1, 129.4, 130.1, 132.2, 133.8, 138.1, 140.6, 143.43, 144.4, 146.8, 147.2 (Ar–C and C=N),188.2, 194.9 (C=O); MS m/z (%) 511 (M+, 2), 406 (10), 266 (6), 219 (11), 168 (7), 147 (7), 125 (11), 104 (25), 98 (17), 83 (93), 79 (44), 69 (35), 54 (53), 44 (100). Anal. Calcd. for C27H21N5O4S (511.55): C, 63.58; H, 4.14; N, 13.69. Found: C, 63.78; H, 4.05; N, 13.29%.

Ethyl 4-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazole-4-carbonyl)-1-phenyl-1H-pyrazole-3-carboxylate (6c)

Yellow solid, mp 207–209 °C; IR (KBr) νmax 15,984 (C=N), 1660, 1724 (2C=O), 2931, 2974 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 1.18 (t, J = 7.6 Hz, 3H, CH3CH2), 2.34 (s, 3H, CH3), 4.27 (q, J = 7.1 Hz, 2H, CH2CH3), 6.96–8.43 (m, 12H, Ar–H), 8.99 (s, 1H, pyrazole-H5); MS m/z (%) 527 (M+, 6), 484 (22), 366 (26), 328 (33), 268 (50), 226 (35), 210 (37), 151 (49), 124 (78), 115 (61), 75 (100), 42 (45). Anal. Calcd. for C27H21N5O5S (527.55): C, 61.47; H, 4.01; N, 13.28. Found: C, 61.77; H, 3.75; N, 12.94%.

(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)(1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)methanone (6d)

Orange solid, mp 219–220 °C; IR (KBr) νmax 1595 (C=N),1638 (C=O), 2924, 3105 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.34 (s, 3H, CH3), 6.98–8.52 (m, 14H, Ar–H), 9.28 (s, 1H, pyrazole-H5); 13C-NMR (DMSO-d 6): δ 26.9 (CH3), 113.1, 113.3, 115.0, 115.6, 122.5, 122.6, 123.1, 123.6, 126.5, 126.7, 128.4, 131.1, 131.7, 132.1, 132.3, 136.5, 137.1, 141.5, 141.6, 142.4, 142.6, 142.8 (Ar–C and C=N), 197.2 (C=O); MS m/z (%) 582 (M+, 6), 532 (12), 383 (16), 286 (11), 219 (21), 135 (49), 79 (16), 83 (27), 76 (67), 60 (28), 45 (100). Anal. Calcd. for C28H18N6O5S2 (582.61): C, 57.72; H, 3.11; N, 14.42. Found: C, 57.99; H, 2.80; N, 14.12%.

Synthesis of 3-(dimethylamino)-1-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)prop-2-en-1-one (9).

Amixture of acetyl pyrazole 1 (3.27 g, 10 mmol) and dimethylformamide–dimethylacetal (DMF–DMA) (10 mmol) in dry toluene (20 mL) was refluxed in microwave oven at 500 W and 150 °C for 5 min., then left to cool to room temperature. The precipitated product was filtered off, washed with light petroleum (40–60 °C), and dried. Recrystallization from benzene afforded enaminone 1 as orange solid, mp 250–252 °C; IR (KBr) νmax 1642 (C=O), 2920, 3080 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.34 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.06 (s, 3H, CH3), 5.24 (d, J = 12.8 Hz, 1H, N–CH=), 7.05 (t, J = 1.2 Hz, 1H, thiophene-H), 7.14 (d, J = 1.2 Hz, 1H, thiophene-H), 7.50 (d, J = 1.2 Hz, 1H, thiophene-H), 7.65 (d, J = 12.8 Hz, 1H, =CH–CO), 7.90 (d, J = 8.8 Hz, 2H, Ar–H), 8.37 (d, J = 8.8 Hz, 2H, Ar–H); 13C-NMR (DMSO-d 6): δ 12.4, 36.1, 44.0 (CH3), 120.4, 124.3, 124.4, 125.8, 127.0, 127.1, 128.4, 134.0, 142.5, 143.5, 145.4, 145.8, 146.3 (Ar–C and C=N), 194.0 (C=O); MS m/z (%) 382 (M+, 3), 300 (11), 286 (11), 189 (9), 132 (7), 104 (100), 77 (58), 64 (16), 51 (13), 43 (12). Anal. Calcd. for C19H18N4O3S (382.44): C, 59.67; H, 4.74; N, 14.65. Found: C, 59.58; H, 4.44; N, 14.39%.

(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)(3-(naphthalen-2-yl)isoxazol-4-yl)methanone (13a)

Yellow solid, mp 203–205 °C; IR (KBr) νmax 1597 (C=N), 1660 (C=O), 2976, 3117 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.31 (s, 3H, CH3), 7.13–8.45 (m, 14H, Ar–H), 9.67 (s, 1H, isoxazole-H5); 13C-NMR (DMSO-d 6): δ 26.9 (CH3), 110.0, 113.3, 115.0, 115.1, 115.5, 122.5, 123.3, 124.5, 125.0, 126.5, 126.7, 128.4, 130.8, 133.6, 135.4, 136.9, 137.0, 141.5, 141.6, 142.6, 148.8, 152.4, 160.0 (Ar–C and C=N), 188.3 (C=O); MS m/z (%) 506 (M+, 2), 435 (9), 412 (14), 379 (45), 214 (12), 142 (10), 105 (26), 93 (21), 77 (51), 65 (62), 60 (52), 43 (100). Anal. Calcd. for C28H18N4O4S (506.53): C, 66.39; H, 3.58; N, 11.06. Found: C, 66.04; H, 3.21; N, 10.86%.

(3-(Furan-3-yl)isoxazol-4-yl)(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)methanone (13b)

Orange solid, mp 209–211 °C; IR (KBr) νmax 1598 (C=N), 1664 (C=O), 2925, 3107 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.34 (s, 3H, CH3), 7.13–8.61 (m, 10H, Ar–H), 9.23 (s, 1H, pyrazole-H5); MS m/z (%) 446 (M+, 2), 392 (100), 349 (43), 317 (23), 285 (11), 234 (16), 191 (16), 172 (20), 130 (26), 102 (26), 77 (69). Anal. Calcd. for C22H14N4O5S (446.44): C, 59.19; H, 3.16; N, 12.55. Found: C, 59.50; H, 2.80; N, 12.17%.

Alternate synthesis of 6a and 13a

Equimolar amounts of enaminone 9 (0.382 g, l mmol) and hydrazonoyl halide 3a or hyroximoyl chloride 10a (1 mmol) in dry toluene (15 mL) containing an equivalent amount of triethylamine (0.5 mL) was refluxed in microwave oven at 500 W and 150 °C for 6 min., gave products identical in all respects (mp, mixed mp and IR spectra) with compounds 6a and 13a, respectively.

Synthesis of thiazoles 18a–c and 21a, b and thiadiazoles 23a, b : Method A

To a stirred solution of acetyl pyrazole 1 (0.327 g, 1 mmol), thiosemicarbazide 16 (0.091 g, 1 mmol) and the appropriate hydrazonoyl halides 3a, b, e or 3c, f or 3d, g (1 mmol) in dioxane (15 mL), an equivalent amount of triethylamine (0.05 mL) was added. The reaction mixture was heated under reflux for 4–8 h (monitored through TLC). Excess of solvent was removed under reduced pressure and the reaction mixture was triturated with MeOH. The product separated was filtered, washed with MeOH, dried and recrystallized from the proper solvent to give thiazoles 18a–c and 21a, b and thiadiazoles 23a, b, respectively.

Method B

Repetition of the same reactions of method A with heating in microwave oven at 500 W and 150 °C for 4–10 min., gave products identical in all respects with those separated from method A. The products 18a–c, 21a, b and 23a, b together with their physical constants are listed below.

4-Methyl-2-(2-(1-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazinyl)-5-(phenyldiazenyl)thiazole (18a)

Orange solid, mp 219–220 °C; IR (KBr) νmax 1600 (C=N), 2974 (C–H), 3396 (NH) cm−1; 1H NMR (DMSO-d 6 ) δ 2.32 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.48 (s, 3H, CH3), 6.99–7.93 (m, 12H, Ar–H), 10.65 (s, 1H, NH); 13C-NMR (DMSO-d 6): δ 9.2, 12.5, 24.6 (CH3), 114.5, 121.4, 123.1, 125.2, 126.3, 127.0, 127.9, 128.1, 128.5, 128.9, 135.3, 140.4, 140.9, 143.1, 144.1, 145.3, 145.79, 153.3, 163.4 (Ar–C and C=N); MS m/z (%) 542 (M+, 6), 432 (16), 253 (13), 138 (11), 106 (69), 90 (12), 78 (100), 64 (11), 51 (34). Anal. Calcd. for C26H22N8O2S2 (542.64): C, 57.55; H, 4.09; N, 20.65. Found: C, 57.87; H, 3.70; N, 20.35%.

4-Methyl-2-(2-(1-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazinyl)-5-(p-tolyldiazenyl)thiazole (18b).

Orange solid, mp 226–228 °C; IR (KBr) νmax 1600 (C=N), 2924 (C–H), 3438 (NH) cm−1; 1H NMR (DMSO-d 6 ) δ 2.17 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.47 (s, 3H, CH3), 6.99–7.89 (m, 11H, Ar–H), 10.65 (s, 1H, NH); 13C-NMR (DMSO-d 6): δ 12.0, 14.3, 15.7, 26.8 (CH3), 105.3, 111.5, 114.9, 116.3, 117.9, 119.8, 120.8, 122.2, 126.4, 126.6, 127.9, 128.1, 131.9, 132.6, 137.6, 141.7, 142.1, 142.3, 170.2 (Ar–C and C=N); MS m/z (%) 556 (M+, 18), 431 (18), 314 (25), 251 (43), 193 (32), 166 (29), 152 (43), 136 (20), 119 (45), 104 (67), 90 (68), 75 (100), 62 (55), 52 (28), 41 (41). Anal. Calcd. for C27H24N8O2S2 (556.66): C, 58.26; H, 4.35; N, 20.13. Found: C, 58.58; H, 4.05; N, 19.80%.

5-((4-Chlorophenyl)diazenyl)-4-methyl-2-(2-(1-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene)hydrazinyl)thiazole (18c)

Orange solid, mp 232–235 °C; IR (KBr) νmax 1598 (C=N), 2922 (C–H), 3436 (NH) cm−1; 1H NMR (DMSO-d 6 ) δ 2.32 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.47 (s, 3H, CH3), 6.99–7.93 (m, 11H, Ar–H), 10.65 (s, 1H, NH); 13C-NMR (DMSO-d 6): δ 12.2, 19.1, 24.7 (CH3), 120.3, 125.1, 125.3, 125.4, 127.0, 127.1, 127.2, 128.2, 128.4, 134.3, 140.3, 140.4, 143.9, 144.1, 144.2, 145.5, 146.3, 146.4, 170.4 (Ar–C and C=N); MS m/z (%) 579 (M++2, 2), 577 (M+, 5), 548 (7), 378 (14), 333 (11), 271 (100), 211 (20), 181 (20), 153 (18), 118 (16), 104 (66), 94 (36), 77 (52), 69 (36), 57 (37). Anal. Calcd. for C26H21N8ClO2S2 (577.08): C, 54.11; H, 3.67; N, 19.42. Found: C, 54.44; H, 3.35; N, 19.12%.

Synthesis of 2-(1-(5-methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazinecarbothioamide (19)

Amixture of acetyl pyrazole 1 (3.27 g, 10 mmol) and thiosemicarbazide 16 (0.91 g, 10 mmol) in ethanol (20 mL) containing catalytic amounts of concentrated HCl was refluxed in microwave oven at 500 W and 150 °C for 6 min., then left to cool to room temperature. The precipitated product was filtered off, washed with ethanol, and dried. Recrystallization from acetic acid afforded thiosemicarbazone 19 as yellow solid, (78% yield), mp 212–215 °C; IR (KBr) νmax 1596 (C=N), 2926 (C–H), 3157, 3241, 3388 (NH and NH2) cm−1; 1H NMR (DMSO-d 6 ) δ 2.17 (s, 3H, CH3), 2.34 (s, 3H, CH3), 7.10 (t, J = 1.2 Hz, 1H, thiophene-H), 7.23 (d, J = 1.2 Hz, 1H, thiophene-H), 7.56 (d, J = 1.2 Hz, 1H, thiophene-H), 7.86 (d, J = 8.8 Hz, 2H, Ar–H), 8.20 (s, 2H, NH2), 8.38 (d, J = 8.8 Hz, 2H, Ar–H), 10.28 (s, 1H, NH); MS m/z (%) 400 (M+, 8), 322 (21), 284 (30), 211 (18), 176 (24), 150 (26), 130 (25), 112 (29), 105 (71), 97 (40), 83 (45), 69 (63), 57 (62), 43 (100). Anal. Calcd. for C17H16N6O2S2 (400.48): C, 50.98; H, 4.03; N, 20.98. Found: C, 51.30; H, 3.73; N, 20.65%.

2-(2-(1-(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazinyl)-5-(2-phenylhydrazono)thiazol-4(5H)-one (21a)

Orange solid, mp 203–205 °C; IR (KBr) νmax 1600 (C=N), 1680 (C=O), 2932 (C–H), 3211, 3420 (2NH) cm−1; 1H NMR (DMSO-d 6 ) δ 2.24 (s, 3H, CH3), 2.42 (s, 3H, CH3), 7.12–7.92 (m, 12H, Ar–H), 9.82 (s, 1H, NH), 10.27 (s, 1H, NH); 13C-NMR (DMSO-d 6): δ 12.1, 23.2 (CH3), 112.6, 120.9, 125.3, 125.6, 125.9, 127.0, 127.3, 127.8, 128.2, 128.4, 134.3, 140.2, 140.4, 143.1, 144.7, 145.2, 155.5, 160.1 (Ar–C and C=N), 175.4 (C=O); MS m/z (%) 544 (M+, 3), 367 (18), 267 (15), 194 (17), 177 (18), 129 (25), 115 (29), 102 (38), 91 (39), 79 (35), 72 (93), 60 (100), 43 (71). Anal. Calcd. for C25H20N8O3S2 (544.61): C, 55.13; H, 3.70; N, 20.58. Found: C, 55.44; H, 3.40; N, 20.25%.

2-(2-(1-(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazinyl)-5-(2-(p-tolyl)hydrazono)thiazol-4(5H)-one (21b)

Orange solid, mp 201–203 °C; IR (KBr) νmax 1596 (C=N), 1675 (C=O), 2920, 2978 (C–H), 3272, 3419 (2NH) cm−1; 1H NMR (DMSO-d 6 ) δ 2.28 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.48 (s, 3H, CH3), 6.94–8.43 (m, 11H, Ar–H), 10.51 (s, 1H, NH), 10.54 (s, 1H, NH); 13C-NMR (DMSO-d 6): δ 13.5, 14.5, 21.1 (CH3), 112.0, 114.9, 116.3, 117.5, 119.5, 122.2, 125.3, 126.6, 128.0, 129.8, 136.5, 137.4, 138.4, 142.1, 148.2, 151.8, 154.5, 160.1 (Ar–C and C=N), 173.5 (C=O); MS m/z (%) 558 (M+, 2), 536 (11), 457 (61), 423 (12), 396 (27), 284 (44), 212 (45), 187 (51), 158 (22), 145 (36), 115 (57), 95 (41), 65 (100), 51 (28). Anal. Calcd. for C26H22N8O3S2 (558.63): C, 55.90; H, 3.97; N, 20.06. Found: C, 56.20; H, 3.65; N, 19.70%.

2-((1-(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene)hydrazono)-3,5-diphenyl-2,3-dihydro-1,3,4-thiadiazole (23a)

Orange solid, mp 195–197 °C; IR (KBr) νmax 1591 (C=N), 2924, 3105 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.18 (s, 3H, CH3), 2.43 (s, 3H, CH3), 7.09–8.42 (m, 17H, Ar–H); 13C-NMR (DMSO-d 6): δ 12.1, 24.7 (CH3), 113.6, 120.3, 122.1, 125.3, 125.9, 126.0, 127.5, 127.8, 128.2, 128.4, 130.2, 133.5, 134.3, 135.3, 137.3, 140.4, 143.1, 144.4, 145.5, 146.3, 146.4, 159.4 (Ar–C and C=N); MS m/z (%) 577 (M+, 6), 492 (36), 441 (20), 356 (30), 327 (59), 269 (42), 177 (57), 121 (51), 103 (100), 77 (77), 55 (72), 42 (30). Anal. Calcd. for C30H23N7O2S2 (577.68): C, 62.37; H, 4.01; N, 16.97. Found: C, 62.68; H, 3.70; N, 16.62%.

2-((1-(5-Methyl-1-(4-nitrophenyl)-3-(thiophen-2-yl)-1H-pyrazol-4-yl)ethylidene) hydrazono)-3-(4-nitrophenyl)-5-(thiophen-3-yl)-2,3-dihydro-1,3,4-thiadiazole (23b)

Orange solid, mp 209–210 °C; IR (KBr) νmax 1693 (C=N), 2954 (C–H) cm−1; 1H NMR (DMSO-d 6 ) δ 2.18 (s, 3H, CH3), 2.27 (s, 3H, CH3), 7.10–8.42 (m, 14H, Ar–H); MS m/z (%) 628 (M+, 7), 561 (11), 510 (31), 441 (20), 360 (26), 313 (24), 284 (78), 270 (52), 190 (26), 152 (100), 105 (63), 89 (30), 63 (39). Anal. Calcd. for C28H20N8O4S3 (628.70): C, 53.49; H, 3.21; N, 17.82. Found: C, 53.81; H, 2.90; N, 17.51%.

Alternate synthesis of thiazole 18a and 21a

Equimolar amounts of thiosemicarbazone 19 (0.400 g, l mmol) and hydrazonoyl chloride 3a or 3c (1 mmol) in dioxane (15 mL) containing an equivalent amount of triethylamine (0.05 mL) was refluxed in microwave oven at 500 W and 150 °C for 3 min., gave product identical in all respects (mp, mixed mp and IR spectra) with compounds 18a and 21a, respectively.

Biological activity

Anticancer 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 [49].

Conclusion

In our present work, we herein present an efficient regioselective synthesis of novel 4-heteroaryl-pyrazoles, which have not been reported hitherto in a multicomponent synthesis under microwave irradiation. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their synthesis by alternative methods. The in vitro growth inhibitory activity of the synthesized compounds against hepatocellular carcinoma (HepG-2) and human lung cancer (A-549) cell lines were investigated in comparison with Cisplatin reference drug as a standard drug using MTT assay and the results revealed promising activities of six compounds.

Abbreviations

A-549:

human lung cancer

HepG2:

human hepatocellular carcinoma

EtOH:

ethanol

mp:

melting point

TEA:

triethylamine

IR:

infra-red

ATCC:

American type culture collection

TLC:

thin layer chromatography

References

  1. Murata T, Murai M, Ikeda Y, Miki K, Ohe K (2012) Pd- and Cu-catalyzed one-pot multicomponent synthesis of hetero alpha, alpha’-dimers of heterocycles. Org Lett 14:2296–2299

    Article  CAS  Google Scholar 

  2. Lalli C, Bouma MJ, Bonne D, Masson G, Zhu J (2011) Exploiting the divergent reactivity of alpha-isocyanoacetate: multicomponent synthesis of 5-alkoxyoxazoles and related heterocycles. Chemistry 17:880–889

    Article  CAS  Google Scholar 

  3. Zhang S, Zhang WX, Xi Z (2010) Efficient one-pot synthesis of N-containing heterocycles by multicomponent coupling of silicon-tethered diynes, nitriles, and isocyanides through intramolecular cyclization of iminoacyl-Zr intermediates. Chemistry. 16:8419–8426

    Article  CAS  Google Scholar 

  4. Lopez C, Zougagh M, Algarra M, Rodriguez-Castellon E, Campos BB, Esteves da Silva JC, Jimenez-Jimenez J, Rios A (2015) Microwave-assisted synthesis of carbon dots and its potential as analysis of four heterocyclic aromatic amines. Talanta 132:845–850

    Article  CAS  Google Scholar 

  5. Agudelo Mesa LB, Padro JM, Reta M (2013) Analysis of non-polar heterocyclic aromatic amines in beefburguers by using microwave-assisted extraction and dispersive liquid–ionic liquid microextraction. Food Chem 141:1694–1701

    Article  CAS  Google Scholar 

  6. Pawelczyk A, Zaprutko L (2009) Microwave assisted synthesis of unsaturated jasmone heterocyclic analogues as new fragrant substances. Eur J Med Chem 44:3032–3039

    Article  CAS  Google Scholar 

  7. Jeselnik M, Varma RS, Polanc S, Kocevar M (2001) Catalyst-free reactions under solvent-free conditions: microwave-assisted synthesis of heterocyclic hydrazones below the melting points of neat reactants. Chemical Commun 18:1716–1717

    Article  Google Scholar 

  8. Al-Qalaf F, Mandani F, Abdelkhalik MM, Bassam AA (2009) Synthesis of 5-substituted 3-amino-1H-pyrazole-4-carbonitriles as precursors for microwave assisted regiospecific syntheses of pyrazolo[1,5-a]pyrimidines. Molecules 14:78–88

    Article  CAS  Google Scholar 

  9. Ezer M, Yildirim LT, Bayro O, Verspohl EJ, Dundar OB (2012) Synthesis and antidiabetic activity of morpholinothiazolyl-2,4-thiazolidindione derivatives. J Enzyme Inhib Med Chem 27:419–427

    Article  CAS  Google Scholar 

  10. Zhang K, Yan JF, Tang XM, Liu HP, Fan L, Zhou GM, Yang DC (2011) Synthesis of novel beta-aminoalcohols containing nabumetone moiety with potential antidiabetic activity. Yaoxue Xuebao 46:412–421

    CAS  Google Scholar 

  11. Dutt P, Sarkar AK (1993) Alterations in rat intestinal sucrase and alkaline phosphatase activities in alloxan induced experimental diabetes. Indian J Biochem Biophys 30:177–180

    CAS  Google Scholar 

  12. Tarach JS (1978) Electronmicroscopic cytochemical studies on lysosomes and peroxisomes of a rat cardiac muscle in the experimental alloxan diabetes. Acta Histochem 62:32–43

    Article  CAS  Google Scholar 

  13. Ranatunge RR, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Young DV, Zemetseva IS (2004) Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles. Bioorg Med Chem 12:1357–1366

    Article  CAS  Google Scholar 

  14. Sakya SM, Cheng H, Lundy KM, De Mello, Shavnya A, Minich ML, Rast B, Dutra J, Li C, Rafka RJ, Koss DA, Li J, Jaynes BH, Ziegler CB, Mann DW, Petras CF, Seibel SB, Silvia AM, George DM, Hickman A, Haven ML, Lynch MP (2006) 5-Heteroatom-substituted pyrazoles as canine COX-2 inhibitors: part 2. Structureeactivity relationship studies of 5-alkylethers and 5-thioethers. Bioorg Med Chem Lett 16:1202–1206

    Article  CAS  Google Scholar 

  15. Reddy GJ, Pallavi K, Reddy RS, Reddy KS (2005) Synthesis of 1,3-diaryl-4-(pyridine-4-yl)pyrazoles as a new class of pyrazole based diaryl heterocycles. Indian J Chem 44:812–814

    Google Scholar 

  16. Sauzem PD, Sant’Anna GDS, Machado P, Duarte MMMF, Ferreira J, Mello CF, Beck P, Bonacorso HG, Zanatta N, Martins MAP, Rubin MA (2009) Effect of 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles on chronic inflammatory pain model in rats. Eur J Pharmacol 61:91–100

    Article  Google Scholar 

  17. Koca I, Ozgur A, Coskun KA, Tutar Y (2013) Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety. Bioorg Med Chem 21:3859–3865

    Article  CAS  Google Scholar 

  18. Tyagarajan S, Chakravarty PK, Zhou B, Taylor B, Eid R, Fisher MH, Parsons WH, Wyvratt MJ, Lyons KA, Klatt T, Li X, Kumar S, Williams B, Felix J, Priest BT, Brochu RM, Warren V, Smith M, Garcia M, Kaczorowski GJ (2010) Discovery of a novel class of biphenyl pyrazole sodium channel blockers for treatment of neuropathic pain. Bioorg Med Chem Lett 20:7479–7482

    Article  CAS  Google Scholar 

  19. Pattan SR, Rabara PA, Pattan JS, Bukitagar AA, Wakale VS, Musmade DS (2009) Synthesis and evaluation of some novel substituted 1,3,4-oxadiazole and pyrazole derivatives for antitubercular activity. Indian J Chem 48B:1453–1456

    CAS  Google Scholar 

  20. Shih SR, Chu TY, Reddy G, Tseng SN, Chen HL, Tang WF, Wu MS, Yeh JY, Chao YS, Hsu J, Hsieh HP, Horng JT (2010) Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity. J Biomed Sci 17:13

    Article  Google Scholar 

  21. Lo HY, Man CC, Fleck RW, Farrow NA, Ingraham RH, Kukulka A, Proudfoot JR, Betageri R, Kirrane T, Patel U, Sharma R, Hoermann MA, Kabcenell A, Lombaert SD (2010) Substituted pyrazoles as novel sEH antagonist: investigation of key binding interactions within the catalytic domain. Bioorg Med Chem Lett 26:6379–6383

    Article  Google Scholar 

  22. Kasımogullari R, Bulbul M, Arslan BS, Gokçe B (2010) Synthesis, characterization and antiglaucoma activity of some novel pyrazole derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide. Eur J Med Chem 45:4769–4773

    Article  Google Scholar 

  23. Padmaja A, Rajasekhar C, Muralikrishna A, Padmavathi V (2011) Synthesis and antioxidant activity of oxazolyl/thiazolylsulfonylmethyl pyrazoles and isoxazoles. Eur J Med Chem 46:5034–5038

    Article  CAS  Google Scholar 

  24. Xia Y, Dong ZW, Zhao BX, Ge X, Meng N, Shin DS, Miao JY (2007) Synthesis and structure activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives as potential agents against A549 lung cancer cells. Bioorg Med Chem 15:6893–6899

    Article  CAS  Google Scholar 

  25. Daidone G, Maggio B, Raffa D, Plescia S, Schillaci D, Maria V, Raimondi (2004) Synthesis and in vitro antileukemic activity of new 4-triazenopyrazole derivatives. Farmaco 59:413–417

    Article  CAS  Google Scholar 

  26. Farghaly AR (2010) Synthesis of some new indole derivatives containing pyrazoles with potential antitumor activity. ARKIVOC 11:177–187

    Google Scholar 

  27. Soliman EA, El-Zahar MI, El-Masry AH, Kamel M, Gohar RS (2010) Synthesis and anticancer evaluation of novel tetrahydronaphthalen-6-ylthiazole heterocycles against human HePG2 and MCF7 cell lines. Der Pharma Chem. 2:507–521

    CAS  Google Scholar 

  28. El-Zahar MI, EL-Karim SA, Haiba ME, Khedr MA (2011) Synthesis, antitumor activity and molecular docking study of novel benzofuran-2-yl pyrazole pyrimidine derivatives. Acta Pol Pharm Drug Res 68:357–373

    CAS  Google Scholar 

  29. Tanitame A, Oyamada Y, Ofuji K, Terauchi H, Kawasaki M, Wachi M, Yamagishi JI (2005) Synthesis and antibacterial activity of a novel series of DNA gyrase inhibitors: 5-[(E)-2-arylvinyl]pyrazoles. Bioorg Med Chem Lett 15:4299–4303

    Article  CAS  Google Scholar 

  30. Dawood KM, Eldebss TMA, El-Zahabi HSA, Yousef MH, Metz P (2013) Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents. Eur J Med Chem 70:740–749

    Article  CAS  Google Scholar 

  31. Gomha SM, Khali KD, El-Zanate AM, Riyadh SM (2015) A Facile Green Synthesis and anti-cancer activity of bis-arylhydrazononitriles, triazolo[5,1-c][1,2,4]triazine, and 1,3,4-thiadiazoline. Heterocycles 87(5):1109–1120

    Google Scholar 

  32. Gomha SM, Badrey MG, Edrees MM (2016) Heterocyclization of a bis-thiosemicarbazone of 2,5-diacetyl-3,4-disubstituted-thieno[2,3-b]thiophene bis-thiosemicarbazones leading to bis-thiazoles and bis-1,3,4-thiadiazoles as anti-breast cancer agents. J Chem Res 40:120–125

    Article  CAS  Google Scholar 

  33. Gomha SM, Kheder NA, AAbdelhamid AO, Mabkhot YN (2016) One pot single step synthesis and biological evaluation of some novel bis(1,3,4-thiadiazole) derivatives as potential cytotoxic agents. Molecules 21:15321–15328

    Article  Google Scholar 

  34. Gomha SM, Ahmed SA, Abdelhamid AO (2015) Synthesis and cytotoxicity evaluation of some novel thiazoles, thiadiazoles, and pyrido[2,3-d][1, 2, 4]triazolo[4,3-a]pyrimidin-5(1H)-one incorporating triazole moiety. Molecules 20:1357–1376

    Article  Google Scholar 

  35. Gomha SM, Khalil KD (2012) A convenient ultrasound-promoted synthesis and cytotoxic activity of some new thiazole derivatives bearing a coumarin nucleus. Molecules 17:9335–9347

    Article  CAS  Google Scholar 

  36. Gomha SM, Riyadh SM, Mahmmoud EA, Elaasser MM (2015) Synthesis and anticancer activity of arylazothiazoles and 1,3,4-thiadiazoles using chitosan-grafted-poly(4-vinylpyridine) as a novel copolymer basic catalyst. Chem Heterocycl Compd 51:1030–1038

    Article  CAS  Google Scholar 

  37. Gomha SM, Riyadh SM, Abbas IM, Bauomi MA (2013) Synthetic utility of ethylidenethio-semicarbazide: synthesis and and anti-cancer activity of 1,3-thiazines and thiazoles with imidazole moiety. Heterocycles 87:341–356

    Article  CAS  Google Scholar 

  38. Gomha SM, Abdel-aziz HM (2015) Synthesis and antitumor activity of 1,3,4-thiadiazole derivatives bearing coumarine ring. Heterocycles 91:583–592

    Article  CAS  Google Scholar 

  39. Abbas IM, Gomha SM, Elaasser MM, Bauomi MA (2015) Synthesis and biological evaluation of new pyridines containing imidazole moiety as antimicrobial and anticancer agents. Turk J Chem 39:334–346

    Article  CAS  Google Scholar 

  40. Gomha SM, Salah TA, Abdelhamid AO (2015) Synthesis, characterization and pharmacological evaluation of some novel thiadiazoles and thiazoles incorporating pyrazole moiety as potent anticancer agents. Monatsh Chem 146:149–158

    Article  CAS  Google Scholar 

  41. Hassaneen HM, Mousa AH, Abeed NM, Shawali AS (1988) Chemistry of C-Heteroarylhydrazidoyl Halides. Synthesis and reactions of N-(p-Nitrophenyl)-C-(2-thienyl)-formohydrazidoyl Halides. Heterocycles 27:695–706

    Article  CAS  Google Scholar 

  42. Al-Bogam AS, Mekky AEM (2016) Microwave-assisted regioselective synthesis of novel bis (azoles) and bis(azoloazines). J Heterocycl Chem 53:1554–1562

    Article  Google Scholar 

  43. Zaki YH, Sayed AR, Elroby SA (2016) Regioselectivity of 1,3-dipolar cycloadditions and antimicrobial activity of isoxazoline, pyrrolo[3,4-d]isoxazole-4,6-diones, pyrazolo[3,4-d]pyridazines and pyrazolo[1,5-a]pyrimidines. Chem Central J. 10:17(1–13)

    Article  Google Scholar 

  44. Eldebss TMA, Gomha SM, Abdulla MM, Arafa RK (2015) Novel pyrrole derivatives as selective CHK1 inhibitors: design, regioselective synthesis and molecular modeling. Med Chem Commun 6:852–859

    Article  CAS  Google Scholar 

  45. Gaber HM, Bagley MC, Muhammad ZA, Gomha SM (2017) Recent developments in chemical reactivity of N,N-dimethylenamino ketones as synthons for various heterocycles. RSC Adv 7:14562–14610

    Article  CAS  Google Scholar 

  46. Gomha SM, Shawali AS, Abdelhamid AO (2014) Convenient method for synthesis of various fused heterocycles via utility of 4-acetyl-5-methyl-1-phenyl-pyrazole as precursor. Turk J Chem 38:865–879

    Article  Google Scholar 

  47. Gomha SM, Abdelrazek FM, Abdelrahman AH, Metz P (2016) Synthesis of some novel thiazole, thiadiazole and 1,4-phenylene-bis-thiazole derivatives as potent antitumor agents. Heterocycles 92:954–967

    Article  CAS  Google Scholar 

  48. Shawali S, Gomha SM (2000) A new entry for short and regioselective synthesis of [1,2,4]triazolo[4,3-b][1,2,4]-triazin-7(1H)-one. Adv Synth Catal 342:599–604

    CAS  Google Scholar 

  49. Gomha SM, Riyadh SM, Mahmmoud EA, Elasser MM (2015) synthesis and anticancer activities of thiazoles, 1,3-thiazines, and thiazolidine using chitosan-grafted-poly(vinylpyridine) as basic catalyst. Heterocycles 91:1227–1243

    Article  CAS  Google Scholar 

Download references

Authors’ contributions

SMG and YNM designed research; SMG, ZAM, RAMF and MME performed research and analyzed the data. All authors read and approved the final manuscript.

Acknowledgements

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).

Competing interests

The authors declare that they have no competing interests.

Sample availability

Samples of the compounds are available from the authors.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt

    Sobhi M. Gomha & Rasha A. M. Faty

  2. Department of Organic Chemistry, National Organization for Drug Control and Research (NODCAR), Giza, 12311, Egypt

    Mastoura M. Edrees & Zeinab A. Muhammad

  3. Faculty of Science, King Khalid University, Abha, Kingdom of Saudi Arabia

    Mastoura M. Edrees

  4. Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh, 11451, Kingdom of Saudi Arabia

    Yahia N. Mabkhot

Authors
  1. Sobhi M. Gomha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mastoura M. Edrees
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rasha A. M. Faty
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeinab A. Muhammad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yahia N. Mabkhot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sobhi M. Gomha.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gomha, S.M., Edrees, M.M., Faty, R.A.M. et al. Microwave-assisted one pot three-component synthesis of some novel pyrazole scaffolds as potent anticancer agents. Chemistry Central Journal 11, 37 (2017). https://doi.org/10.1186/s13065-017-0266-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13065-017-0266-4

Keywords

BMC Chemistry

ISSN: 2661-801X

Contact us