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. 2021 Mar 2;6(10):7147–7156. doi: 10.1021/acsomega.1c00202

Antiproliferative Activity of Some Newly Synthesized Substituted Pyridine Candidates Using 4-(Aaryl)-6-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile as Synthon

Amira A El-Sayed †, Elsayed A Elsayed ‡,§, Abd El-Galil E Amr ∥,⊥,*
PMCID: PMC7970580  PMID: 33748628

Abstract

graphic file with name ao1c00202_0007.jpg

Herein, we used nicotinonitrile derivatives 4a,b as scaffolds to build novel and active antineoplastic agents. The reaction of nicotinonitrile derivatives 4a,b with POCl3/PCl5 and/or hydrazine hydrate afforded 2-chloropyridones 6a,b and 2-hydrazinyl nicotinonitrile derivatives 11a,b, respectively, as building blocks for various heterocyclic compounds. The structures of all of the synthesized heterocycles were elucidated from their spectral and elemental analyses. The cytotoxic activities of the prepared derivatives were evaluated against different cancer cell lines. Results revealed potential cytotoxic effects of the synthesized compounds against evaluated cell lines, where NCIH 460 and RKOP 27 cell lines were the most affected by the prepared compounds. Derivative 14a was the most effective against all tested cell lines in terms of the obtained IC50 values (25 ± 2.6, 16 ± 2, 127 ± 25, 422 ± 26, and 255 ± 2 nM against NCIH 460, RKOP 27, HeLa, U937, and SKMEL 28 cells, respectively).

1. Introduction

The recent broad importance of nicotinonitriles,1 thiophenes,2 and naphthalenes3 in synthesis of heterocyclic derivatives and their biological activities has encouraged authors to study these moieties to construct novel series of pharmacologically active nicotinonitrile derivatives.

Cancer is one of the most important health concerns worldwide, being the second-most common cause of death after heart diseases in developed countries, with lung, liver, cervical, and breast cancers being the most devastating malignancies. It has been estimated that more than six million new cases are reported each year across the world.4

Pyridine ring is an essential fragment of one of the antitumor and anti-inflammatory mediators.5,6 Moreover, cyanopyridines (nicotinonitriles) have anti-inflammatory,7 analgesic,8 and antihypertensive9 properties, in addition to being an antitumor tool.10 Nicotinonitrile derivatives containing the 2-naphthyl moiety 1a,b showed cytotoxic activity against McF-7 and HEPG2.11 Nicotinonitrile derivatives containing the pyrazole moiety 2a,b also showed a significant cytotoxic activity against hepatocellular and cervical carcinomas.12 Novel fused nicotinonitrile derivatives 3a,b were constructed and evaluated as anticancer agents against NCI-H460, MCF-7, and SF-268 cell lines13 (Figure 1).

Figure 1.

Figure 1

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Cytotoxic activity of compounds against McF-7, HEPG2, HeLa cell, NCI-H460, MCF-7, and SF-268.

From this viewpoint and as a continuation of our previous works,14−18 in heterocyclic synthesis, we have herein synthesized some novel heterocumulenes containing nicotinonitriles, thiophenes, and naphthalenes and examined their antiproliferative activities in comparison to positive controls.

2. Results and Discussion

2.1. Chemistry

In our increasing interest in ethyl cyanoacetate as well as synthesis of pyridones,12 we would like to report a mild, cost-effective procedure for the one-pot multicomponent syntheses of 4-(4-chlorophenyl)-6-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile and 6-(naphthalen-1-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (4a,b) by the condensation of aldehydes, namely, 4-chlorobenzaldehydeor thiophene-2-carboxaldehyde, respectively, 1-(naphthalen-1-yl)ethanone and ethyl cyanoacetate, in the presence of a catalytic amount of ammonium acetate and drops of piperidine at ambient temperature in an ethanol medium (Scheme 1). The structures of nicotinonitriles 4a,b were confirmed by their spectral and elemental analyses. Infrared (IR) spectra exhibited 3142 and 3154 cm–1 for NH; 2219 and 2220 cm–1 for C≡N, and 1649 and 1655 cm–1 for C=O. 1H NMR showed 12.92 and 13.08 for NH, which disappeared with D2O. The 13C NMR spectrum revealed a peak at 161.73 ppm for C=O (compound 4b).

Scheme 1. Syntheses of Nicotinonitrile Derivatives 4a,b.

Scheme 1

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In an attempt to prepare certain novel heterocycles,19−21 determine their insecticidal effectiveness,22−24 and evaluate their pharmaceutical significance,25−28 compounds 4a,b were allowed to react with phenylisothiocyanate to yield 4-(4-chlorophenyl)-3-cyano-6-(naphthalen-1-yl)-2-oxo-N-phenyl-pyridine-1(2H)-carbothioamide and 3-cyano-6-(naphthalen-1-yl)-2-oxo-N-phenyl-4-(thiophen-2-yl)pyridine-1(2H)-carbothioamide (5a,b). Their structures were established from elemental and spectral analyses. Here, the 1H NMR spectrum revealed one peak at 12.92 and 12.83 ppm, respectively, which vanished with D2O corresponding to one NH proton. The 13C NMR spectrum revealed a peak at 162.14 ppm for C=S (compound 5b).

On the other hand, chlorination and thiation of compounds 4a,b afforded nicotinonitrile derivatives 6a,b and 7a,b, respectively. The structures of compounds 6 and 7 were substantiated from their elemental and spectral analyses. The formation of compound 6a,b was evidently expounded by the absence of the stretching band of νC=O in the IR spectrum. Alternatively, the formation of compound 7a,b was evidently expounded by the absence of the stretching band of νC=O and the presence of the strong band at 1233 and 1238 cm–1, respectively, corresponding to νC=S in the IR spectrum. Also, the 1H NMR spectrum revealed one peak at 8.42 and 8.88 ppm, respectively, which vanished with D2O corresponding to one NH proton. The structures of compounds 7a,b were chemically elucidated by the reaction of thiourea with 2-chloropyridine derivatives 6a,b.

It has been reported that pyridines display significant pharmaceutical importance;29 consequently, our efforts were devoted to synthesizing and investigating further innovative pyridine analogues with dual functions: anticancer and antimicrobial. In keeping with this scope, some pyridine-3-carbonitriles, bearing biologically active functionalities, were adopted to be synthesized (Scheme 2).

Scheme 2. Synthetic Routes for Compounds 5–11.

Scheme 2

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The proclivity of 2-chloropyridine derivatives 6a,b toward nitrogen nucleophiles is studied in this work (Scheme 2). Upon reaction of 2-chloropyridine derivatives 6a,b with n-octyl amine as the mononucleophilic reagent, two moles of 2-chloropyridine derivatives were reacted, affording 2,2′-(octylazanediyl)bis(4-(4-chlorophenyl)-6-(naphthalen-1-yl)nicotinonitrile) and 2,2′-(octyl-azanediyl)bis(6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile) (8a,b). The structures of compounds 8a,b were confirmed by their spectral analyses; the IR spectra exhibited no absorption band corresponding to NH, and the acidic NH function did not appear in 1H NMR.

Alternatively, during the reaction of 2-chloropyridine derivatives 6a,b with 1,4 diaminobenzene, two moles of 2-chloropyridine derivatives were consumed, producing bis nicotinonitrile derivatives 9a,b. On the contrary, one mole of 2-chloropyridine derivatives was reacted with ethylene diamine and hydrazine hydrate to give (2-aminoethyl)aminonicotinonitriles 10a,b, and 2-hydrazinyl nicotinonitriles 11a,b, respectively.

2-Hydrazinyl nicotinonitrile derivatives 11a,b were allowed to react with electrophilic reagents such as acetic acid and benzyl acetoacetate, affording the triazolopyridines 12a,b and pyrazolyl nicotinonitriles 13a,b. However, reaction of the hydrazinyl derivatives 11a,b with phenylacetyl chloride afforded the nicotinonitrile derivatives 14a,b instead of the triazolopyridine derivatives 15a,b (Scheme 3).

Scheme 3. Synthetic Routes for Compounds 12–14.

Scheme 3

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2.2. Antiproliferative Activity

The antiproliferative activities of the prepared derivatives were evaluated against different cancer cell lines in comparison with their effect on one normal cell line. Results obtained (Figure 2) showed that all tested derivatives have promising potentials against tested cell lines. Furthermore, it can be seen that different compounds affected different cell lines depending on the cell type. This can be attributed to the fact that cell response to different derivatives depends on the membrane structure and organization as well as the nature of the affecting compound itself.30−33 From the IC50 values calculated, it can also be noticed that NCIH 460 and RKOP 27 cells were the most affected among tested cell lines, where the obtained IC50 values ranged from 25 ± 2.6 to 66 ± 9 and 16 ± 2 to 77 ± 4 nM for NCIH 460 and RKOP 27 cells, respectively.

Figure 2.

Figure 2

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IC50 values obtained for the prepared derivatives against different tested cell lines. (A) U937 and SK-MEL-28 cells; (B) NCIH 460 and RKOP 27 cells; and (C) HeLa and PBMC cells.

On the other hand, other cell lines required higher concentrations of the prepared compounds to be affected (IC50 values: U937 cells ranged from 422 ± 26 to 836 ± 69 nM; SKMEL 28 cells ranged from 255 ± 2 to 774 ± 21 nM; HeLa cells ranged from 127 ± 25 to 277 ± 6 nM). The results for normal PBMC cells showed that cells required high doses to be affected (IC50 values ranged from 121 340 ± 3250 to 186 680 ± 10 690 nM), which indicates that the prepared derivatives are less toxic to normal cells tested. The compound–cancer cell activity patterns showed that compound 14a is the most active against all tested cancer cells, where it recorded the lowest IC50 values obtained (25 ± 2.6, 16 ± 2, 127 ± 25, 422 ± 26, and 255 ± 2 nM for NCIH 460, RKOP 27, HeLa, U937, and SKMEL 28 cells, respectively).

Furthermore, it can also be noticed that compounds 5a, 6a,b, 7a,b, 8b, 9a, 10a, 11b, 12b, 13a,b, 14b, and 15a,b showed variable degrees of moderate antiproliferative potentials against all studied cell lines. Also, it can be seen that their cytotoxic potentials were higher when compared to the corresponding positive controls. However, they recorded much lower IC50 values when tested against normal PBMC cells, reflecting their higher toxicity on normal cells.

Additionally, the results obtained for positive control drugs tested parallel to the prepared compounds revealed that the prepared derivatives are very effective when compared to their corresponding IC50 values obtained on their corresponding positive controls (Table 1).

Table 1. IC50 Values Obtained for Prepared Derivatives against Different Tested Cell Lines.

  IC50 values (nM)
comp. no. U937 SKMEL-28 N CIH 460 RKOP 27 HeLa PBMC
4a 766 ± 19 590 ± 15 66 ± 9 30 ± 1.5 250 ± 19 121 340 ± 3250
4b 836 ± 69 669 ± 9.8 58 ± 6.9 39 ± 9.8 246 ± 69 133 300 ± 5300
5a 1530 ± 255 1155 ± 318 518 ± 56.6 635 ± 45.8 973 ± 185 80 618 ± 2320
5b 980 ± 55 755 ± 18 32 ± 5.5 56 ± 3.2 277 ± 55 144 560 ± 4600
6a 1341 ± 174 1854 ± 321 689 ± 98 512 ± 32 896 ± 115 73 496 ± 3500
6b 2554 ± 374 1369 ± 215 728 ± 88 695 ± 56 795 ± 96 89 640 ± 2940
7a 1634 ± 298 1235 ± 196 764 ± 102 596 ± 96 1015 ± 136 78 369 ± 1636
7b 1569 ± 321 1129 ± 137 638 ± 138 697 ± 72 1369 ± 213 69 970 ± 2050
8a 544 ± 74 774 ± 21 48 ± 7.4 40 ± 2.1 229 ± 74 157 780 ± 7600
8b 1369 ± 284 1259 ± 168 468 ± 69 486 ± 49 1038 ± 326 72 698 ± 1786
9a 1439 ± 258 1532 ± 176 698 ± 76 725 ± 89 1273 ± 239 86 538 ± 1690
9b 559 ± 63 563 ± 35 66 ± 6.3 77 ± 3.5 244 ± 63 168 540 ± 5690
10a 1812 ± 369 1786 ± 236 896 ± 78 596 ± 59 1159 ± 206 72 136 ± 896
10b 642 ± 69 669 ± 26 46 ± 6.9 46 ± 2.6 211 ± 69 179 250 ± 8690
11a 458 ± 72 572 ± 36 44 ± 7.2 55 ± 3.6 255 ± 72 186 680 ± 10 690
11b 1594 ± 215 1296 ± 106 478 ± 96 846 ± 96 1265 ± 227 83 069 ± 1096
12a 581 ± 51 510 ± 41 33 ± 5.1 48 ± 4.1 185 ± 51 174 900 ± 16 900
12b 1468 ± 151 1369 ± 389 648 ± 76 869 ± 87 1435 ± 108 76 806 ± 2030
13a 1692 ± 89 1496 ± 218 765 ± 89 879 ± 68 1273 ± 103 63 607 ± 3050
13b 1758 ± 68 1359 ± 182 869 ± 76 698 ± 79 1359 ± 139 68 617 ± 4610
14a 422 ± 25 255 ± 2 25 ± 2.6 16 ± 2 127 ± 25.5 165 760 ± 18 500
14b 976 ± 125 1360 ± 98 789 ± 69 869 ± 87 1391 ± 110 69 618 ± 3596
15a 1865 ± 159 1585 ± 76 769 ± 86 698 ± 84 1038 ± 68 63 640 ± 2986
15b 1989 ± 235 1369 ± 92 869 ± 79 736 ± 67 1139 ± 89 67 166 ± 2769
doxorubicin 4450 ± 50          
aldelseukin   3450 ± 64        
gemcitabine     2130 ± 50      
capecitabine       4330 ± 64    
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Throughout the present work, a multicomponent reaction approach was used to synthesize compounds 6a,b and 11a,b, which were used as scaffolds for synthesizing novel derivatives.

Our results showed that compound 14a is the most effective against all tested cell lines. This can be attributed to the length of the side chain present in the compound. Furthermore, resonance properties and the 1,3-migration of the hydrogen proton promoted the formation of keto-enol forms, which resulted in forming hydrogen-bonding with the pyridine group.

3. Conclusions

In the present study, we synthesized novel scaffolds, namely, 2-chloro-4-(4-chloro-phenyl)-6-(naphthalen-1-yl)nicotinonitrile (6a), 2-chloro-6-(naphthalen-1-yl)-4-(thiophen-2-yl)-nicotinonitrile (6b), 4-(4-chlorophenyl)-2-hydrazinyl-6-(naphthalen-1-yl)nicotine-nitrile (11a), and 2-hydrazinyl-6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile (11b), by multicomponent reaction systems. From these compounds, sequences of diverse nicotinonitrile products were synthesized, and their structural and spectral data were determined. Antiproliferative screening studies showed that all synthesized compounds exhibited promising potential antiproliferative effects toward the evaluated cell lines. Additionally, large-cell lung and colon cancer cell lines were the most affected. Furthermore, compound 14a showed the highest antiproliferative effects among all tested compounds, where it had IC50 values of 25 ± 2.6, 16 ± 2, 127 ± 25, 422 ± 26, and 255 ± 2 nM against NCIH 460, RKOP 27, HeLa, U937, and SKMEL 28 cells, respectively. Conclusively, the obtained results suggest further investigation to deduce the possible mechanism of action of the synthesized compounds against cancer cell lines.

4. Experimental Section

4.1. Chemistry

All melting points were determined on a Gallenkamp apparatus and are uncorrected. The IR spectra were measured on a Pye-UnicamSP300 instrument in potassium bromide discs. The 1H NMR and 13C NMR spectra were recorded on a Varian Mercury VX (400 MHz) spectrometer (with operating frequencies of 400 MHz for 1H using TMS as an internal standard and 100 MHz for 13C). Chemical shifts (δ) are reported in parts per million (ppm), and coupling constants (J) are reported in hertz (Hz). NMR spectra were recorded at a certain temperature for all compounds and were referenced to the residual signals of DMSO-d6. Mass spectra were run on a MAT Finnigan SSQ 7000 spectrometer, using the electron impact technique (EI). Elemental analyses were carried out at the Micro Analytical Center of Cairo University, Giza, Egypt.

4.1.1. Syntheses of Nicotinonitrile Derivatives 4a,b

A mixture of 1-acetyl naphthalene (2 mL, 0.01 mol) and aldehydes, namely, p-chlorobenzaldehyde and/or 2-thiophencarboxyaldehyde (1.6 gm and/or 1.3 mL, 0.01 mol), ethyl cyanoacetate (1.3 mL, 0.01 mol), ammonium acetate (5.4 gm, 0.07 mol), and drops of piperidine in EtOH (25 mL) was refluxed for 2 h. The precipitate that formed was filtered off, washed with cold water, dried, and recrystallized from ethanol/dioxane to yield the title compounds 4a,b.

4.1.1.1. 4-(4-Chlorophenyl)-6-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (4a)

Yield 88%, mp 184–186 °C. IR, ν, cm–1: 3142 (NH); 2219 (C≡N), 1649 (C=O). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 12.92 (s, 1H, NH, disappeared with D2O), 8.55–7.31 (m, 12H, Ar H). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 166.21, 154.22, 152.33, 136.00, 135.00, 134.01, 132.77, 131.17, 130.67, 130.31, 129.01, 128.82, 128.71, 128.52, 128.22, 127.66, 126.32, 125.21, 124.51, 121.22, 116.32, 107.21 (22C). MS (EI, 70 eV): m/z (%) = 357 (16) [M]+. Anal. calcd. for C22H13ClN2O (356.8): C, 74.06; H, 3.67; N, 7.85. Found C, 74.12; H, 3.72; N, 7.90%.

4.1.1.2. 6-(Naphthalen-1-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (4b)

Yield 81%, pale-yellow, mp 262–264 °C. IR, ν, cm–1: 3154 (NH), 2220 (C≡N), 1655 (C=O). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 13.08 (s, 1H, NH, disappeared with D2O), 8.09–7.57 (m, 11H, Ar H, and thiophene ring). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 161.73, 160.32, 151.24, 134.77, 134.30, 133.59, 132.88, 131.05, 130.59, 130.01, 129.92, 129.34, 128.94, 128.06, 127.67, 127.02, 126.84, 125.82, 125.33, 116.42 (20C). MS (EI, 70 eV): m/z (%) = 328 (32) [M]+. Anal. calcd. for C20H12N2OS (328.39): C, 73.15; H, 3.68; N, 8.53. Found C, 73.20; H, 3.71; N, 8.56%.

4.1.2. Reaction of Compounds 4a,b with Phenyl Isothiocyanates to Afford 5a,b

To a solution of compounds 4a,b (0.5 g, 0.0015 mol) in dimethylformamide (DMF) (7 mL), phenylisothiocyanate (0.2 mL, 0.0015 mol) and drops of trimethyl amine (TEA) were added. The reaction mixture was refluxed for 2 h and cooled at room temperature and then poured on ice/water and extracted by diethyl ether. The precipitated solid products were collected and recrystallized from EtOH to afford compounds 5a,b.

4.1.2.1. 4-(4-Chlorophenyl)-3-cyano-6-(naphthalen-1-yl)-2-oxo-N-phenylpyridine-1(2H)-carbothioamide (5a)

Yield 88%, yellow, mp 180–183 °C. IR, ν, cm–1: 3115 (NH); 2218 (C≡N), 1638 (C=O), 1227 (C=S). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 12.92 (s, 1H, NH, disappeared with D2O), 8.54–7.58 (m, 17H, Ar H). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 167.20, 165.22, 154.32, 138.10, 137.35, 135.62, 135.48, 135.12, 133.60, 133.50, 131.01, 130.76, 129.21, 128.96, 128.00, 127.60, 127.08, 126.22, 125.64, 124.70, 122.25, 116.98, 115.32, 114.50, 104.65 (29C). MS (EI, 70 eV): m/z (%) = 491 (8) [M]+. Anal. calcd. for C29H18ClN3OS (491.09): C, 70.80; H, 3.69; N, 8.54. Found C, 70.82; H, 3.71; N, 8.55%.

4.1.2.2. 3-Cyano-6-(naphthalen-1-yl)-2-oxo-N-phenyl-4-(thiophen-2-yl)pyridine-1(2H)-carbothioamide (5b)

Yield 72%, pale-yellow, mp 238–240 °C. IR, ν, cm–1: 3110 (NH), 2214 (C≡N), 1648 (C=O), 1240 (C=S). 1H NMR spectrum (DMSO-d6, 42 °C), δH, ppm: 12.83 (s, 1H, NH, disappeared with D2O), 8.11–7.28 (m, 16H, Ar H, and thiophene ring). 13C NMR spectrum (DMSO-d6, 42 °C), δC, ppm: 169.12, 166.20, 164.22, 138.10, 137.35, 136.60, 135.62, 135.48, 135.12, 131.01, 130.76, 129.21, 128.96, 128.00, 127.60, 127.50, 127.08, 126.22, 125.64, 124.70, 122.25, 116.98, 115.32, 114.50, 104.65 (27C). MS (EI, 70 eV): m/z (%) = 463 (24) [M]+. Anal. calcd. for C27H17N3OS2 (463.08): C, 69.96; H, 3.70; N, 9.06. Found C, 69.95; H, 3.68; N, 8.99%.

4.1.3. Synthesis of Chloropyridone (6a,b)

A mixture of 4a,b (4.8 g, 0.01 mol) and PCl5 (3 g, 0.03 mol) in POCl3 (5 mL, 0.03 mol) was refluxed for 7 h; then, it was poured on crushed ice. The formed solid was filtered, dried, and crystallized from EtOH to give compounds 6a,b.

4.1.3.1. 2-Chloro-4-(4-chlorophenyl)-6-(naphthalen-1-yl)nicotinonitrile (6a)

Yield 74%, yellow, mp 202–204 °C. IR, ν, cm–1: 2224 (C≡N). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.88–7.56 (m, 12H, Ar H); 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 162.01, 155.23, 152.43, 136.07, 135.26, 134.27, 133.86, 131.29, 131.04, 130.41, 129.56, 129.20, 128.45, 127.76, 126.88, 125.32, 124.62, 120.32, 115.63, 107.17 (22C). MS (EI, 70 eV): m/z (%) = 374 (15) [M]+. Anal. calcd. for C22H12Cl2N2 (374.04): C, 70.42; H, 3.22; N, 7.47. Found C, 70.41; H, 3.20; N, 7.45%.

4.1.3.2. 2-Chloro-6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile (6b)

Yield 73%, pale-yellow, mp > 300 °C. IR, ν, cm–1: 2232 (C≡N); 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.30–7.57 (m, 11H, Ar H, and thiophene ring). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 160.23, 160.01, 150.21, 134.74, 134.52, 133.45, 132.77, 131.25, 130.55, 130.01, 129.81, 129.33, 128.44, 128.07, 127.77, 127.12, 126.88, 125.82, 125.22, 116.22 (20C). MS (EI, 70 eV): m/z (%) = 346 (18) [M]+. Anal. calcd. for C20H11ClN2S (346.03): C, 69.26; H, 3.20; N, 8.08. Found C, 69.25; H, 3.19; N, 8.00%.

4.1.4. Synthesis of 2-Thioxo-pyridine-3-carbonitrile (7a,b)

To a solution of cyanopyridones 4a,b (1 g, 0.003 mol) in dry toluene (20 mL), phosphorus pentasulfide (1 g, 0.004 mol) was added. The reaction mixture was refluxed for 1 h; then, it was filtered off while hot. The solid product was crystallized from EtOH to give compounds 7a,b.

Correspondingly, to a solution of chloropyridones 6a,b (1 g, 0.002 mol) in EtOH (20 mL), thiourea (0.5 g, 0.01 mol) was added. The reaction mixture was refluxed for 4 h; then, it was filtered off while hot. The solid product was crystallized from EtOH to give compounds 7a,b.

4.1.4.1. 4-(4-Chlorophenyl)-6-(naphthalen-1-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (7a)

Yield 52%, pale-yellow, mp 160–162 °C. IR, ν, cm–1: 3122 (NH), 2224 (C≡N), 1233 (C=S). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.42 (s, 1H, NH, disappeared with D2O), 8.16–7.58 (m, 12H, Ar H). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 163.02, 155.22, 152.31, 136.07, 135.22, 134.26, 133.66, 131.28, 131.04, 130.41, 129.44, 129.25, 129.20, 128.99, 128.55, 127.77, 126.76, 125.21, 124.62, 120.22, 115.62, 107.11 (22C). MS (EI, 70 eV): m/z (%) = 373 (25) [M]+. Anal. calcd. for C22H13ClN2S (372.87): C, 70.87; H, 3.51; N, 7.51. Found C, 70.86; H, 3.49; N, 7.50%.

4.1.4.2. 6-(Naphthalen-1-yl)-4-(thiophen-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (7b)

Yield 41%, yellow, mp 144–146 °C. IR, ν, cm–1: 3125 (NH), 2221 (C≡N), 1238 (C=S). 1H NMR spectrum (DMSO-d6, 46 °C), δH, ppm: 8.88 (s, 1H, NH, disappeared with D2O), 8.44–7.33 (m, 11H, Ar H, and thiophene ring). 13C NMR spectrum (DMSO-d6, 46 °C), δC, ppm: 161.94, 153.44, 146.64, 136.15, 135.33, 133.85, 132.56, 131.86, 130.96, 130.46, 129.40, 129.05, 127.72, 126.90, 125.87, 125.37, 122.99, 118.56, 116.29, 104.35 (20C). MS (EI, 70 eV): m/z (%) = 344 (12) [M]+. Anal. calcd. for C20H12N2S2 (344.04): C, 69.74; H, 3.51; N, 8.13. Found C, 69.76; H, 3.53; N, 8.14%.

4.1.5. Reaction of Chloropyridone (6a,b) with Diverse Amines: Syntheses of Compounds 8–11

To a solution of chloropyridones 6a,b (0.5 g, 0.0015 mol) in EtOH (20 mL), amines, namely, n-octyl amine (0.2 mL, 0.0014 mol), p-phenelyenediamine (0.2 g, 0.0018 mol), ethylene diamine (0.1 mL, 0.0014 mol), and/or hydrazine hydrate (0.15 mL, 0.003 mol), were added. The reaction mixture was refluxed for 2 h and cooled at room temperature. The precipitated solid product was collected and recrystallized from EtOH to afford compounds 8–11.

4.1.5.1. 2,2′-(Octylazanediyl)bis(4-(4-chlorophenyl)-6-(naphthalen-1-yl)nicotinonitrile) (8a)

Yield 66%, white, mp 164–166 °C. IR, ν, cm–1: 2222 (C≡N). 1H NMR spectrum (DMSO-d6, 42 °C), δH, ppm: 8.85–7.57 (m, 24H, Ar H), 1.62 (t, 2H, CH2), 1.15–1.22 (m, 12H, 6CH2), 0.78 (t, 3H, CH3). 13C NMR spectrum (DMSO-d6, 42 °C), δC, ppm: 162.02, 155.23, 152.49, 136.11, 135.26, 134.26, 133.88, 131.19, 131.06, 130.42, 129.51, 127.78, 126.91, 125.86, 125.33, 124.71, 115.63, 111.08, 107.15, 85.50, 49.15, 31.65, 29.50, 29.18, 27.34, 27.18, 22.51, 14.40 (52C). MS (EI, 70 eV): m/z (%) = 806 (22) [M]+. Anal. calcd. for C52H41Cl2N5 (806.84): C, 77.41; H, 5.12; N, 8.68. Found C, 77.35; H, 5.10; N, 8.64%.

4.1.5.2. 2,2′-(Octylazanediyl)bis(6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile) (8b)

Yield 60%, white, mp 138–140 °C. IR, ν, cm–1: 2222 (C≡N). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.88–7.33 (m, 22H, Ar H, and thiophene ring), 1.66 (t, 2H, CH2), 1.21–1.24 (m, 12H, 6CH2), 1.03 (t, 3H, CH3). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 160.22, 154.23, 152.44, 136.11, 135.22, 134.22, 133.72, 132.22, 131.21, 130.44, 129.25, 129.19, 127.78, 126.80, 125.66, 125.26, 124.99, 116.71, 110.21, 106.22, 49.10, 31.68, 29.54, 29.20, 27.36, 27.18, 22.52, 14.44 (48C). MS (EI, 70 eV): m/z (%) = 749 (6) [M]+. Anal. calcd. for C48H39N5S2 (749.26): C, 76.87; H, 5.24; N, 8.55. Found C, 76.88; H, 5.25; N, 8.55%.

4.1.5.3. 2,2′-(1,4-Phenylenebis(azanediyl))bis(4-(4-chlorophenyl)-6-(naphthalen-1-yl)nicotine Nitrile) (9a)

Yield 91%, gray, mp 210–212 °C. IR, ν, cm–1: 3222 (NH), 2220 (C≡N). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.89–7.58 (m, 28H, Ar H), 5.70 (s, 2H, NH, disappeared with D2O). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 162.88, 162.08, 161.31, 159.21, 153.44, 148.24, 148.11, 147.21, 132.55, 131.91, 130.99, 129.71, 129.22, 128.88, 127.71, 126.84, 125.81, 125.46, 125.20, 125.00, 122.91, 104.22, 104.01 (50C). MS (EI, 70 eV): m/z (%) = 785 (26) [M]+. Anal. calcd. for C50H30Cl2N6 (785.73): C, 76.43; H, 3.85; N, 10.70. Found C, 76.40; H, 3.80; N, 10.66%.

4.1.5.4. 2,2′-(1,4-Phenylenebis(azanediyl))bis(6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotine Nitrile) (9b)

Yield 93%, gray, mp 138–140 °C. IR, ν, cm–1: 3225 (NH), 2224 (C≡N), 1H NMR spectrum (DMSO-d6, 47 °C), δH, ppm: 8.88–7.15 (m, 26H, Ar H, and thiophene ring), 6.40 (s, 2H, NH, disappeared with D2O); 13C NMR spectrum (DMSO-d6, 47 °C), δC, ppm: 161.92, 161.40, 159.31, 153.87, 153.44, 148.61, 148.22, 147.22, 132.65, 131.85, 130.97, 129.39, 129.05, 128.99, 128.54, 127.71, 126.89, 125.86, 125.36, 122.98, 104.33, 104.25 (46C). MS (EI, 70 eV): m/z (%) = 728 (10) [M]+. Anal. calcd. for C46H28N6S2 (728.18): C, 75.80; H, 3.87; N, 11.53. Found C, 75.82; H, 3.87; N, 11.54%.

4.1.5.5. 2-((2-Aminoethyl)amino)-4-(4-chlorophenyl)-6-(naphthalen-1-yl)nicotinonitrile (10a)

Yield 63%, gray, mp 100–102 °C. IR, ν, cm–1: 3379, 3222 (NH2, NH), 2205 (C≡N). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.83–7.42 (m, 12H, Ar H), 7.73 (s, 2H, NH2, disappeared with D2O), 7.38 (s, H, NH, disappeared with D2O), 3.67 (t, 2H, CH2), 3.15 (t, 2H, CH2). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 161.25, 161.02, 156.21, 136.23, 135.56, 133.88, 133.71, 130.81, 130.61, 129.55, 128.13, 127.53, 127.33, 127.01, 126.71, 126.59, 125.81, 125.30, 116.12, 90.73, 41.40, 37.23 (24C). MS (EI, 70 eV): m/z (%) = 398 (16) [M]+. Anal. calcd. for C24H19ClN4 (398.13): C, 72.27; H, 4.80; N, 14.05. Found C, 72.25; H, 4.79; N, 14.00%.

4.1.5.6. 2-((2-Aminoethyl)amino)-6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile (10b)

Yield 71%, orange, mp 128–131 °C. IR, ν, cm–1: 3374, 3228 (NH2, NH), 2207 (C≡N). 1H NMR spectrum (DMSO-d6, 43 °C), δH, ppm: 8.3–7.55 (m, 11H, Ar H, and thiophene ring), 7.74 (s, 2H, NH2, disappeared with D2O), 7.38 (s, H, NH, disappeared with D2O), 3.57 (t, 2H, CH2), 2.97 (t, 2H, CH2). 13C NMR spectrum (DMSO-d6, 43 °C), δC, ppm: 160.49, 160.05, 156.45, 137.34, 135.56, 133.99, 133.62, 130.80, 130.06, 129.85, 128.97, 128.23, 127.93, 127.19, 126.82, 126.59, 125.86, 125.30, 116.11, 90.82, 41.26, 37.33 (22C). MS (EI, 70 eV): m/z (%) = 370 (15) [M]+. Anal. calcd. for C22H18N4S (370.13): C, 71.33; H, 4.90; N, 15.12. Found C, 71.33; H, 4.91; N, 15.14%.

4.1.5.7. 4-(4-Chlorophenyl)-2-hydrazinyl-6-(naphthalen-1-yl)nicotinonitrile (11a)

Yield 74%, yellow, mp 160–162 °C. IR, ν, cm–1: 3323, 3261, 3183 (NH2, NH), 2220 (C≡N). 1H NMR spectrum (DMSO-d6, 45 °C), δH, ppm: 8.89–7.53 (m, 12H, Ar H), 2.65 (s, 2H, NH2, disappeared with D2O), 2.30 (s, H, NH, disappeared with D2O). 13C NMR spectrum (DMSO-d6, 45 °C), δC, ppm: 162.02, 155.24, 152.47, 136.10, 135.26, 134.27, 133.87, 131.36, 131.06, 130.42, 129.45, 129.32, 129.03, 127.76, 126.91, 125.87, 125.33, 124.72, 115.64, 107.35 (22C). MS (EI, 70 eV): m/z (%) = 370 (35) [M]+. Anal. calcd. for C22H15ClN4 (370.10): C, 71.25; H, 4.08; N, 15.11. Found C, 71.26; H, 4.10; N, 15.13%.

4.1.5.8. 2-Hydrazinyl-6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile (11b)

Yield 82%, dark-yellow, mp 140–142 °C. IR, ν, cm–1: 3315, 3265, 3189 (NH2, NH), 2223 (C≡N). 1H NMR spectrum (DMSO-d6, 48 °C), δH, ppm: 8.87–7.25 (m, 11H, Ar H, and thiophene ring), 2.60 (s, 2H, NH2, disappeared with D2O), 2.25 (s, H, NH, disappeared with D2O). 13C NMR spectrum (DMSO-d6, 48 °C), δC, ppm: 161.94, 158.00, 153.64, 148.25, 138.46, 136.27, 135.33, 133.84, 132.66, 131.90, 129.40, 129.24, 127.72, 126.90, 125.87, 126.00, 116.49, 166.24, 104.36, 101.46 (20C). MS (EI, 70 eV): m/z (%) = 342 (24) [M]+. Anal. calcd. for C20H14N4S (342.09): C, 70.15; H, 4.12; N, 16.36. Found C, 70.17; H, 4.13; N, 16.37%.

4.1.6. Synthesis of [1,2,4]Triazolo[4,3-a]pyridine 8-Carbonitrile (12a,b)

A solution of hydrazides 11a,b (1 g) in EtOH (10 mL) and drops of glacial acetic acid was refluxed for 2 h and cooled at room temperature. The precipitated solid product was collected and recrystallized from EtOH to afford compounds 12a,b.

4.1.6.1. 7-(4-Chlorophenyl)-3-methyl-5-(naphthalen-1-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonitrile (12a)

Yield 62%, yellow, mp 174–176 °C. IR, ν, cm–1: 2220 (C≡N), 1577 (C=N). 1H NMR spectrum (DMSO-d6, 41 °C), δH, ppm: 8.89–7.58 (m, 12H, Ar H), 2.48 (s, 3H, CH3). 13C NMR spectrum (DMSO-d6, 41 °C), δC, ppm: 162.04, 159.49, 155.61, 155.27, 152.94, 152.47, 134.29, 131.50, 131.24, 131.08, 129.52, 129.45, 129.32, 129.03, 127.79, 126.92, 125.88, 125.35, 124.74, 107.14, 106.97, 39.58 (24C). MS (EI, 70 eV): m/z (%) = 394 (42) [M]+. Anal. calcd. for C24H15ClN4 (394.10): C, 73.00; H, 3.83; N, 14.19. Found C, 73.02; H, 3.86; N, 14.20%.

4.1.6.2. 3-Methyl-5-(naphthalen-1-yl)-7-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-8-carbonitrile (12b)

Yield 65%, pale-brown, mp 110–112 °C. IR, ν, cm–1: 2223 (C≡N), 1572 (C=N). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 8.87–7.18 (m, 11H, Ar H, and thiophene ring), 2.45 (s, 3H, CH3). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 165.04, 162.49, 159.49, 155.51, 155.23, 152.84, 152.41, 134.29, 131.32, 131.01, 130.02, 129.55, 129.45, 129.13, 129.03, 128.80, 127.77, 125.71, 125.35, 107.11, 106.96, 39.55 (22C). MS (EI, 70 eV): m/z (%) = 366 (17) [M]+. Anal. calcd. for C22H14N4S (366.09): C, 72.11; H, 3.85; N, 15.29. Found C, 72.09; H, 3.83; N, 15.26%.

4.1.7. Synthesis of 2-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)nicotinonitrile (13a,b)

To a solution of hydrazides 11a,b (0.5 g, 0.001 mol) in EtOH (20 mL), drops of glacial acetic acid and two drops of pipridine as well as benzyl acetoacetate (0.2 mL, 0.001 mol) were added. The reaction mixture was refluxed for 2 h and cooled at room temperature. The precipitated solid product was collected and recrystallized from EtOH to afford compounds 13a,b.

4.1.7.1. 4-(4-Chlorophenyl)-2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-6-(naphthalen-1-yl)nicotinonitrile (13a)

Yield 53%, pale-green, mp 234–236 °C. IR, ν, cm–1: 3152 (NH), 2223 (C≡N), 1671 (C=O). 1H NMR spectrum (DMSO-d6, 44 °C), δH, ppm: 10.25 (s, H, NH, disappeared with D2O), 8.92–7.51 (m, 12H, Ar H), 2.61 (s, 3H, CH3), 1.24 (s, 1H, CH). 13C NMR spectrum (DMSO-d6, 44 °C), δC, ppm: 162.05, 159.50, 155.65, 155.28, 152.94, 152.46, 134.64, 131.33, 131.08, 129.60, 129.46, 129.25, 129.03, 128.74, 128.16, 127.80, 127.47, 126.92, 125.88, 125.36, 124.75, 124.65, 120.35, 40.07 (26C). MS (EI, 70 eV): m/z (%) = 436 (8) [M]+. Anal. calcd. for C26H17ClN4O (436.11): C, 71.48; H, 3.92; N, 12.82. Found C, 71.51; H, 3.95; N, 12.83%.

4.1.7.2. 2-(5-Methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-6-(naphthalen-1-yl)-4-(thiophen-2-yl)nicotinonitrile (13b)

Yield 60%, off-white, mp 141–143 °C. IR, ν, cm–1: 3169 (NH), 2220 (C≡N), 1676 (C=O). 1H NMR spectrum (DMSO-d6, 45 °C), δH, ppm: 10.11 (s, H, NH, disappeared with D2O), 8.88–7.43 (m, 11H, Ar H, and thiophene ring), 2.58 (s, 3H, CH3); 1.26 (s, 1H, CH). 13C NMR spectrum (DMSO-d6, 45 °C), δC, ppm: 163.05, 159.52, 155.55, 155.21, 152.92, 152.46, 134.64, 131.23, 131.08, 129.61, 129.41, 129.15, 129.03, 128.77, 128.11, 127.70, 127.47, 126.42, 125.81, 125.36, 124.75, 124.61, 120.31, 40.05 (24C). MS (EI, 70 eV): m/z (%) = 408 (18) [M]+. Anal. calcd. for C24H16N4OS (408.10): C, 70.57; H, 3.95; N, 13.72. Found C, 70.60; H, 3.98; N, 13.76%.

4.1.8. Synthesis of 3-Cyano-pyridin-2-yl-2-phenylacetohydrazide (14a,b)

To a solution of hydrazides (11a,b) (0.5 g, 0.001 mol) in dry pyridine (10 mL), phenylacetyl chloride (0.2 mL, 0.001 mol) was added. The reaction mixture was stirred for half an hour in an ice bath. Then, the reaction mixture was poured on ice/water and acidified by conc. HCl. The precipitated solid product was collected and recrystallized from EtOH to afford compounds 14a,b.

4.1.8.1. N′-(4-(4-Chlorophenyl)-3-cyano-6-(naphthalen-1-yl)pyridin-2-yl)-2-phenylaceto-hydrazide (14a)

Yield 33%, yellow, mp 182–184 °C. IR, ν, cm–1: 3199 (NH), 2222 (C≡N), 1670 (C=O). 1H NMR spectrum (DMSO-d6, 40 °C), δH, ppm: 10.07 (s, 2H, NH, disappeared with D2O), 8.89–7.58 (m, 17H, Ar H), 3.49 (s, 2H, CH2). 13C NMR spectrum (DMSO-d6, 40 °C), δC, ppm: 169.45, 162.05, 159.50, 155.65, 155.28, 152.95, 152.47, 134.29, 131.31, 131.08, 129.52, 129.46, 129.32, 129.03, 128.15, 127.80, 126.92, 126.80, 125.88, 125.34, 124.73, 107.19, 106.96, 85.60, 34.86, 40.04 (30C). MS (EI, 70 eV): m/z (%) = 488 (26) [M]+. Anal. calcd. for C30H21ClN4O (488.14): C, 73.69; H, 4.33; N, 11.46. Found C, 73.65; H, 4.29; N, 11.43%.

4.1.8.2. N′-(3-Cyano-6-(naphthalen-1-yl)-4-(thiophen-2-yl)pyridin-2-yl)-2-phenylacetohydrazide (14b)

Yield 41%, white, mp 178–180 °C. IR, ν, cm–1: 3198 (NH), 2224 (C≡N), 1679 (C=O). 1H NMR spectrum (DMSO-d6, 25 °C), δH, ppm: 10.00 (s, 2H, NH, disappeared with D2O), 8.12–7.18 (m, 16H, Ar H, and thiophene ring), 3.39 (s, 2H, CH2). 13C NMR spectrum (DMSO-d6, 25 °C), δC, ppm: 169.55, 161.99, 159.41, 155.61, 155.21, 152.99, 152.44, 134.21, 132.22, 132.11, 131.52, 129.66, 129.32, 128.88, 127.81, 126.80, 126.71, 125.61, 125.42, 107.19, 106.11, 86.04, 36.32, 40.01 (28C). MS (EI, 70 eV): m/z (%) = 460 (15) [M]+. Anal. calcd. for C28H20N4OS (460.14): C, 73.02; H, 4.38; N, 12.17. Found C, 73.10; H, 4.41; N, 12.19%.

4.2. Screening of Antiproliferative Activities

The newly prepared derivatives were screened for their potential antiproliferative activities against a battery of cancer cell lines, including leukemia (U937), melanoma (SKMEL-28), and large-cell lung (NCIH 460), colon (RKOP 27), and cervical (HeLa) cancer cell lines. Additionally, normal primary peripheral blood mononuclear (PBMC) cells were used as normal cells to assess the toxicity of the prepared derivatives against normal cells. The screening depended mainly on a standard MTT assay.30,31 Cancer cells were obtained from ATCC culture collection, while PBMC cells were isolated from whole blood. The whole blood was diluted with phosphate-buffered saline (PBS) and then gently layered over an equal volume of Ficoll in a Falcon tube and centrifuged for 30–40 min at 400–500 g without a break. This resulted in the formation of four layers, each containing different cell types—the uppermost layer contained plasma, which can be removed by pipetting.

Briefly, cells were seeded in 96-well culture plates using an RPMI 1640 medium at a final concentration of 20 000 cells/mL and incubated at standard incubation conditions for 24 h until cells adhered. Afterward, different serial dilutions of the synthesized compounds (0–1 μM/DMSO) were added to each well plate, and the plates were further incubated for 72 h. Accordingly, 20 μL (MTT, 5 mg/(mL PBS)) was pipetted and further incubation was allowed for 4 h. The medium was washed out and DMSO (100 μL/well) was added. The developed formazan color was read with the help of a microplate reader at 570 nm.32,33 IC50 values were calculated from the linear regression of the dose–response curve obtained using Origin 6.1 software (OriginLab Corporation, Northampton, MA). All experiments were run three times, and data are shown as mean ± standard deviation (SD). Doxorubicin, aldelseukin, gemcitabine, capecitabine, and fluorouracil were used as positive controls for comparison. Control compounds were prepared and diluted as the prepared derivatives.

Acknowledgments

The authors are grateful to the Deanship of Scientific Research, King Saud University, for funding this work through Research Group Project “RGP-1435-047”.

Author Contributions

The listed authors contributed to this work as follows: A.A.E.-S. developed the concept of the work, interoperated the results and the experimental part, and prepared the manuscript; A.E.-G.E.A. and E.A.E. helped in the preparation of the manuscript and performed the revision before submission; and E.A.E. performed the anticancer studies and received financial support for the work. All authors read and approved the final manuscript.

The authors declare no competing financial interest.

References

  1. Asokan C. V.; Anabha E. R.; Thomas A. D.; Jose A. M.; Lethesh K. C.; Prasanth M.; Krishanraj K. U. A facile method for the synthesis of nicotinonitriles from ketones via a one-pot chloromethyleneiminium salt mediated three-component reaction. Tetrahedron Lett. 2007, 48, 5641–5643. 10.1016/j.tetlet.2007.06.032. [DOI] [Google Scholar]
  2. Mirsha R.; Jha K. K.; Kumar S.; Tomer I. Synthesis, properties and biological activity of thiophene. Pharma Chem. 2011, 3, 38–54. [Google Scholar]
  3. Medarde M.; Maya A. B. S.; Pe′Rez-Melero C. N. Naphthalene Combretastatin Analogues: Synthesis, Cytotoxicity and Antitubulin Activity. J. Enzyme Inhib. Med. Chem. 2004, 19, 521–540. 10.1080/14756360412331280473. [DOI] [PubMed] [Google Scholar]
  4. Ojiva I.; Vite G. D.; Altmann K. H.. Anticancer Agents; American Chemical Society: Washington, 2001. [Google Scholar]
  5. Son J. K.; Zhao L. X.; Basnet A.; Thapa P.; Karki R. Y.; Jahng Y.; Jeong T. C.; Jeong B. S.; Lee C. S.; Lee E. S. Synthesis of 2,6-diaryl-substituted pyridines and their antitumor activities. Eur. J. Med. Chem. 2008, 43, 675–682. 10.1016/j.ejmech.2007.05.002. [DOI] [PubMed] [Google Scholar]
  6. Amr A.-G. E.; Abdulla M. M. Anti-inflammatory profile of some synthesized heterocyclic pyridone and pyridine derivatives fused with steroidal structure. Bioorg. Med. Chem. 2006, 14, 4341–4352. 10.1016/j.bmc.2006.02.045. [DOI] [PubMed] [Google Scholar]
  7. Murata T.; Shimada M.; Sakakibara S.; Yoshino T.; Masuda T.; Shintani T.; Sato H.; Koriyama Y.; Fukushima K.; Nunami N.; Yamauchi M.; Fuchikami K.; Komura H.; Watanabe A.; Ziegelbauer K. B.; Bacon K. B.; Lowinger T. B. Synthesis and structure–activity relationships of novel IKK-b inhibitors. Part 3: Orally active anti-inflammatory agents. Bioorg. Med. Chem. Lett. 2004, 14, 4019–4022. 10.1016/j.bmcl.2004.05.041. [DOI] [PubMed] [Google Scholar]
  8. Manna F.; Chimenti F.; Bolasco A.; Bizzarri B.; Filippelli W.; Filippelli A.; Gagliardi L. Anti-inflammatory, analgesic and antipyretic 4,6-disubstituted 3-cyano-2-aminopyridines. Eur. J. Med. Chem. 1999, 34, 245–254. 10.1016/S0223-5234(99)80057-9. [DOI] [Google Scholar]
  9. Baldwin J. J.; Engelhardt E. L.; Hirschmann R.; Ponticello G. S.; Atkinson J. G.; Wasson B. K.; Sweet C. S.; Scriabine A. Heterocyclic Analogues of the Antihypertensive P-Adrenergic Blocking Agent (S)-2-[3-(tert-Butylamino)-2hydroxypropoxy]-3-cyanopyridine. J. Med. Chem. 1980, 23, 65–70. 10.1021/jm00175a012. [DOI] [PubMed] [Google Scholar]
  10. Lu Z.; Ott G. R.; Anand R.; Liu R.-Q.; Covington M. B.; Vaddi K.; Qian M.; Newton R. C.; Christ D. D.; Trzaskos J.; Duan J. J.-W. Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-a converting enzyme (TACE): Discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1′ substituents. Bioorg. Med. Chem. Lett. 2008, 18, 1958–1962. 10.1016/j.bmcl.2008.01.120. [DOI] [PubMed] [Google Scholar]
  11. Kotb E. R.; El-Hashash M. A.; Salama M. A.; Kalf H. S.; Abdel Wahed N. A. M. Synthesis and Reactions of Some Novel Nicotinonitrile Derivatives for Anticancer and Antimicrobial Evaluation. Acta Chim. Slov. 2009, 56, 908–919. [Google Scholar]
  12. El-Sayed A. A.; Amr A. E.; El-Ziaty A. K.; El-Sayed E. A. Cytotoxic Effects of Newly Synthesized Heterocyclic Candidates Containing Nicotinonitrile and Pyrazole Moieties on Hepatocellular and Cervical Carcinomas. Molecules 2019, 24, 1965–1974. 10.3390/molecules24101965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fekry R. M.; El-Sayed H. A.; Assy M. G.; Shalby A.; Mohamed A. S. Synthesis and anticancer activity of some novel fused nicotinonitrile derivatives. Org. Chem.: Curr. Res. 2016, 5, 4 10.4172/2161-0401.1000171. [DOI] [Google Scholar]
  14. Al-Harbi N. O.; Bahashwan S. A.; Fayed A. A.; Aboonq M. S.; Amr A. E. Anti-parkinsonism, hypoglycemic and anti-microbial activities of new poly fused ring heterocyclic candidates. Int. J. Biol. Macromol. 2013, 57, 165–173. 10.1016/j.ijbiomac.2013.03.019. [DOI] [PubMed] [Google Scholar]
  15. Ghozlan S. A. S.; Al-Omar M. A.; Amr A. E.; Ali K. A.; El-Wahab A. A. A. Synthesis and antimicrobial activity of some heterocyclic 2,6-bis(substituted)-1,3,4-thiadiazolo-, oxadiazolo-, and oxathiazolidino- pyridine derivatives from 2,6-pyridine dicarboxylic acid dihydrazide. J. Heterocycl. Chem. 2011, 48, 1103–1110. 10.1002/jhet.690. [DOI] [Google Scholar]
  16. Mohamed S. F.; Youssef M. M.; Amr A. E.; Kotb E. R. Antimicrobial activities of some synthesized pyridines, oxazines and thiazoles from 3-aryl-1-(2-naphthyl)prop-2-en-1-ones. Sci. Pharm. 2008, 76, 279–303. 10.3797/scipharm.0804-09. [DOI] [Google Scholar]
  17. Khalifa N. M.; Al-Omar M. A.; Amr A. E.; Baiuomy A. R.; Abdel-Rahman R. F. Synthesis and biological evaluation of some novel fused thiazolo[3,2-a]pyrimidines as potential analgesic and anti-inflammatory agents. Russ. J. Bioorg. Chem. 2015, 41, 192–200. 10.1134/S1068162015020090. [DOI] [PubMed] [Google Scholar]
  18. Hossan A. S. M.; Abu-Melha H. M. A.; Al-Omar M. A.; Amr A. E. Synthesis and antimicrobial activity of some new pyrimidinone and oxazinone derivatives fused with thiophene rings using 2-chloro-6-ethoxy-4-acetylpyridine as starting material. Molecules 2012, 17, 13642–13655. 10.3390/molecules171113642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mahmoud M. R.; El-Ziaty A. K.; Hussein A. M. Synthesis and spectral characterization of novel thiazolopyridine and pyrimidine derivatives. Synth. Commun. 2013, 43, 961–978. 10.1080/00397911.2011.615445. [DOI] [Google Scholar]
  20. Hemdan M. M.; El-Sayed A. A. Synthesis of some new heterocycles derived from novel 2-(1,3-dioxisoindolin-2-yl)benzoyl isothiocyanate. J. Heterocycl. Chem. 2016, 53, 487–492. 10.1002/jhet.2287. [DOI] [Google Scholar]
  21. Hemdan M. M.; Fahmy A. F. M.; El-Sayed A. A. Microwave-assisted synthesis of phthalimides, phthalazinesand quinazolines. ChemXpress 2015, 8, 31–36. [Google Scholar]
  22. Hassan H.; Salama A.; El-Ziaty A. K.; El-Sakhawy M. New chitosan/silica/zinc oxide nanocomposite as adsorbent for dye removal. Int. J. Biol. Macromol. 2019, 131, 520–526. 10.1016/j.ijbiomac.2019.03.087. [DOI] [PubMed] [Google Scholar]
  23. Elshahawi M. M.; EL-Ziaty A. K.; Morsy J. M.; Aly A. F. Synthesis and Insecticidal Efficacy of Novel Bis Quinazolinone Derivatives. J. Heterocycl. Chem. 2016, 53, 1443–1448. 10.1002/jhet.2445. [DOI] [Google Scholar]
  24. El-Naggar A. M.; Eissa I. H.; Belal A.; El-Sayed A. A. Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5 (4 H)-ones as potential tubulin polymerization inhibitors targeting the colchicine. RSC Adv. 2020, 10, 2791–2811. 10.1039/C9RA10094F. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hemdan M. M.; El-Sayed A. A. Use of phthalimidoacetyl isothiocyanate as a scffold in synthesis of target heterocyclic systems with their antimicrobial assessment. Chem. Pharm. Bull. 2016, 64, 483–489. 10.1248/cpb.c16-00099. [DOI] [PubMed] [Google Scholar]
  26. Rizk S. A.; El-Sayed A. A.; Mounier M. M. Synthesis of Novel Pyrazole Derivatives as Antineoplastic Agent. J. Heterocycl. Chem. 2017, 54, 3358–3371. 10.1002/jhet.2956. [DOI] [Google Scholar]
  27. Shiba S. A.; El-Ziaty A. K.; El-Aasar N. K.; Al-Saman H. A. Uses of piperonal in the synthesis of novel prop-2-enoyl amides, esters, heterocyclic systems and study of their antibacterial activities. J. Chem. Res. 2008, 2008, 500–506. 10.3184/030823408X340834. [DOI] [Google Scholar]
  28. El-Sayed N. S.; Shiraz A. N.; El-Meligy M. G.; El-Ziaty A. K.; Nagib Z.; A. Parang K. Synthesis, characterization, and in vitro cytotoxicity of fatty acyl-CGKRK-chitosanoligo saccharides conjugates for siRNA delivery. Int. J. Biol. Macromol. 2019, 112, 496–702. 10.1016/j.ijbiomac.2018.01.213. [DOI] [PubMed] [Google Scholar]
  29. Chaubey A.; Pandeya S. N. Pyridine a versatile nucleuse in pharmaceutical field. Asian J. Pharm. Clin. Res. 2011, 4, 5–8. [Google Scholar]
  30. Elsayed E. A.; Sharaf-Eldin M. A.; Wadaan M. In vitro evaluation of cytotoxic activities of essential oil from Moringa oleifera seeds on HeLa, HepG2, MCF-7, CACO-2 and L929 cell lines. Asian Pac. J. Cancer Prev. 2015, 16, 4671–4675. 10.7314/APJCP.2015.16.11.4671. [DOI] [PubMed] [Google Scholar]
  31. Elsayed E. A.; Farooq M.; Dailin D.; El-Enshasy H. A.; Othman N. Z.; Malek R.; Danial E.; Wadaan M. In Vitro and In Vivo biological screening of kefiran polysaccharide produced by lactobacillus kefiranofaciens. Biomed. Res. 2017, 28, 594–600. [Google Scholar]
  32. Amr A. E.-G. E.; El-Naggar M.; Al-Omar M. A.; Elsayed E. A.; Abdalla M. M. In vitro and in vivo anti-breast cancer activities of some synthesized pyrazolinyl-estran-17-one candidates. Molecules 2018, 23, 1572 10.3390/molecules23071572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Elsayed E. A.; Sharaf-Eldin M. A.; El-Enshasy H. A.; Wadaan M. In vitro assessment of anticancer properties of Moringa peregrina essential seed oil on different cell lines. Pak. J. Zool. 2016, 48, 853–859. [Google Scholar]

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