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Synthesis and Antitumor Activity of Some Novel Thiophene, Pyrimidine, Coumarin, Pyrazole and Pyridine Derivatives

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Synthesis and Antitumor Activity of Some Novel Thiophene, Pyrimidine, Coumarin, Pyrazole and Pyridine Derivatives Acta Pharm. 67 (2017) 15–33 Original research paper DOI: 10.1515/acph-2017-0004 Synthesis and antitumor activity of some novel thiophene, pyrimidine, coumarin, pyrazole and pyridine derivatives MOHAMMED ALBRATTY1 2-Cyano-N-(thiazol-2-yl) acetamide (2a) and 2-cyano-N-(oxazol- 1,2 KARAM AHMED EL-SHARKAWY * 2-yl) acetamide (2b) were obtained via the reaction of ethyl cya- SHAMSHER ALAM1 noacetate with either 2-aminothiazole (1a) or 2-aminooxazole 1 Department of Pharmaceutical (1b). The formed products were directed toward the reaction Chemistry, College of Pharmacy with cyclopentanone and elemental sulfur in the presence of Jazan University, P.O. Box 114 triethylamine to give cyclopenta[b]thiophene derivatives (3a,b). Jazan 45142, Saudi Arabia The latter products were reacted with either ethyl cyanoacetate or malononitrile to form compounds 4a,b and 5a,b, respectively. 2 Department of Organic Chemistry Compounds 4a,b were aimed at synthesizing some heterocyclic Faculty of Biotechnology compounds; thus internal cyclization reactions were intro- October University for Modern duced to form compounds 6a,b. Also, compounds 4a,b reacted Sciences and Arts (MSA) with salicylaldehyde, hydrazine derivatives and either urea or El-Wahat Road thiourea to produce coumarin derivatives (7a,b), pyrazole de- 6 October City, Egypt rivatives (8a-d) and pyrimidine derivatives (9a-d), respectively. Reaction of either benzaldehyde or benzene diazonium chlo- ride (11) with compounds 4a,b afforded compounds 10a,b and 12a,b, respectively. On the other hand, compounds 5a,b under- went internal cyclization to form pyrimidine derivatives 13a,b. Also, when compounds 5a,b reacted with either ethyl cyanoac- etate or malononitrile, they gave pyridine derivatives (15a-d) through the formation of intermediates (14a-d). Finally, forma- tion of fused pyrimidine derivatives (17a,b) was achieved through the reaction of compounds 5a,b and salicylaldehyde applying two different pathways. The first pathway used a cata- lytic amount of piperidine to form compounds 16a,b; the latter products underwent cyclization to give compounds 17a,b. The second pathway, using a catalytic amount of sodium ethoxide solution directly in one step, afforded compounds 17a,b. Struc- tures of the newly synthesized compounds were established 1 13 using IR, H NMR, C NMR and mass spectrometry and their antitumor activity was investigated. Some of these compounds showed promising inhibitory effects on three different cell lines. However, fused pyrimidine acetonitrile derivatives 6a and 6b exerted the highest inhibitory effect, comparable to that of doxorubicin. Accepted September 17, 2016 Keywords: thiophene, pyrimidine, coumarin, pyrazole, pyri- Published online September 26, 2016 dine, antitumor activity * Correspondence; e-mail: [email protected] 15 M. Albratty et al.: Synthesis and antitumor activity of some novel thiophene, pyrimidine, coumarin, pyrazole and pyridine deriva- tives, Acta Pharm. 67 (2017) 15–33. Amino-thiophene derivatives were shown to be one of the most important groups of heterocyclic compounds with a wide spectrum of biological activities such as antitumor (1), antimitotic (2) and antiviral (3), in addition to either thiazol-amide with fungicidal ac- tivity (4) or oxazole-amide with antimicrobial activity (5). Furthermore, thieno[2,3-d]pyri- midine derivatives show antibacterial (6) and antiproliferative activity (7). Also, chromene- -3-carboxamide acts as an anti-Helicobacter pylori agent (8) and pyrazole derivatives have a specific effect with favorable antitumor activity (9). In addition, pyridine derivatives show anticonvulsant and anti-inflammatory (10), potential antitubercular (11) and anticonvul- sant activity (12), among others. In this article, we have described the synthesis of new heterocyclic compounds, thio- phene, pyrimidine, coumarin, pyrazole and pyridine derivatives, in an attempt to improve the antitumor activity against three different cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer). EXPERIMENTAL Melting points were determined in open capillaries and are not corrected. A Yanaco CHN CORDER MT-6 elemental analyzer (Japan) was used. IR spectra were recorded in KBr pellets using a PA-9721 IR spectrophotometer (Shimadzu, Japan). A Jeol 300 MHz 1 13 (Japan) instrument was used to record the H NMR and C NMR spectra. CD3SOCD3 was used as a solvent and TMS as internal standard. Chemical shifts were expressed asδ (ppm). Kratos (75 eV) MS equipment (Germany) was used for mass spectra recording. The synthetic pathways used are represented in Schemes 1–4 while the physicochem- ical and spectral data of the newly synthesized compounds are given in Tables I and II. Syntheses 2-Cyano-N-(thiazol-2-yl)acetamide (2a) and 2-cyano-N-(oxazol-2-yl)acetamide (2b). – To a solution of either 2-aminothiazole (1a) (5.007 g, 0.05 mol) or 2-aminooxazole (1b) (4.204 g, 0.05 mol) in 50 mL of absolute ethanol containing triethylamine (0.5 mL) as a catalyst, H O H2N N N X X TEA N + O N EtOH O N a X = S 1a,b O 2a,b b X = O TEA, S8, EtOH H2N O N O N S NH2 N NH S N S N N H O H N X H TEA, dioxane N N X TEA, dioxane X O N O N O N 5a,b 3a,b 4a,b Scheme 1 16 M. Albratty et al.: Synthesis and antitumor activity of some novel thiophene, pyrimidine, coumarin, pyrazole and pyridine deriva- tives, Acta Pharm. 67 (2017) 15–33. ethyl cyanoacetate (5.656 g, 0.05 mol) was added and the reaction mixture was heated under reflux for 3 h, cooled and poured onto ice. Conc. HCl (a few drops) was added. The formed precipitate was filtered out and recrystallized from 1,4 dioxane to afford the de- sired product. 2-Amino-N-(thiazol-2-yl)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide (3a) and 2-amino-N-(oxazol-2-yl)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxamide (3b). – To a so- lution of either compound 2a (5.016 g, 0.03 mol) or 2b (4.534 g, 0.03 mol) in 50 mL of absolute EtOH containing triethylamine (1.0 mL), cyclopentanone (2.524g, 0.03 mol) and elemental sulfur (0.96 g, 0.03 mol) were added. The whole reaction mixture was heated under reflux for 2 h, then poured into an ice/water mixture containing a few drops of concentrated hydrochloric acid and the formed solid product, in each case, was collected by filtration and recrystallized from absolute ethanol. S N N N X O N 6a,b a X = S b X = O NaOEt reflux Y N NH2 N O O O N CHO O Y S NH S NH S NH H2N NH2 OH H H NaOEt NH piperidine N reflux dioxane N X O X O X O N 4a,b N 7a,b N 9a-d a X = S a X = S a X = S, Y = O b X = O b X = O b X = O, Y = O piperidine c X = S, Y = S RNHNH2 etanol d X = O, Y = S H2N R N S N NH NH O X N 8a-d a X = S, R = H b X = O, R = H c X = S, R = Ph d X = O, R = Ph Scheme 2 17 M. Albratty et al.: Synthesis and antitumor activity of some novel thiophene, pyrimidine, coumarin, pyrazole and pyridine deriva- tives, Acta Pharm. 67 (2017) 15–33. NH N N O O O S CHO + N N - NH N S NH Ph N Cl S NH 11 H H NaOH NH piperidine N EtOH, 0-5 oC EtOH N X O X O X O N N 10a,b N 12a,b 4a,b N H2N N HN X a X = S N S NaOEt b X = O N N H N X S N O N 13a,b 5a,b Scheme 3 N O N X O N N CHO O H X H2N N N X H N S NH N Y H OH S N S N piperidine H NaOEt S N N N NH2 dioxane X N H2N Y NH O N H2N 2 5a,b CN O O a, X = S Y 16a,b b, X = O 14a-d 15a-d a, X = S CHO a, X = S, Y = CN a, X = S, Y = NH b, 2 X = O NaOEt b, X = O, Y = CN b, X = O, Y = NH2 DMF c, X = S, Y = COOEt c, X = S, Y = OH d, X = O, Y = COOEt d, X = O, Y = OH OH O N S N O HN X N 17a,b a, X = S b, X = O Scheme 4 2-(2-Cyanoacetamido)-N-(thiazol-2-yl)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbox- amide (4a) and 2-(2-cyanoacetamido)-N-(oxazol-2-yl)-5,6-dihydro-4H-cyclopenta[b]thiophene-3- carboxamide (4b). – To a solution of either compound 3a (5.307 g, 0.02 mol) or 3b (4.986 g, 0.02 mol) in 1,4-dioxane (50 mL) containing triethylamine (0.5 mL), ethyl cyanoacetate (2.262 g, 0.02 mol) was added. The resulting reaction mixture was heated under reflux for 3 h, cooled and poured into an ice/water mixture with a few drops of conc. HCl added. The precipitate that formed was filtered and recrystallized from absolute ethanol. 18 M. Albratty et al.: Synthesis and antitumor activity of some novel thiophene, pyrimidine, coumarin, pyrazole and pyridine deriva- tives, Acta Pharm. 67 (2017) 15–33. Table I. Physicochemical data for synthesized compounds Compd. Mol. formula M. p. Yield Calcd./found (%) (Mr) (°C) (%) C H N S C H N OS 43.10 3.01 25.13 19.18 2a 6 5 3 229–231 74 167.19 43.32 3.23 24.98 18.96 C H N O 47.69 3.33 27.81 2b 6 5 3 2 201–202 70.5 – 151.12 47.85 3.11 27.56 C H N OS 49.79 4.18 15.84 24.17 3a 11 11 3 2 169–171 81 265.35 49.55 4.02 15.99 24.39 C H N O S 53.00 4.45 16.86 12.86 3b 11 11 3 2 209–211 77 249.29 53.25 4.22 16.57 12.70 C H N O S 50.59 3.64 16.86 19.29 4a 14 12 4 2 2 242–244 66 332.4 50.40 3.44 16.63 19.13 C H N O S 53.16 3.82 17.71 10.14 4b 14 12 4 3 186–188 71 316.34 53.41 3.59 17.50 9.88 C H N OS 50.74 3.95 21.13 19.35 5a 14 13 5 2 195–196 73 331.42 50.96 3.66 21.35 19.17 C H N O S 53.32 4.16 22.21 10.17 5b 14 13 5 2 158–160 61 315.35 53.15 3.97 22.49 10.47 C H N OS 53.49 3.21 17.82 20.40 6a 14 10 4 2 211–213 76 314.39 53.77 3.45 17.55 20.16 C H N O S 56.37 3.38 18.78 10.75 6b 14 10 4 2 227–229 71 298.32 56.58 3.52 18.99 10.46 C H N O S 57.65 3.46 9.60 14.66 7a 21 15 3 4 2 171–173 65 437.49 57.95 3.19 9.83 14.91 C H N O S 59.85 3.59 9.97 7.61 7b 21 15 3 5 150–151 61 421.43 60.12 3.35 9.73 7.91 C H N OS 48.54 4.07 24.26 18.51 8a 14 14 6 2 123–125 62 346.43 48.75 3.85 24.02 18.23 C H N O S 50.90 4.27 25.44 9.71 8b 14 14 6 2 155–157 58 330.36 51.13 4.49 25.67 9.45 C H N OS 56.58 4.29 19.89 15.18 8c 20 18 6 2 178–180 55 422.53 56.29 4.04 19.65 15.34 C H N O S 59.10 4.46 20.68 7.89 8d 20 18 6 2 218–220 51 406.46 59.38 4.21 20.95 7.61 19 M.
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