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Journal of Chemistry
Volume 2013 (2013), Article ID 427158, 10 pages
http://dx.doi.org/10.1155/2013/427158
Research Article

The Reaction of Cyclopentanone with Cyanomethylene Reagents: Novel Synthesis of Pyrazole, Thiophene, and Pyridazine Derivatives

National Organization for Drug Control & Research, P.O. Box 29, Cairo, Egypt

Received 28 May 2013; Revised 1 September 2013; Accepted 6 September 2013

Academic Editor: Alexander Kornienko

Copyright © 2013 Wagnat W. Wardakhan and Eman M. Samir. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The reaction of cyclopentanone with either malononitrile or ethyl cyanoacetate gave the corresponding condensated products. The latter underwent some heterocyclic reactions to give new pyrazole, thiophene, and pyridazine derivatives. The antitumor evaluation of the newly synthesized products against the three cancer cells, namely, breast adenocarcinoma (MCF-7), nonsmall cell lung cancer (NCI-H460), and CNS cancer (SF-268) showed that some of them have high inhibitory effect towards three cell lines which is higher than the standard.

1. Introduction

Heterocyclic compounds are worthy of attention for many reasons, chief among which are their biological activities, with many important drugs bearing thiazol, thiophene and pyridine derivatives. Therefore, organic chemists have been making extensive efforts to produce heterocyclic compounds by developing new and efficient synthetic transformations [110]. Many pyrazoles, thiophenes, and thiazoles were reported with a wide spectrum of biological activities which are known; they possess potent analgesic [11, 12], anticonvulsant, anti-inflammatory and antibacterial [13, 14], antipyretics [15], antitumor [16, 17], antiparasitic [18], antimicrobial [19], antihistaminic (H1) [20], antianxiety test in mice [21], antiarrhythmic [22], and serotonin antagonist [23]. In the present work, we studied the reaction of cyclopentanone with cyanomethylene reagents followed by heterocyclization of the products together with studying the antitumor evaluation of the newly synthesized products.

2. Experimental

Melting points were determined on an Electrothermal melting point apparatus (Electrothermal 9100) and are uncorrected. IR spectra were recorded for KBr discs on a Pye Unicam SP-1000 spectrophotometer. 1H NMR spectra were measured on a Varian EM-390 at 200 MHz in DMSO- as solvent using TMS as internal standard. The mass spectra were recorded with Hewlett Packard 5988 A GC/MS system and GCMS-QP 1000 Ex Shimadzu instruments. Analytical data were obtained from the Microanalytical Data Unit at Cairo University, Giza, Egypt. Antitumor evaluation for the newly synthesized products was performed by a research group at the National Research Center and the National Cancer Institute at Cairo University. Fetal bovine serum (FBS) and l-glutamine were from Gibco Invitrogen Co. (Scotland, UK). RPMI-1640 medium was from Cambrex (New Jersey, NJ, USA). Dimethyl sulfoxide (DMSO), doxorubicin, penicillin, streptomycin, and sulforhodamine B (SRB) were from Sigma Chemical Co. (Saint Louis, MO, USA). Stock solutions of all compounds were prepared in DMSO and kept at −20°C. Appropriate dilutions of the compounds were freshly prepared just prior to assays. Final concentrations of DMSO did not interfere with the cell growth. MCF-7 was obtained from the European Collection of Cell Cultures (ECACC, Salisbury, UK), and NCI-H460 and SF-268 were kindly provided by the National Cancer Institute (NCI, Cairo, Egypt). The physical properties, yield %, solvent of crystallization, and microanalytical data of the synthesized products were indicated through Table 1. Spectral data were inserted through Table 2.

tab1
Table 1: Physical and microanalysis of the newly synthesized compounds 3a16b.
tab2
Table 2: Spectral data of the newly synthesized products.

2.1. 2-Cyclopentylidenemalononitrile 3a and Ethyl 2-cyano-2-Cyclopentylideneacetate 3b

General Procedure. To a dry solution of cyclopentanone 1 (0.84 g, 0.01 mol) either malononitrile 2a (0.66 g, 0.01 mol) or ethyl cyanoacetate 2b (1.13 g, 0.01 mol) was added followed by the addition of ammonium acetate (0.50 g). The reaction mixture, in each case, was heated in an oil bath at 120°C then left to cool. The solidified product was triturated with ethanol, and the formed solid product was collected by filtration to give compounds 3a,b.

2.2. Synthesis of 2-(2-Phenylhydrazono-cyclopentylidene)-malononitrile 5a, 2-(2-(P-chlorophenyl)-hydrazono-cyclopentylidene)-malononitrile 5b, Ethyl 2-Cyano-2-(2-phenylhydrazo)-cyclopentylideneacetate 5c, Ethyl 2-Cyano-2-(2-(p-chlorophenylhydrazo)-cyclopentylideneacetate 5d

To a solution of either 3a (1.32 g, 0.01 mol) or 3b  (1.79 g, 0.01 mol) in cold (0–5°C) ethanol (30 mL) containing sodium acetate (2.5 g) either of benzenediazonium chloride 4a,b (0.01 mol or 4-chlorobenzenediazonium chloride (0.01 mol) (prepared by adding sodium nitrite solution (0.70 g, 0.01 mol) to a cold solution of the appropriate aniline or its derivative (0.01 mol) in concentrated hydrochloric acid (20 mL, 18 N) with continuous stirring) was added with stirring. The whole reaction mixture was kept at room temperature for 2 h, and the formed solid product was filtered off to yield 5ad.

2.3. Synthesis of 3,5-Diamino-4-(2-phenylhydrazono-cyclopent-1-yl)pyrazol 7a, 3-Amino-1-phenyl4-(2-phenylhydrazono-cyclopent-1-yl)pyrazol 7b, 3-Amino-5-hydroxy-4-(2-phenylhydrazono-cyclopent-1-yl)pyrazol 7c and 3-Amino-1-phenyl-5-hydroxy-4-(2-phenylhydrazono-cyclopent-1-yl)pyrazol 7d

General Procedure. To a solution of either 5a  (2.36 g, 0.01 mol) or 5c (2.83 g, 0.01 mol) in 1,4-dioxane (20 mL), either hydrazine hydrate 6a (0.5 mL, 0.01 mol) or phenylhydrazine 6b (1.08 g, 0.01 mol). The reaction mixture was heated under reflux for 1 h. The solid product, obtained upon cooling, was filtered off and dried to give compounds 7ad.

2.4. Synthesis of 2-(Benzylidenecyclopentylidene)malononitrile 9a and Ethyl 2-(2-Benzylidenecyclopentylidene)-2-cyanoacetate 9b

General Procedure. To a solution of either 3a (1.32 g, 0.01 mol) or 3b  (1.79 g, 0.01 mol) in 1,4-dioxane (30 mL) containing piperidine (0.50 mL), benzaldehyde (1.06 g, 0.01 mol) was added. The reaction mixture was heated under reflux for 2 h. The solid product, obtained upon cooling, was filtered off to give compounds 9a,b.

2.5. Synthesis of 5-Amino-7-phenyl-2,3-dihydro-1H-indene-4,6-dicarbonitrile 11a, Ethyl 6-Amino-7-cyano-4-phenyl-2,3-dihydro-1H-indene-5-carboxylate 11b, Ethyl 5-Amino-6-cyano-7-phenyl-2,3-dihydro-1H-indene-4-carboxylate 11c and Diethyl 5-Amino-7-phenyl-2,3-dihydro-1H-indene-4,6-dicarboxylate 11d

General Procedure. To a solution of either 9a  (2.20 g, 0.0. mol) or 9b  (2.67 g, 0.01 mol) in 1,4-dioxane (40 mL) containing triethylamine (0.50 mL, 0.01 mol), either malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.07 g, 0.01 mol) was added. The reaction mixture, in each case, was heated under reflux for 3 h. The solid product, obtained upon cooling, was collected by filtration to give compounds 11ad.

2.6. Synthesis of 2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile 13a and Ethyl 2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate 13b

To a solution of either 3a (1.32 g, 0.01 mol) or 3b  (1.79 g, 0.01 mol) in ethanol (20 mL) containing triethylamine (0.50 mL, 0.01 mol) elemental sulphur (0.32 g, 0.01 mol) was added. The reaction mixture, in each case, was heated under reflux for 1 h. The separated solid was flittered off to afford 13a,b.

2.7. Synthesis of 2-Amino-4-(2-phenylhydrazono)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile 14a and Ethyl 2-Amino-4-(2-phenylhydrazono)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate 14b

To a solution of either 5a (2.36 g, 0.01 mol) or 5b (2.70 g, 0.01 mol) in 1,4-dioxane (20 mL) containing triethylamin (0.5 mL, 0.01 mol), elemental sulphur (0.32 g, 0.01 mol) was added. The whole reaction mixture was heated under reflux for 1 h then left to cool. The separated solid was filtered off to afford 14a,b.

2.8. Synthesis of N-(3-Cyano-4-(2-phenylhydrazono)-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)acetamide 15a and Ethyl 2-Acetamido-4-(2-phenylhydrazono)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate 15b

To a solution of either of compound 14a  (2.68 g, 0.01 mol) or 14b  (3.15 g, 0.01 mol) with acetic anhydride (1.02 g, 0.01 mol) in dimethyl formamide (20 mL) was heated under reflux for 2 h then left to cool. The solid product, so formed in each case, was collected by filtration. The reaction mixture was evaporated under vacuum and the remaining product was triturated with ethanol. The separated solid was filtered off to afford 15a,b.

2.9. Synthesis of 3-Amino-2-phenyl-3,5,6,7-tetrahydro-2H-4-carbonitrile 16a and 3-Oxo-2-phenyl-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridazine-4-carbonitrile 16b

A solution of either 5a  (2.36 g, 0.01 mol) or 5b (2.70 g, 0.01 mol) in 1,4-dioxane (20 mL) containing triethylamine (0.5 mL, 0.01 mol) was heated under reflux for 4 h, then the excess solvent was evaporated under vacuum. The remaining product, in each case, was triturated with diethyl ether, and the formed solid product was filtered off to give 16a,b.

3. Results and Discussions

The reaction of cyclopentanone with either malononitrile or ethylcyanoacetate gave the Knoevenagel condensated products 3a and 3b, respectively. The structures of the latter products were based on analytical and spectral data. Thus, the 1H NMR spectrum of 3a  showed a multiplet at δ 1.34–2.44 indicating the four CH2 groups. Next, we studied the reaction of either 3a or 3b with either benzenediazonium chloride or p-chlorobenzenediazonium chloride. The reaction was carried out in ethanol 0–5°C and afforded the corresponding arylhydrazone derivatives 5a–d, respectively. Either compound 5a  or  5c reacts with either hydrazine hydrate or phenylhydrazine to give the corresponding pyrazole derivatives 7a–d, respectively (Scheme 1). The analytical and spectral data of the latter products are in agreement with the proposed structures. Thus, the 1H NMR spectrum of 7a showed the presence of a multiplet at 1.32–2.36 corresponding to the three CH2 groups, a triplet at 2.81 indicating the CH group, two singlets (D2O exchangeable) at 4.21, 4.85 ppm for the two NH2 groups, a multiplet at 7.29–7.40 ppm corresponding to one phenyl group, and two singlets (D2O exchangeable) corresponding to the two NH groups. On the other hand, the reaction of either 3a or 3b with benzaldehyde afforded the benzylidene derivatives 9a and 9b, respectively.

427158.sch.001
Scheme 1

The reaction of either (9a) or 9b with either malononitrile or ethyl cyanoacetate gave the benzocyclopentane derivatives 11a–d, respectively. Formation of the latter products is explained in terms of the first addition of the cyanomethylene reagent to the ylidene moiety followed by the Micheal addition of the CH group to the nitrile and subsequent elimination of HCN. Structures of 11a–d  were confirmed on the basis of their analytical and spectral data, respectively. Thus, the 1H NMR spectrum of 11a  showed a multiplet at 1.30–2.36 ppm, a singlet at 4.48 ppm for the NH2 group, and a multiplet at 7.26–7.38 ppm indicating the C6H5 group. Further confirmations for the structures of such compounds were obtained through the reaction of either 3a  or  3b with either -cyanocinnamonitrile 12a  or ethyl -cyanocinnamate 12b  to give the same products 11a–d, respectively (identical finger print IR, mixed m.p.).

Next, we moved towards studying reactivity of either 3a or 3b towards Gewald’s thiophene synthesis. Thus, the reaction of either 3a or 3b with elemental sulphur in 1,4-dioxane and the presence of a catalytic amount of triethylamine gave the cyclopenta[ ]thiophene derivatives 13a and 13b, respectively (Scheme 2). The latter products were obtained previously by Mohareb and Al-Farouk [24] using another reaction route. Moreover, carrying the same reaction with the arylhydrazone derivatives 5a and 5b gave the thienocyclopentene derivatives 14a and 14b, respectively. Compounds 14a  and 14b were reacted with acetic anhydride in dimethyl formamide to give the N-acetyl products 15a and 15b, respectively. Compounds 5a,b  underwent ready cyclization in 1,4-dioxane solution containing triethylamine to give the cyclopenta[ ]pyridazine derivatives 16a and 16b, respectively (Scheme 3).

427158.sch.002
Scheme 2
427158.sch.003
Scheme 3

4. Antitumor Activity Tests

4.1. Reagents

Fetal bovine serum (FBS) and L-glutamine, were from Gibco Invitrogen Co. (Scotland, UK). RPMI-1640 medium was from Cambrex (NJ, USA). Dimethyl sulfoxide (DMSO), doxorubicin, penicillin, streptomycin, and sulforhodamine B (SRB) were from Sigma Chemical Co. (Saint Louis, USA).

4.2. Cell Cultures

Three human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (nonsmall cell lung cancer), and SF-268 (CNS cancer) were used. MCF-7 was obtained from the European Collection of Cell Cultures (ECACC, Salisbury, UK), and NCI-H460 and SF-268 were kindly provided by the National Cancer Institute (NCI, Cairo, Egypt). They grow as monolayer and routinely maintained in RPMI-1640 medium supplemented with 5% heat inactivated FBS, 2 mM glutamine, and antibiotics (penicillin 100 U/mL, streptomycin 100 μg/mL), at 37°C in a humidified atmosphere containing 5% CO2. Exponentially growing cells were obtained by plating  cells/mL for MCF-7 and SF-268 and  cells/mL for NCI-H460, followed by 24 h of incubation. The effect of the vehicle solvent (DMSO) on the growth of these cell lines was evaluated in all the experiments by exposing untreated control cells to the maximum concentration (0.5%) of DMSO used in each assay.

4.3. Tumor Cell Growth Assay

The effects of 3a,b–15a, b on the in vitro growth of human tumor cell lines were evaluated according to the procedure adopted by the National Cancer Institute (NCI, USA) in the “In vitro Anticancer Drug Discovery Screen” that uses the protein-binding dye sulforhodamine B to assess cell growth [25]. Briefly, exponentially, cells growing in 96-well plates were then exposed for 48 h to five serial concentrations of each compound, starting from a maximum concentration of 150 μM. Following this exposure, period adherent cells were fixed, washed, and stained. The bound stain was solubilized, and the absorbance was measured at 492 nm in a plate reader (Bio-Tek Instruments Inc., Powerwave XS, Wincoski, USA). For each test compound and cell line, a dose-response curve was obtained, and the minimum concentration inhibition of 50% (IC50), corresponding to the concentration of the compounds that inhibited 50% of the net cell growth, was calculated as described elsewhere [26]. For our newly synthesized products, we selected the three cancer cell lines the breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460), and CNS cancer (SF-268) as our compounds are electron reach systems substituted with electronegative groups, and many reports from our previous work and others [25] used such cell lines together with the use of doxorubicin which was showed to be the best positive control against the three cell lines.

Materials, Methods and Reagents. Fetal bovine serum (FBS) and L-glutamine were obtained from Gibco Invitrogen Co. (Scotland, UK). RPMI-1640 medium was from Cambrex (New Jersey, USA). Dimethyl sulfoxide (DMSO), doxorubicin, penicillin, streptomycin, and sulforhodamine B (SRB) were from Sigma Chemical Co. (Saint Louis, USA). Samples: stock solutions of compounds (3a,b–15a,b) were prepared in DMSO and kept at −20°C. Appropriate dilutions of the compounds were freshly prepared just prior to the assays. Final concentrations of DMSO did not interfere with the cell growth.

Cell Cultures. Three human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer) were used. MCF-7 was obtained from the European Collection of Cell Cultures (ECACC, Salisbury, UK), and NCI-H460 and SF-268 were kindly provided by the National Cancer Institute (NCI, Cairo, Egypt). They grow as monolayer and routinely maintained in RPMI-1640 medium supplemented with 5% heat inactivated FBS, 2 mM glutamine, and antibiotics (penicillin 100 U/mL, streptomycin 100 μg/mL), at 37°C in a humidified atmosphere containing 5% CO2. Exponentially growing cells were obtained by plating  cells/mL for MCF-7 and SF-268 and  cells/mL for NCI-H460, followed by 24 h of incubation. The effect of the vehicle solvent (DMSO) on the growth of these cell lines was evaluated in all the experiments by exposing untreated control cells to the maximum concentration (0.5%) of DMSO used in each assay.

4.4. Structure Activity Relationship

Compounds (3a,b–15a,b) were evaluated for their capacities to inhibit the in vitro growth of breast adenocarcinoma (MCF-7).

4.4.1. Effect on the Growth of Human Tumor Cell Lines

The effect of selected compounds from the newly synthesized products 3a,b–16a,b was evaluated on the in vitro growth of three human tumor cell lines representing different tumor types, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460), and CNS cancer (SF-268), after a continuous exposure of 48 h. The results are summarized in Table 3.

tab3
Table 3: Effect of compounds 3a,b15a,b on the growth of three human tumor cell lines.

All the compounds were able to inhibit the growth of the human tumor cell lines in a dose-dependent manner (data not shown). The p-chlorophenylhydrazone derivative 15a, the indene derivatives 11d, and the pyridazin-6-one derivative 15b showed the best results among the tested compounds, and such reactivity is higher than the standard doxorubicin. On the other hand, compounds 3b, 7c, 9a, 9b, 12a, 12b, 13a, 14a, 15a, 16a,  and 16b showed moderated growth inhibitory effect. Comparing the activities of 15a  and 15b, it is observed that the chloro group in 15b presents a stronger growth inhibitory effect than the amino substituent in 15a, although the results in NCI-H460 cell line are comparable. It is clear from Table 3 that some compounds like 7a, 7b, and 11a showed very low activity towards the three cancer cell lines.

Comparing the reactivities of compounds 11a–d, it is obvious that compound 11d with X = Y = COOEt showed the highest inhibitory effect among the four compounds. On the other hand,  considering the cyclopentenopyridazine derivatives 15a and 15b, the presence of the electronegative C=N group is responsible for the higher cytotoxicity of 15b over 15a. It is clear from Table 3 that compounds 5b,  11d, and  15b  showed the highest cytotoxicity among the newly synthesized products, and such activity is higher than that of the standard material doxorubicin.

5. Conclusions

In this work, we succeeded to synthesis a series of fused thiophene derivatives. The cytotoxicity of the newly synthesized products showed that compounds 5b, 11d, and 15b  are the most active compounds towards the three cancer cell lines.

References

  1. W. Pfau and H. Marquardt, “Cell transformation in vitro by food-derived heterocyclic amines Trp-P-1, Trp-P-2 and N2-OH-PhIP,” Toxicology, vol. 166, no. 1-2, pp. 25–30, 2001. View at Publisher · View at Google Scholar · View at Scopus
  2. V. P. Boyarskiy, K. V. Luzyanin, and V. Yu. Kukushkin, “Acyclic diaminocarbenes (ADCs) as a promising alternative to N-heterocyclic carbenes (NHCs) in transition metal catalyzed organic transformation,” Coordination Chemistry Reviews, vol. 256, no. 17-18, pp. 2029–2056, 2012. View at Publisher · View at Google Scholar
  3. R. K. Singh, N. Sinha, S. Jain, M. Salman, F. Naqvi, and N. Anand, “A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation—part 2: synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)- propionic acid,” Tetrahedron, vol. 61, no. 37, pp. 8868–8874, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. V. Frenna, G. Macaluso, G. Consiglio, B. Cosimelli, and D. Spinelli, “Mononuclear heterocyclic rearrangements—part 16: kinetic study of the rearrangement of some ortho-substituted Z-phenylhydrazones of 3-benzoyl-5- phenyl-1,2,4-oxadiazole into 2-aryl-4-benzoylamino-5-phenyl- 1,2,3-triazoles in dioxane-water and in benzene,” Tetrahedron, vol. 55, no. 44, pp. 12885–12896, 1999. View at Publisher · View at Google Scholar · View at Scopus
  5. B. S. Jursic, F. Douelle, K. Bowdy, and E. D. Stevens, “A new facile method for preparation of heterocyclic α-iminonitriles and α-oxoacetic acid from heterocyclic aldehydes, p-aminophenol, and sodium cyanide,” Tetrahedron Letters, vol. 43, no. 30, pp. 5361–5365, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. K. V. Padoley, S. N. Mudliar, and R. A. Pandey, “Heterocyclic nitrogenous pollutants in the environment and their treatment options—an overview,” Bioresource Technology, vol. 99, no. 10, pp. 4029–4043, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. A. W. Erian, S. M. Sheriff, A. A. Alassar, and Y. M. Elkholy, “β-Enaminonitriles in heterocyclic synthesis: a novel synthesis and transformations of α-substituted-β-enaminonitriles,” Tetrahedron, vol. 50, no. 6, pp. 1877–1884, 1994. View at Publisher · View at Google Scholar · View at Scopus
  8. J. Bergman, S. Bergman, and T. Brimert, “Syntheses of gem-dinitro heterocyclic compounds, their ring-opening reactions and transformations into indoles, indazoles and benzoxazinones,” Tetrahedron, vol. 55, no. 34, pp. 10447–10466, 1999. View at Publisher · View at Google Scholar · View at Scopus
  9. J. Fuentes, W. Moreda, C. Ortiz, I. Robina, and C. Welsh, “Partially protected D-glucopyranosyl isothiocyanates. Synthesis and transformations into thiourea and heterocyclic derivatives,” Tetrahedron, vol. 48, no. 31, pp. 6413–6424, 1992. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Buscemi, A. Pace, I. Pibiri, N. Vivona, and T. Caronna, “Fluorinated heterocyclic compounds: an assay on the photochemistry of some fluorinated 1-oxa-2-azoles: an expedient route to fluorinated heterocycles,” Journal of Fluorine Chemistry, vol. 125, no. 2, pp. 165–173, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. M. R. Shaaban, T. S. Saleh, A. S. Mayhoub, A. Mansour, and A. M. Farag, “Synthesis and analgesic/anti-inflammatory evaluation of fused heterocyclic ring systems incorporating phenylsulfonyl moiety,” Bioorganic & Medicinal Chemistry, vol. 16, no. 12, pp. 6344–6352, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. M. G. Rimoli, L. Avallone, P. de Caprariis et al., “Research on heterocyclic compounds. XXXVII. Synthesis and antiinflammatory activity of methyl-substituted imidazo[1,2-a]pyrazine derivatives,” European Journal of Medicinal Chemistry, vol. 32, no. 3, pp. 195–203, 1997. View at Publisher · View at Google Scholar · View at Scopus
  13. L. Feng, K. W. Yang, L. S. Zhou et al., “N- heterocyclic dicarboxylic acids: broad-spectrum inhibitors of metallo-β-lactamases with co-antibacterial effect against antibiotic-resistant bacteria,” Bioorganic & Medicinal Chemistry Letters, vol. 22, no. 16, pp. 5185–5189, 2012.
  14. S. Günal, N. Kaloğlu, İ. Özdemir, S. l Demir, and İ. Özdemir, “Novel benzimidazolium salts and their silver complexes: synthesis and antibacterial properties,” Inorganic Chemistry Communications, vol. 21, pp. 142–146, 2012. View at Publisher · View at Google Scholar
  15. S. K. Srivastava, W. Haq, and P. M. S. Chauhan, “Solid phase synthesis of structurally diverse pyrimido[4,5-d] pyrimidines for the potential use in combinatorial chemistry,” Bioorganic & Medicinal Chemistry Letters, vol. 9, no. 7, pp. 965–966, 1999. View at Publisher · View at Google Scholar · View at Scopus
  16. D. Z. Li, Y. Li, X. G. Chen et al., “Synthesis and antitumor activity of heterocyclic acid ester derivatives of 20S-camptothecins,” Chinese Chemical Letters, vol. 18, no. 11, pp. 1335–1338, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. Z. Li, Q. Yang, and X. Qian, “Novel heterocyclic family of phenyl naphthothiazole carboxamides derived from naphthalimides: synthesis, antitumor evaluation, and DNA photocleavage,” Bioorganic & Medicinal Chemistry, vol. 13, no. 9, pp. 3149–3155, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. R. J. Pagliero, S. Lusvarghi, A. B. Pierini, R. Brun, and M. R. Mazzieri, “Synthesis, stereoelectronic characterization and antiparasitic activity of new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines,” Bioorganic & Medicinal Chemistry, vol. 18, no. 1, pp. 142–150, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. S.-F. Barbuceanu, G. Saramet, G. L. Almajan, C. Draghici, F. Barbuceanu, and G. Bancescu, “New heterocyclic compounds from 1,2,4-triazole and 1,3,4-thiadiazole class bearing diphenylsulfone moieties. Synthesis, characterization and antimicrobial activity evaluation,” European Journal of Medicinal Chemistry, vol. 49, pp. 417–423, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. A. D. Settimo, G. Primofiore, F. D. Settimo et al., “1-Substituted 2-benzylaminobenzimidazole derivatives: compounds with H1-antihistamine activity,” European Journal of Medicinal Chemistry, vol. 27, no. 4, pp. 395–400, 1992. View at Publisher · View at Google Scholar · View at Scopus
  21. A. E. Amr, M. H. Sherif, M. G. Assy, M. A. Al-Omar, and I. Ragab, “Antiarrhythmic, serotonin antagonist and antianxiety activities of novel substituted thiophene derivatives synthesized from 2-amino-4,5,6,7-tetrahydro-N- phenylbenzo[b]thiophene-3-carboxamide,” European Journal of Medicinal Chemistry, vol. 45, no. 12, pp. 5935–5942, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. T. Bányász, J. Magyar, A. Varró et al., “EGIS-7229, the new combined class III antiarrhythmic agent Lack of EAD inducing effect,” General Pharmacology, vol. 32, no. 3, pp. 329–333, 1999. View at Publisher · View at Google Scholar
  23. D. M. Swanson, C. R. Shah, B. Lord et al., “Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists,” European Journal of Medicinal Chemistry, vol. 44, no. 11, pp. 4413–4425, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. R. M. Mohareb and F. O. Al-farouk, “Anti-Tumor and anti-Leishmanial evaluations of novel thiophene derivatives derived from the reaction of cyclopentanone with elemental sulphur and cyano-methylene reagents,” Organic Chemistry, vol. 1, pp. 1–6, 2012.
  25. W. W. Wardakhan, E. S. N. Eid, and R. M. Mohareb, “Synthesis and anti-tumor evaluation of novel hydrazide and hydrazide-hydrazone derivatives,” Acta Pharmaceutica, vol. 63, no. 1, pp. 45–57, 2013.
  26. W. W. Wardakhan and E. M. Samir, “New approches for the synthesis of hydrazone derivatives and their antitumor evaluation,” Journal of the Chilean Chemical Society, vol. 58, no. 2, pp. 827–830, 2010.