View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Arabian Journal of Chemistry (2015) xxx, xxx–xxx King Saud University Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com ORIGINAL ARTICLE Synthesis of heterocyclic compounds and its applications Mohan N. Patel *, Parag S. Karia, Pankajkumar A. Vekariya, Anshul P. Patidar Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388 120, Gujarat, India Received 28 February 2015; accepted 26 June 2015 KEYWORDS n n Abstract The octahedral ruthenium(II) complexes [Ru(L )(PPh3)2Cl2][L= biphenyl furanyl Heterocyclic compound; pyridine derivatives] were synthesized and characterized using LC–MS, IR spectroscopy, elemental Ruthenium(II) complexes; analysis and magnetic measurements. Complexes show enhancement in antibacterial activity Nucleic acid intercalating compared to free ligands. From the binding mode investigation by absorption titration and agent; viscosity measurement, it is observed that complexes bind to DNA via intercalation and also Cytotoxicity complexes promote the cleavage of supercoiled pUC19 plasmid DNA. Cytotoxicity analysis shows 100% mortality of Brine shrimp after 48 h. ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction containing planar polycyclic hetero aromatic ligands (Ji et al., 2001). Studies on DNA-binding of the complexes are Recently, metal complexes as DNA interacting agents have crucial in development of nucleic acid interaction, chemother- been talk in medicinal inorganic chemistry (Fei et al., 2014; apy and photodynamic treatment (Huppert, 2008; Zhao et al., 2011; Abou-Hussen and Linert, 2009; Patel, Balasubramanian and Neidle, 2009; Georgiades et al., 2010). 2004; Wu et al., 2011; Khan et al., 2014). DNA intrastrand Recently, ruthenium(II) polypyridyl complexes have been cross-linking agents are found useful in treatment of cancers, found to induce apoptosis in A549 cells (Bing-Jie et al., psoriasis and various anemias. Several ruthenium complexes 2014). Also, the main ligands of Ru(II)–polypyridyl complexes have been developed as an alternative to cis-platin as potential possess extended conjugated planar aromatic structures can anticancer agents with lower toxicity than the platinum coun- insert and stack between the base pairs of DNA. terparts (Clarke and Keppler, 1993; Keppler et al., 1993; Considerable effects are observed in the binding mode, sites Clarke et al., 1999; Sava and Bergamo, 2000). Large interest and affinities upon slight changes in the molecular structures has been drawn toward the interaction of Ru(II) complexes of Ru(II) complexes which provide the opportunity to discover important information on site-specific DNA probes. * Corresponding author. Tel.: +91 (2692) 226856x218. Therefore, studies on modifying the main ligand is quite signif- E-mail address: [email protected] (M.N. Patel). icant for understanding the optical properties of DNA-binding Peer review under responsibility of King Saud University. and action mechanism of ruthenium complexes. In continuation of our earlier work (Patel et al., 2014), biological activity of the synthesized complexes was carried out by performing antibacterial, DNA binding, DNA cleavage Production and hosting by Elsevier and cytotoxicity study. http://dx.doi.org/10.1016/j.arabjc.2015.06.031 1878-5352 ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Patel, M.N. et al., Synthesis of heterocyclic compounds and its applications. Arabian Journal of Chemistry (2015), http://dx.doi.org/ 10.1016/j.arabjc.2015.06.031 2 M.N. Patel et al. 2. Experimental 2.3.1. Synthesis of 4-(4-fluorophenyl)-2-(furan-2-yl)-6-p- tolylpyridine [L1] 2.1. Reagents and materials Substituted enone synthesized by the reaction of p- fluorobenzaldehyde and p-methylacetophenone, was refluxed All the chemicals were of analytical grade. Ruthenium chloride with pyridinium salt of 2-acetylfuran in presence of ammo- trihydrate, 2-acetylfuran, 4-chlorobenzaldehyde, 4-fluoro- nium acetate for 6 h. The reaction mixture was allowed to cool bezaldehyde, 4-bromobezaldehyde, 3-chlorobenzaldehye, 3- at room temperature. The solid product was filtered and fluorobezaldehyde and 3-bromobezaldehyde were purchased recrystallized from hexane. Yield: 53%, mp: 118 °C, Anal. from Sigma Chemical Co. (India). Ethidium bromide (EB), Calc. for C22H16FNO (329.37): Calc. (%): C, 80.23; H, 4.90; 1 bromophenol blue, agarose and Luria Broth (LB) were pur- N, 4.25. Found (%): C, 80.21; H, 4.93; N, 4.27. H NMR chased from Himedia (India). Culture of pUC19 bacteria (CDCl3, 400 MHz): d (ppm) 8.068–8.064 (d-poor resolved, (MTCC 47) was purchased from Institute of Microbial 2H, H200,600), 7.823–7.819 (d, 1H, H3), 7.765–7.730 (complex, Technology (Chandigarh, India). 3H, H5,300,500), 7.590–7.584 (dd-poor resolved, 1H, H50), 7.345– 7.325 (d, 2H, H3000;5000 ), 7.284–7.209 (complex, 3H, H40;2000;60 ), 6.606–6.593 (dd, 1H, H30), 2.456 (s, 3H, ACH3). IR (KBr, 2.2. Physical measurements 1 4000–400 cm ): 3032, v(CAH)ar stretching; 1543, v(C‚C); 1497, v(C‚N); 1304, pyridine skeleton band; 1220, v(CAF); 918, Perkin–Elmer 240 Elemental Analyzer was used to collect 13 818, (p-substituted ring); 740, v(CAH)ar bending. C NMR micro analytical data. Room temperature magnetic susceptibil- (CDCl3, 100 MHz) d (ppm): 157.19 (C400), 155.83 (C2), 149.96 ity was measured by Gouy’s method. FT–IR data were col- (C6,20), 143.04 (C4), 139.37 (C50), 136.88 (C100), 131.48 (C1000 ), lected by FT–IR ABB Bomen MB 3000 spectrophotometer. 129.44 (C200;600;4000 ), 128.14 (C3000;5000 ), 124.12 (C3;2000;6000 ), 116.41 The 1H NMR and 13C NMR were recorded on a Bruker (C30), 114.78 (C300,500), 112.25 (C5), 109.07 (C40), 20.53 ACH3. Avance (400 MHz). UV–Vis spectra of the complexes were recorded on UV-160A UV–Vis spectrophotometer, Shimadzu 2.3.2. Synthesis of 4-(4-chlorophenyl)-2-(furan-2-yl)-6-p- (Japan). Cleavage of pUC19 DNA was quantified by tolylpyridine [L2] AlphaDigiDocä RT. Version V.4.0.0. It has been synthesized using pyridinium salt of 2-acetyl furan and the enone prepared by the reaction between p- 2.3. Synthesis of ligands chlorobenzaldehyde and p-methylacetophenone. Yield: 59%, mp: 110 °C, Anal. Calc. for C22H16ClNO (345.82): Calc. (%): Modification of Krohnke pyridine synthesis (Krohnke, 1976) C, 76.41; H, 4.66; N, 4.05. Found (%): C, 76.44; H, 4.67; N, 1 6 1 has been used for the synthesis of ligands [L –L ] (Scheme 1). 4.08. H NMR (CDCl3, 400 MHz): d (ppm) 8.064–8.044 (dd, Scheme 1 General reaction scheme for the synthesis of ligands. Please cite this article in press as: Patel, M.N. et al., Synthesis of heterocyclic compounds and its applications. Arabian Journal of Chemistry (2015), http://dx.doi.org/ 10.1016/j.arabjc.2015.06.031 Synthesis and applications of heterocyclic compounds 3 2H, H200,600), 7.823–7.821 (dd, 1H, H50), 7.757 (s, 1H, H3), 70%, mp: 78 °C, Anal. Calc. for C22H16ClNO (345.82): Calc. 7.714–7.693 (d, 2H, H3000;5000 ), 7.588 (s, 1H, H5), 7.524–7.503 (%): C, 76.41; H, 4.66; N, 4.05. Found (%): C, 76.40; H, 1 (d, 2H, H300,500), 7.345–7.325 (d, 2H, H2000;6000 ), 7.284–7.271 (dd, 4.68; N, 4.04. H NMR (CDCl3, 400 MHz): d (ppm) 8.072– 1H, H40), 6.606–6.594 (dd, 1H, H30), 2.456 (s, 3H, –CH3). IR 8.052 (d, 2H, H200,600), 7.910–7.901(t, 1H, H3), 7.820–7.817 (d, À1 (KBr, 4000–400 cm ): 3063, v(CAH)ar stretching; 1543, 1H, H5), 7.756–7.753 (d, 1H, H2000 ), 7.700–7.681 (d, 1H, H6000 ), v(C‚C); 1489, v(C‚N); 1327, pyridine skeleton band; 1040, 7.630–7.595 (complex, 2H, H3000;5000 ), 7.433–7.394 (t, 1H, H40), v(CACl); 987, 810, (p-substituted ring) 733, v(CAH)ar bending. 7.348–7.329 (d, 2H, H300,500), 7.248–7.275 (d-poor resolved, 13 A C NMR (CDCl3, 100 MHz) d (ppm): 156.52 (C400), 154.13 1H, H50), 6.609–6.597 (dd, 1H, H30), 2.458 (s, 3H, CH3). IR À1 A (C2), 150.83 (C20), 144.66 (C6), 139.89 (C4), 138.54 (C50), (KBr, 4000–400 cm ): 3063, v(C H)ar stretching; 1551, ‚ ‚ 136.11 (C100;1000 ), 132.60 (C200;600;4000 ), 130.22 (C3;3000;5000 ), 128.61 v(C C); 1489, v(C N); 1381, pyridine skeleton band; 1225, A 13 (C2000;6000 ), 126.40 (C300,500), 124.08 (C5), 117.52 (C40), 115.91 v(C Cl); 864,748, (m-substituted ring). C NMR (CDCl3, (C30), 20.66 ACH3. 100 MHz) d (ppm): 156.54 (C300), 154.02 (C2), 150.00 (C20), 143.51 (C6), 139.05 (C4), 138.08 (C100), 135.50 (C50), 132.01 2.3.3. Synthesis of 4-(4-bromophenyl)-2-(furan-2-yl)-6-p- (C1000;4000 ), 130.00 (C3000;5000 ), 128.47 (C500;2000;6000 ), 126.03 (C200,400,600), A tolylpyridine [L3] 123.40 (C3,5), 116.50 (C40), 115.17 (C30), 21.44 CH3. It has been synthesized using the pyridinium salt of 2-acetyl 2.3.6.