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Synthesis, characterization and antimicrobial activity of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh)and its Nickel(II), Palladium(II), Platinum(II), Copper(II), Cobalt(II) complexes
Inorganic Chemistry Communications 14 (2011) 1550–1553
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Inorganic Chemistry Communications j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n o c h e
Mini-Review
Synthesis, characterization and antimicrobial activity of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh)and its Nickel(II), Palladium(II), Platinum(II), Copper(II), Cobalt(II) complexes Halime Güzin Aslan a,⁎, Servet Özcan b, Nurcan Karacan c a b c
Department of Chemistry, Faculty of Sciences, Erciyes University 33053 Melikgazi-Kayseri, Turkey Department of Biology, Faculty of Sciences, Erciyes University 33053 Melikgazi-Kayseri, Turkey Department of Chemistry, Faculty of Arts Sciences, Gazi University 06500 Teknikokullar, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 22 March 2011 Accepted 25 May 2011 Available online 2 June 2011 Keywords: Antimicrobial activity Sulfonamides Aromatic sulfonamide Sulfonamide complexes
a b s t r a c t In this study Benzenesulfonicacid-1-methylhydrazide (bsmh) derivatives such as salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh) and its Ni(II), Pd(II), Pt(II), Cu(II), Co(II) complexes were synthesized for the first time. The structure of these complexes was investigated by using elemental analyses, the FT-IR, LC–MS and UV–VIS spectrophotometric methods, magnetic susceptibility and conductivity measurement techniques. The complexes were found to have general compositions [ML2]. Using disk diffusion methods all the synthesized complexes were evaluated in vitro as antimicrobial agents against representative strains of grampositive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 11778, Enterococcus faecalis ATCC 29212, Bacillus subtilis ATCC 6633, Staphylococcus epidermidis ATCC 12228, Enterobacter aerogenes ATCC 13048) and gram-negative bacteria (Pseudomonas fluorescens ATCC 49838, Klebsiella pneumoniae ATCC 13883, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) and as an antifungal agent against Candida albicans (ATCC 90028). All the bacteria and fungus studied were screened against some antibiotics to compare with our chemical zone diameters. Published by Elsevier B.V.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical measurements . . . . . . . . . . . . . . . . . . . . . . . . . General procedure for the synthesis . . . . . . . . . . . . . . . . . . . Synthesis of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh) . Synthesis of Ni(II), Pd(II), Pt(II), Cu(II), Co(II) complexes . . . . . . Biological activity: in vitro evaluation . . . . . . . . . . . . . . . . . . Determination of inhibition zones. . . . . . . . . . . . . . . . . Results and discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . The characterization of the compounds . . . . . . . . . . . . . . . . . FT-IR spectra . . . . . . . . . . . . . . . . . . . . . . . . . . NMR spectra. . . . . . . . . . . . . . . . . . . . . . . . . . . Mass spectra. . . . . . . . . . . . . . . . . . . . . . . . . . . Electronic spectra and magnetic behavior . . . . . . . . . . . . . Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. Tel.: + 90 5326887509; fax: + 90 3524374933. E-mail address: [email protected] (H.G. Aslan). 1387-7003/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.inoche.2011.05.024
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Introduction The sulfonamide \SO2NH\group occurs in numerous biologically active compounds which include antimicrobial drugs, saluretics, carbonic anhydrase inhibitors, insulin-releasing sulfonamides, antithyroid agents, antitumor drugs and in a number of other biological activities. Furthermore, low cost and low toxicity are their principle advantages [1–15]. Methanesulfonamide derivatives possess DNA-binding ability, show cytostatic effects, and some of them, like Amsacrine, are used in cancer chemotherapy treatment [16–19]. Some sulfonylhydrazines are known to have antineoplastic effects which prevent malign cells from growing and spreading [20]. Imidosulfonylhydrazones have antibacterial and antinociceptive properties [21]. Acidic sulfonyl hydrazone derivatives have analgesic and anti-inflammatory properties [22]. Benzaldehyde arylsulfonylhydrazones possess antineoplastic activity against human stomach cancer SGC 7901 cells [23]. 4substituted benzenesulfonylhydrazone has been found to have antibacterial activity [24]. A further extension of this area was made by the formation of the silver (I) complex of sulfonylamide which emphasized the role of metals in enhancing biological activity [25]. The transition metal complexes of hydrazides and sulfonamides also have applications in chemotherapy. The synergetic action of sulfonamides with trimethoprim has brought about an enormous resurgence of sulfonamide usage in many areas over the past decade. This prompted us to synthesize a series of novel symmetric aromatic sulfonamide complexes. We obtained a series of new sulfonamide complexes (1–5) and characterized their structure by FT-IR, LC/MS, UV–VIS, magnetic susceptibility and elemental analysis techniques. We also studied their antibacterial activities against gram-positive and gram-negative bacteria and as an antifungal agent using the disk diffusion method. All of the bacteria and fungus studied were screened against standard antibiotics to compare them with our chemical zone diameters. The structural formula of the series of aromatic sulfonamide complexes (1–5) is given in Fig. 1.
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Merck). Visualization was made with ultraviolet light. The molar magnetic susceptibilities were measured on powdered samples using the Gouy method. The molar conductance measurements were carried out using a Siemens WPA C 35 conductometer. All extracted solvents (all from Merck) were dried over anhydrous Na2SO4 and evaporated with a BUCHI rotary evaporator. Reagents were obtained commercially from Aldrich (ACS grade) and used as received. General procedure for the synthesis Synthesis of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh) A solution of bsmh [26] (4.95 ml, 50 mmol) in 5 ml ethanol was mixed with a solution of salicylaldehyde (5.31 ml, 50 mmol) in 5 ml ethanol and stirred all night. The product was recrystallized from acetonitrile three times. This resulted in a light yellow solid which is stable at normal conditions and soluble only in DMSO and DMF [26]. Synthesis of Ni(II), Pd(II), Pt(II), Cu(II), Co(II) complexes All complexes were prepared by the following general method. A sample of anhydrous MCl2 (M: Ni, Pd, Pt, Cu, Co) (0.01 mol) was dissolved in a mixture of ethanol and DMSO and a solution of hydrazone derivatives (0.02 mol, 7.8 g) in a mixture of DMSO and NaOH solution in ethanol (0.02 mol, 0.8 g) was added. The reaction mixture was heated at 40 °C for 30 min and left in an ice bath for 3 h. The solid complexes which formed were collected by filtration, washed with a small volume of ethanol and ether, and then dried in a desiccator over CaCl2[26]. The analytical and physical data for the Hsalbsmh ligand and its complexes are given in Table 1. Biological activity: in vitro evaluation
The infrared spectra of the compounds as KBr-disks were recorded in the range of 4000–400 cm − 1 with a Mattson 1000 FT-IR spectrometer. LC/MS-APC1 was recorded on an AGILENT 1100. UV– VIS spectra were recorded on a UNİCAM-UV 2–100 spectrophotometer. The melting point was recorded on an Opti MELT 3 hot stage apparatus. TLC was conducted on 0.25 mm silica gel plates (60 F254,
The biological activity of the synthesized sulfonamide derivatives was individually screened against a panel of microorganisms, including gram-positive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 11778, Enterococcus faecalis ATCC 29212, Bacillus subtilis ATCC 6633, Staphylococcus epidermidis ATCC 12228, Enterobacter aerogenes ATCC 13048) and gram-negative bacteria (Pseudomonas fluorescens ATCC 49838, Klebsiella pneumoniae ATCC 13883, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) and yeast (Candida albicans ATCC 90028). Cultures were obtained from Erciyes University, Faculty of Sciences, Department of Biology. Bacterial strains were cultured overnight at 35 °C in Triptic Soy Broth (TSB) and the yeast was cultured overnight at 35 °C in Yeast Peptone Dextrose Broth (YPDB) in a rotary shaker at 200 rpm. Overnight cultures were then transferred to a fresh medium and the turbidity of all broth cultures was adjusted to 0.1 absorbance at 640 nm on a spectrophotometer. These stock cultures were stored in the dark at 4 °C during the study.
Fig. 1. Fig. 1. M_Co(II), Ni(II), Cu(II), Pd(II), Pt(II) trans-bis(salicylaldehydebenzensülfonyl-1-methylhydrazonato) metal(II).
Determination of inhibition zones The disk diffusion antibacterial screenings [27–31] of synthesized sulfonamide derivatives dissolved in DMSO were performed using Miller-Hinton Agar (MHA) for the bacterial strains and Yeast Peptone Dextrose Agar (YPDA) for the yeast cells. 100 μl of the culture suspensions adjusted to OD640 0.1 (equivalent to 0.5 Mc Farland Turbidity) was swabbed over the entire surface of the medium (Bauer-Kirby, 1966; NCCLS 2000). Sterile 6-mm-diameter disks (1.2 mm thickness Whatman filter paper) were impregnated with 50 μl dissolved extracts (including 1.2 mg total extract per disk) and placed onto MHA or YPDA. Negative controls were prepared by using 50 μl of DMSO alone. For the bacterial cells ampicilin (50 μg/disk), trimethoprim (30 μg/disk), tetracycline (30 μg/disk) on MHA, and for the yeast cells miconazole (40 μg/disk) and nystatin (30 μg/disk) on YPDB were used as reference standards to determine the sensitivity of each strain. The inoculated plates were incubated at 35 °C for 18–24 h. Antibacterial activity was measured as the diameter (mm) of the clear
Experimental Physical measurements
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H.G. Aslan et al. / Inorganic Chemistry Communications 14 (2011) 1550–1553
Table 1 Analytical and physical data for Hsalbsmh ligand and complexes. Comp.
%C Found (Calculated)
%H
%N
%S
%Met
E.N (°C)
Empirical formula (formula weight)
Color
B.M
Conductivity (μs)
Hsalbsmh
57.916 (57.931) 52.740 (52.765) 49.072 (49.090) 43.446 (43.464) 52.350 (52.367) 52.760 (52.745)
4.860 (4.880) 4.134 (4.111) 3.844 (3.825) 3.405 (3.387) 4.094 (4.080) 4.096 (4.110)
9.648 (9.663) 8.768 (8.790) 8.159 (8.178) 7.259 (7.240) 8.741 (8.724) 8.801 (8.787)
11.042 (11.022) 10.085 (10.061) 9.380 (9.360) 8.298 (8.288) 9.998 (9.985) 10.050 (10.057)
–
167
L.Yellow
–
–
9.180 (9.208) 15.536 (15.563) 25.230 (25.212) 9.904 (9.894) 9.228 (9.242)
258
C14H14N2SO3 290.336 C28H26N4S2O6Ni 637.361 C28H26N4S2O6Pd 684.032 C28H26N4S2O6Pt 773.748 C28H26N4S2O6Cu 642.213 C28H26N4S2O6Co 637.601
L.Brown
0.34
1.14
Brown
0
0.90
Orange
0
0.50
D.Yellow
2.6
0.58
Brown
3.89
0.62
Ni(sal)2 Pd(sal)2 Pt(sal)2 Cu(sal)2 Co(sal)2
zone of growth inhibition. Four disks per plate were used and each test was run in duplicate. Results and discussion The results of elementary analysis showed 1:2 (metal/ligand) stoichiometry for all the complexes. The analytical results were in good agreement with those required by the general formula [ML2]. The molar conductivity (Λm) of the 10 − 3 M solutions of the complexes in DMSO at 25 °C was measured and all complexes were found to be of non-electrolytic nature. The Hsalbsmh ligand and its complexes which we studied have not been previously reported in the literature. The characterization of the compounds FT-IR spectra The wave number of the selected vibration of the IR spectra of the compounds is listed in Table 2. The IR spectra of the compounds were found to be very similar to each other. The most characteristic vibrations of the compounds are as follows: the asymmetric (vas) and symmetric (vs) stretching vibrations of the SO2 groups were observed at ~1231 and ~ 1250 cm − 1, ~ 1170 and ~1186 cm − 1 respectively. The C_N group stretching vibration band was found between 1601 and 1659 cm − 1. The (C_N) stretching vibration band of Hsalbsmh is observed at 1650 cm− 1. Upon the complex formation, the (C_N) stretching vibration band is shifted to a lower wave number (between 1647 and 1601 cm− 1). The (C\O) stretching vibration band of Hsalbsmh is observed 1258 cm− 1. Upon the complex formation, the (C\O) stretching vibration band is shifted to a higher wave number (between 1366 and 1400 cm− 1). NMR spectra The 1H-NMR spectrum of the Hsalbsmh compound showed that the OH proton had a wide peak at 10.30 ppm, and the N_CH proton at 8.60 ppm. Based on these data, the structure of the phenol-imine compound of Hsalbsmh was in the DMSO solution. On the other hand, the
Table 2 Wave number (cm− 1) of selected vibration of the compounds. Compound
vC\O
vas(SO2)
vs(SO2)
vC_N
Hsalbsmh Ni(salbsmh)2 Pd(salbsmh)2 Pt(salbsmh)2 Cu(salbsmh)2 Co(salbsmh)2
1258 1366 1367 1368 1400 1375
1250 1244 1231 1230 1240 1243
1180 1186 1173 1170 1175 1176
1659 1633 1621 1621 1647 1601
395 299 389 310
IR spectrophotometer observation of the ν(C\O) stretching vibration at 1258 cm − 1 and the ν(C_N) stretching vibration at 1659 cm − 1 convinced us to propose that the structure of phenol-imine was in the solid phase. The peaks of H and C atoms belonging to CH3, which is connected to the N atom, were observed at 2.60 ppm and 35.22 ppm, respectively. The aromatic C atom peaks were as follows: 158.22–117.13.
Mass spectra LC/MS shows that Ni(salbsmh)2, Pd(salbsmh)2, Cu(salbsmh)2, and Co(salbsmh)2 give the molecular ion [ML2] + at the desired positions: 637.20, 685.40, 642.30, and 637.95 m/z and Pt(salbsmh)2 gives the molecular ion, [PdL2+ NH4] + at 790.70 m/z. Ni (salbsmh)2 gives the isotope abundance at the desired positions [M ++ 2] [Ni metal isotope abundance] at 639.2 m/z and Hsalbsmh gives the molecular ion [Hsalbsmh + Na] + at 313.10 m/z Separately, all complexes and Hsalbsmh give the fragmentation of the C6H5 group, which is observed at 79.2 m/z.
Electronic spectra and magnetic behavior The significant electronic spectra of the ligand and complexes are recorded in DMSO. The important bands of the ligand are observed in the region of 430–332 nm. The magnetic moments of the complexes (as B.M.) were measured at room temperature. Nickel, palladium and platinum complexes have diamagnetic characters, and therefore their complexes have a square planar geometry. The effective magnetic moment values for Cu (salbsmh)2 and Co(salbsmh)2 complexes were 2.06 and 3.89 B.M., respectively. Low magnetic moment values support tetrahedral configurations for the Cu and Co complexes [32]. The magnetic moments of complexes (as B.M.) were measured at room temperature. The magnetic moment value (0.34 B.M.) for Ni (salbsmh)2, as well as the broad band in its electronic spectrum centered at 363 nm, suggested a square planar geometry around the nickel(II) ion. The observed band was due to the 1B1g → 1A1g and 1 A2g → 1A1g transitions in the square planar geometry. The electronic spectrum of the Pd(II) and Pt(II) complexes 353–354 nm, attributed to the 1A2g → 1B1g and 3B1g → 1A1g transitions respectively, indicated a square planar environment around the metal ions. The observed magnetic moments of the Palladium (II) and Platinum (II) complexes were 0 B.M. The electronic spectrum of the Cu (II) complex consisted of band 354 nm, arising from the 2Eg → 1T2g transition similar to that found for the tetrahedral complexes. At room temperature, the magnetic moment (2.06 B.M.) corresponded to a tetrahedral symmetry. The magnetic moment value (3.89 B.M.) for Co(salbsmh)2, the broad band in its electronic spectrum centered at 425 nm, suggested a tetrahedral geometry around the Co(II) ion. The observed band was due to the 4 T1(F) → 4A2 transition in the tetrahedral geometry [32].
H.G. Aslan et al. / Inorganic Chemistry Communications 14 (2011) 1550–1553
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Table 3 Inhibition zone of complexes by disk diffusion method (mm).
P. fluorescens P.aeruginosa E. coli K. pneumonia E.aerogenes S. aureus B. cereus B. subtilis S. epidermidis E. faecalis C. albicans
Ni
Pd
Pt
Cu
Co
Hsalbsmh
Tetrasilin (30 μg)
Trimetoprim (30 μg)
Miconazole (30 μg)
Nystatin (40 μg)
15 0 10 9 0 0 0 0 0 0 0
11 10 10 12 13 15 14 18 14 14 12
11 9 11 10 14 12 13 17 13 13 10
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 9 9 0 12 0 0
12 6 13 6 6 13 11 9 14 11 14
19 12 23 23 19 0 19 26 0 0 0
0 0 0 31 29 27 0 20 37 28 0
0 0 0 0 0 0 0 0 0 0 26
0 0 0 0 0 0 0 0 0 0 18
Inhibition zone (mm, 140 μg/disk) M(salbsmh)2.
Biological activity In the present study, the antimicrobial activities of compounds were screened against various pathogens in vitro by disk diffusion methods. Tetracycline, trimethoprim, micanazole, and nystatin were used as positive controls against both bacteria and yeast in the disk diffusion method. The results of the antibacterial and antifungal studies of all the synthesized compounds and those of the antibiotics are depicted in Table 3. Hsalbsmh and its Pd, Pt complexes were effective against all the gram-positive, gram-negative bacteria and fungi. The presence of electron densities in the \SO2NH\ group of sulfonamides contributes positively to the increase of the activity of the ligand against tested bacteria [33], but a decrease in electron densities by the coordination of donor atoms caused a decrease of activity [34]. Perhaps for this reason the nickel complex displayed good activity against gram-negative bacteria but the Co complex displayed poor activity against gram-positive bacteria, and the Cu complex displayed no activity against any bacteria or fungi. When these complexes were compared with each other, the Pd and Pt complexes displayed more activity than the Ni and Co complexes. The Cu complex displayed no activity against the tested bacteria. Conclusions In conclusion, a series of novel aromatic sulfonamide complexes were synthesized and their antimicrobial activities were evaluated. All compounds demonstrated potent inhibition against all the strains tested. From the spectroscopic characterization, it was concluded that sulfonylhydrazones act as bidentate ligands, coordinating through \C_N and phenolic \OH via deprotonation. Further research in this area is in progress at our laboratory. Consequently, these compounds may be recommended for industrial application. Acknowledgments The authors are grateful to the TUBITAK Research Foundation for its financial support under project number 104 T 390. References [1] W. Sneader, Drug Discovery: The Evolution of Modern Medicines, Wiley, New York, 1985. [2] C. Hansch, P.G. Sammes, J.B. Taylor, Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, 1990. [3] E. Dural, Farmakoloji, Nobel Tıp Kitap, İstanbul, 2002. [4] N. Pres, V.M. Chavez, E. Ticona, M. Calderon, I.S. Apolinario, A. Culotta, et al., Clinical Infectious Diseases, Natasha Press, Society of America, 2001. [5] Internet: Nokardia, http://www.wikipedia.org/wiki/Nocardia. 2005. [6] Internet: Drug, http://www.nlm.nih.gov/medlineplus/druginformation.html. 2003.
[7] M.B. Noss, G.J. Christ, A. Melman, Sildenafil: a new oral therapy for erectile dysfunction, Drugs Today 35 (1999) 211–217. [8] G. Brock, Sildenafil citrate (Viagra(R)), Drugs Today 36 (2000) 125–134. [9] J. Adkins, D. Faulds, Amprenavir, Drugs Today 55 (1998) 837–842. [10] B. Conway, S.D. Shafran, Pharmacology and clinical experience with amprenavir, Opin. Invest. Drug. 9 (2000) 371–382. [11] T.D. Penning, J.J. Taley, S.R. Bertenshaw, Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl]benzenesulfonamide (SC58635, celecoxib), J. Med. Chem. 40 (1997) 1347–1365. [12] Y. Tamura, F. Watanabe, T. Nakatani, Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives, J. Med. Chem. 41 (1998) 640–649. [13] P. Dauban, R.H. Dodd, Synthesis and GABA(A) receptor activity of 6-oxa-analogs of neurosteroids, Org. Lett. 2 (2000) 2327–2329. [14] A.G. Newcombe, Mesyl derivatives of hydrazine, Can. J. Chem. 33 (1955) 1250–1255. [15] H. Kloes, Farbenfabriken Bayer Akt.-Ges. 9 (1959) 411. [16] N.R. Lomax, V.L. Narayanan, Chemical structures of interest to the division of cancer treatment, Developmental Therapeutics Program, VI, National Cancer Institute, Bethesta, MD, 1988. [17] P.B. Jensen, B.S. Soerensen, J.F.E. Demant, M. Sehested, P.S. Jensen, L. Vindeloey, et al., In vitro evaluation of the potential aclarubcin in the treatment of small cell carcinoma of the lung, Cancer Res. 50 (1990) 3311. [18] G.J. Finlay, B.C. Baguley, K. Snow, W. Judd, Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues, Natl. Cancer Inst. 82 (1990) 662. [19] H. Rutner, N. Lewin, E.C. Woodburry, T.J. McBride, K.V. Rao, Cancer Chemother. Rep. 58 (1974) 803. [20] R.P. Baumann, K. Shyam, P.G. Penketh, J.S. Remack, T.P. Brent, A.C. Sartorelli, -1,2Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (VNP40101M): II. Role of O6 -alkylguanine-DNA alkyltransferase in cytotoxicity, Cancer Chemother. Pharmacol. 53 (4) (2004) 288–295. [21] L.L. Silva, K.N. Oliveira, R.J. Nunes, Synthesis and characterization of chloromaleimidobenzenesulfonylhydrazones, ARKIVOC 13 (2006) 124–129. [22] L.M. Lima, E.G. Amarante, A.L.P. Miranda, C.A.M. Fraga, E.J. Barreiro, Synthesis and antinociceptive profile of novel acidic sulfonylhydrazone derivatives, from natural safrole, Pharm. Common. 5 (1999) 673–678. [23] X.P. Gou, Y. Xu, L. Tang, F. Yan, F. Chen, Representative cDNA library from isolated rice sperm cells, Acta. Bot. Sin. 43 (2001) 1093–1096. [24] H. Zimmer, B.H. Benjamin, E.H. Gerlach, K. Fry, A.C. Pronay, H. Schmank, Synthesis of trisubstituted vinyl chlorides, J. Org. Chem. 24 (1959) 1667–1669. [25] C.E. Brown, J.L. Towle, N1-Silver derivatives of sulfonamide and some related compounds, Am. Chem. Soc. 63 (1941) 3523. [26] H.G. Aslan, Ph.D. Thesis, Gazi University, Ankara, (2008). [27] K.K. Anderson, in: D.N. Jones (Ed.), Comprehensive Organic Chemistry, 3, Pergamon Press, Oxford, 1979, p. 345. [28] S.L. Graham, T.H. Scholz, The reaction of sulfinic acid salts with hydroxylamine-Osulfonic acid. A useful synthesis of primary sulfonamides, Synthesis 12 (1986) 1031–1032. [29] A. Boruah, M. Boruah, D. Prajapati, J.S. Sandhu, The efficient chemoselective reduction of azides to primary amines, Synlett (1997) 1253. [30] S. Iyer, A.K. Sattar, Ni[P(OPh)3]4 catalyzed transfer hydrogenation using HCOONH4, Synth. Commun. 28 (1998) 1721. [31] W.Y. Chan, C. Berthelette, A mild, efficient method for the synthesis of aromatic and aliphatic sulfonamides, Tetrahedron Lett. 43 (2002) 4537. [32] A.B.P. Lever, Inorg. Electronic Spectroscopy, second ed. Elsevier, Amsterdam, 1984. [33] Y.M. Al-Hıari, B.A. Sweileh, Novel synthesis and antimicrobial activity of 3,7dimethylphenoxathiin nucleus and some related analogs, Asian J. Chem. 18 (2006) 2285. [34] N. Zanatta, S.H. Alues, H.S. Coelho, et al., Synthesis, antimicrobial activity, and QSAR studies of furan-3-carboxamides, Bioorg. & Med. Chem. 15 (2007) 1947.
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Inorganic Chemistry Communications j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n o c h e
Mini-Review
Synthesis, characterization and antimicrobial activity of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh)and its Nickel(II), Palladium(II), Platinum(II), Copper(II), Cobalt(II) complexes Halime Güzin Aslan a,⁎, Servet Özcan b, Nurcan Karacan c a b c
Department of Chemistry, Faculty of Sciences, Erciyes University 33053 Melikgazi-Kayseri, Turkey Department of Biology, Faculty of Sciences, Erciyes University 33053 Melikgazi-Kayseri, Turkey Department of Chemistry, Faculty of Arts Sciences, Gazi University 06500 Teknikokullar, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 22 March 2011 Accepted 25 May 2011 Available online 2 June 2011 Keywords: Antimicrobial activity Sulfonamides Aromatic sulfonamide Sulfonamide complexes
a b s t r a c t In this study Benzenesulfonicacid-1-methylhydrazide (bsmh) derivatives such as salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh) and its Ni(II), Pd(II), Pt(II), Cu(II), Co(II) complexes were synthesized for the first time. The structure of these complexes was investigated by using elemental analyses, the FT-IR, LC–MS and UV–VIS spectrophotometric methods, magnetic susceptibility and conductivity measurement techniques. The complexes were found to have general compositions [ML2]. Using disk diffusion methods all the synthesized complexes were evaluated in vitro as antimicrobial agents against representative strains of grampositive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 11778, Enterococcus faecalis ATCC 29212, Bacillus subtilis ATCC 6633, Staphylococcus epidermidis ATCC 12228, Enterobacter aerogenes ATCC 13048) and gram-negative bacteria (Pseudomonas fluorescens ATCC 49838, Klebsiella pneumoniae ATCC 13883, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) and as an antifungal agent against Candida albicans (ATCC 90028). All the bacteria and fungus studied were screened against some antibiotics to compare with our chemical zone diameters. Published by Elsevier B.V.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical measurements . . . . . . . . . . . . . . . . . . . . . . . . . General procedure for the synthesis . . . . . . . . . . . . . . . . . . . Synthesis of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh) . Synthesis of Ni(II), Pd(II), Pt(II), Cu(II), Co(II) complexes . . . . . . Biological activity: in vitro evaluation . . . . . . . . . . . . . . . . . . Determination of inhibition zones. . . . . . . . . . . . . . . . . Results and discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . The characterization of the compounds . . . . . . . . . . . . . . . . . FT-IR spectra . . . . . . . . . . . . . . . . . . . . . . . . . . NMR spectra. . . . . . . . . . . . . . . . . . . . . . . . . . . Mass spectra. . . . . . . . . . . . . . . . . . . . . . . . . . . Electronic spectra and magnetic behavior . . . . . . . . . . . . . Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. Tel.: + 90 5326887509; fax: + 90 3524374933. E-mail address: [email protected] (H.G. Aslan). 1387-7003/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.inoche.2011.05.024
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Introduction The sulfonamide \SO2NH\group occurs in numerous biologically active compounds which include antimicrobial drugs, saluretics, carbonic anhydrase inhibitors, insulin-releasing sulfonamides, antithyroid agents, antitumor drugs and in a number of other biological activities. Furthermore, low cost and low toxicity are their principle advantages [1–15]. Methanesulfonamide derivatives possess DNA-binding ability, show cytostatic effects, and some of them, like Amsacrine, are used in cancer chemotherapy treatment [16–19]. Some sulfonylhydrazines are known to have antineoplastic effects which prevent malign cells from growing and spreading [20]. Imidosulfonylhydrazones have antibacterial and antinociceptive properties [21]. Acidic sulfonyl hydrazone derivatives have analgesic and anti-inflammatory properties [22]. Benzaldehyde arylsulfonylhydrazones possess antineoplastic activity against human stomach cancer SGC 7901 cells [23]. 4substituted benzenesulfonylhydrazone has been found to have antibacterial activity [24]. A further extension of this area was made by the formation of the silver (I) complex of sulfonylamide which emphasized the role of metals in enhancing biological activity [25]. The transition metal complexes of hydrazides and sulfonamides also have applications in chemotherapy. The synergetic action of sulfonamides with trimethoprim has brought about an enormous resurgence of sulfonamide usage in many areas over the past decade. This prompted us to synthesize a series of novel symmetric aromatic sulfonamide complexes. We obtained a series of new sulfonamide complexes (1–5) and characterized their structure by FT-IR, LC/MS, UV–VIS, magnetic susceptibility and elemental analysis techniques. We also studied their antibacterial activities against gram-positive and gram-negative bacteria and as an antifungal agent using the disk diffusion method. All of the bacteria and fungus studied were screened against standard antibiotics to compare them with our chemical zone diameters. The structural formula of the series of aromatic sulfonamide complexes (1–5) is given in Fig. 1.
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Merck). Visualization was made with ultraviolet light. The molar magnetic susceptibilities were measured on powdered samples using the Gouy method. The molar conductance measurements were carried out using a Siemens WPA C 35 conductometer. All extracted solvents (all from Merck) were dried over anhydrous Na2SO4 and evaporated with a BUCHI rotary evaporator. Reagents were obtained commercially from Aldrich (ACS grade) and used as received. General procedure for the synthesis Synthesis of salicylaldehyde benzenesulfonylhydrazone (Hsalbsmh) A solution of bsmh [26] (4.95 ml, 50 mmol) in 5 ml ethanol was mixed with a solution of salicylaldehyde (5.31 ml, 50 mmol) in 5 ml ethanol and stirred all night. The product was recrystallized from acetonitrile three times. This resulted in a light yellow solid which is stable at normal conditions and soluble only in DMSO and DMF [26]. Synthesis of Ni(II), Pd(II), Pt(II), Cu(II), Co(II) complexes All complexes were prepared by the following general method. A sample of anhydrous MCl2 (M: Ni, Pd, Pt, Cu, Co) (0.01 mol) was dissolved in a mixture of ethanol and DMSO and a solution of hydrazone derivatives (0.02 mol, 7.8 g) in a mixture of DMSO and NaOH solution in ethanol (0.02 mol, 0.8 g) was added. The reaction mixture was heated at 40 °C for 30 min and left in an ice bath for 3 h. The solid complexes which formed were collected by filtration, washed with a small volume of ethanol and ether, and then dried in a desiccator over CaCl2[26]. The analytical and physical data for the Hsalbsmh ligand and its complexes are given in Table 1. Biological activity: in vitro evaluation
The infrared spectra of the compounds as KBr-disks were recorded in the range of 4000–400 cm − 1 with a Mattson 1000 FT-IR spectrometer. LC/MS-APC1 was recorded on an AGILENT 1100. UV– VIS spectra were recorded on a UNİCAM-UV 2–100 spectrophotometer. The melting point was recorded on an Opti MELT 3 hot stage apparatus. TLC was conducted on 0.25 mm silica gel plates (60 F254,
The biological activity of the synthesized sulfonamide derivatives was individually screened against a panel of microorganisms, including gram-positive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 11778, Enterococcus faecalis ATCC 29212, Bacillus subtilis ATCC 6633, Staphylococcus epidermidis ATCC 12228, Enterobacter aerogenes ATCC 13048) and gram-negative bacteria (Pseudomonas fluorescens ATCC 49838, Klebsiella pneumoniae ATCC 13883, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) and yeast (Candida albicans ATCC 90028). Cultures were obtained from Erciyes University, Faculty of Sciences, Department of Biology. Bacterial strains were cultured overnight at 35 °C in Triptic Soy Broth (TSB) and the yeast was cultured overnight at 35 °C in Yeast Peptone Dextrose Broth (YPDB) in a rotary shaker at 200 rpm. Overnight cultures were then transferred to a fresh medium and the turbidity of all broth cultures was adjusted to 0.1 absorbance at 640 nm on a spectrophotometer. These stock cultures were stored in the dark at 4 °C during the study.
Fig. 1. Fig. 1. M_Co(II), Ni(II), Cu(II), Pd(II), Pt(II) trans-bis(salicylaldehydebenzensülfonyl-1-methylhydrazonato) metal(II).
Determination of inhibition zones The disk diffusion antibacterial screenings [27–31] of synthesized sulfonamide derivatives dissolved in DMSO were performed using Miller-Hinton Agar (MHA) for the bacterial strains and Yeast Peptone Dextrose Agar (YPDA) for the yeast cells. 100 μl of the culture suspensions adjusted to OD640 0.1 (equivalent to 0.5 Mc Farland Turbidity) was swabbed over the entire surface of the medium (Bauer-Kirby, 1966; NCCLS 2000). Sterile 6-mm-diameter disks (1.2 mm thickness Whatman filter paper) were impregnated with 50 μl dissolved extracts (including 1.2 mg total extract per disk) and placed onto MHA or YPDA. Negative controls were prepared by using 50 μl of DMSO alone. For the bacterial cells ampicilin (50 μg/disk), trimethoprim (30 μg/disk), tetracycline (30 μg/disk) on MHA, and for the yeast cells miconazole (40 μg/disk) and nystatin (30 μg/disk) on YPDB were used as reference standards to determine the sensitivity of each strain. The inoculated plates were incubated at 35 °C for 18–24 h. Antibacterial activity was measured as the diameter (mm) of the clear
Experimental Physical measurements
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H.G. Aslan et al. / Inorganic Chemistry Communications 14 (2011) 1550–1553
Table 1 Analytical and physical data for Hsalbsmh ligand and complexes. Comp.
%C Found (Calculated)
%H
%N
%S
%Met
E.N (°C)
Empirical formula (formula weight)
Color
B.M
Conductivity (μs)
Hsalbsmh
57.916 (57.931) 52.740 (52.765) 49.072 (49.090) 43.446 (43.464) 52.350 (52.367) 52.760 (52.745)
4.860 (4.880) 4.134 (4.111) 3.844 (3.825) 3.405 (3.387) 4.094 (4.080) 4.096 (4.110)
9.648 (9.663) 8.768 (8.790) 8.159 (8.178) 7.259 (7.240) 8.741 (8.724) 8.801 (8.787)
11.042 (11.022) 10.085 (10.061) 9.380 (9.360) 8.298 (8.288) 9.998 (9.985) 10.050 (10.057)
–
167
L.Yellow
–
–
9.180 (9.208) 15.536 (15.563) 25.230 (25.212) 9.904 (9.894) 9.228 (9.242)
258
C14H14N2SO3 290.336 C28H26N4S2O6Ni 637.361 C28H26N4S2O6Pd 684.032 C28H26N4S2O6Pt 773.748 C28H26N4S2O6Cu 642.213 C28H26N4S2O6Co 637.601
L.Brown
0.34
1.14
Brown
0
0.90
Orange
0
0.50
D.Yellow
2.6
0.58
Brown
3.89
0.62
Ni(sal)2 Pd(sal)2 Pt(sal)2 Cu(sal)2 Co(sal)2
zone of growth inhibition. Four disks per plate were used and each test was run in duplicate. Results and discussion The results of elementary analysis showed 1:2 (metal/ligand) stoichiometry for all the complexes. The analytical results were in good agreement with those required by the general formula [ML2]. The molar conductivity (Λm) of the 10 − 3 M solutions of the complexes in DMSO at 25 °C was measured and all complexes were found to be of non-electrolytic nature. The Hsalbsmh ligand and its complexes which we studied have not been previously reported in the literature. The characterization of the compounds FT-IR spectra The wave number of the selected vibration of the IR spectra of the compounds is listed in Table 2. The IR spectra of the compounds were found to be very similar to each other. The most characteristic vibrations of the compounds are as follows: the asymmetric (vas) and symmetric (vs) stretching vibrations of the SO2 groups were observed at ~1231 and ~ 1250 cm − 1, ~ 1170 and ~1186 cm − 1 respectively. The C_N group stretching vibration band was found between 1601 and 1659 cm − 1. The (C_N) stretching vibration band of Hsalbsmh is observed at 1650 cm− 1. Upon the complex formation, the (C_N) stretching vibration band is shifted to a lower wave number (between 1647 and 1601 cm− 1). The (C\O) stretching vibration band of Hsalbsmh is observed 1258 cm− 1. Upon the complex formation, the (C\O) stretching vibration band is shifted to a higher wave number (between 1366 and 1400 cm− 1). NMR spectra The 1H-NMR spectrum of the Hsalbsmh compound showed that the OH proton had a wide peak at 10.30 ppm, and the N_CH proton at 8.60 ppm. Based on these data, the structure of the phenol-imine compound of Hsalbsmh was in the DMSO solution. On the other hand, the
Table 2 Wave number (cm− 1) of selected vibration of the compounds. Compound
vC\O
vas(SO2)
vs(SO2)
vC_N
Hsalbsmh Ni(salbsmh)2 Pd(salbsmh)2 Pt(salbsmh)2 Cu(salbsmh)2 Co(salbsmh)2
1258 1366 1367 1368 1400 1375
1250 1244 1231 1230 1240 1243
1180 1186 1173 1170 1175 1176
1659 1633 1621 1621 1647 1601
395 299 389 310
IR spectrophotometer observation of the ν(C\O) stretching vibration at 1258 cm − 1 and the ν(C_N) stretching vibration at 1659 cm − 1 convinced us to propose that the structure of phenol-imine was in the solid phase. The peaks of H and C atoms belonging to CH3, which is connected to the N atom, were observed at 2.60 ppm and 35.22 ppm, respectively. The aromatic C atom peaks were as follows: 158.22–117.13.
Mass spectra LC/MS shows that Ni(salbsmh)2, Pd(salbsmh)2, Cu(salbsmh)2, and Co(salbsmh)2 give the molecular ion [ML2] + at the desired positions: 637.20, 685.40, 642.30, and 637.95 m/z and Pt(salbsmh)2 gives the molecular ion, [PdL2+ NH4] + at 790.70 m/z. Ni (salbsmh)2 gives the isotope abundance at the desired positions [M ++ 2] [Ni metal isotope abundance] at 639.2 m/z and Hsalbsmh gives the molecular ion [Hsalbsmh + Na] + at 313.10 m/z Separately, all complexes and Hsalbsmh give the fragmentation of the C6H5 group, which is observed at 79.2 m/z.
Electronic spectra and magnetic behavior The significant electronic spectra of the ligand and complexes are recorded in DMSO. The important bands of the ligand are observed in the region of 430–332 nm. The magnetic moments of the complexes (as B.M.) were measured at room temperature. Nickel, palladium and platinum complexes have diamagnetic characters, and therefore their complexes have a square planar geometry. The effective magnetic moment values for Cu (salbsmh)2 and Co(salbsmh)2 complexes were 2.06 and 3.89 B.M., respectively. Low magnetic moment values support tetrahedral configurations for the Cu and Co complexes [32]. The magnetic moments of complexes (as B.M.) were measured at room temperature. The magnetic moment value (0.34 B.M.) for Ni (salbsmh)2, as well as the broad band in its electronic spectrum centered at 363 nm, suggested a square planar geometry around the nickel(II) ion. The observed band was due to the 1B1g → 1A1g and 1 A2g → 1A1g transitions in the square planar geometry. The electronic spectrum of the Pd(II) and Pt(II) complexes 353–354 nm, attributed to the 1A2g → 1B1g and 3B1g → 1A1g transitions respectively, indicated a square planar environment around the metal ions. The observed magnetic moments of the Palladium (II) and Platinum (II) complexes were 0 B.M. The electronic spectrum of the Cu (II) complex consisted of band 354 nm, arising from the 2Eg → 1T2g transition similar to that found for the tetrahedral complexes. At room temperature, the magnetic moment (2.06 B.M.) corresponded to a tetrahedral symmetry. The magnetic moment value (3.89 B.M.) for Co(salbsmh)2, the broad band in its electronic spectrum centered at 425 nm, suggested a tetrahedral geometry around the Co(II) ion. The observed band was due to the 4 T1(F) → 4A2 transition in the tetrahedral geometry [32].
H.G. Aslan et al. / Inorganic Chemistry Communications 14 (2011) 1550–1553
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Table 3 Inhibition zone of complexes by disk diffusion method (mm).
P. fluorescens P.aeruginosa E. coli K. pneumonia E.aerogenes S. aureus B. cereus B. subtilis S. epidermidis E. faecalis C. albicans
Ni
Pd
Pt
Cu
Co
Hsalbsmh
Tetrasilin (30 μg)
Trimetoprim (30 μg)
Miconazole (30 μg)
Nystatin (40 μg)
15 0 10 9 0 0 0 0 0 0 0
11 10 10 12 13 15 14 18 14 14 12
11 9 11 10 14 12 13 17 13 13 10
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 9 9 0 12 0 0
12 6 13 6 6 13 11 9 14 11 14
19 12 23 23 19 0 19 26 0 0 0
0 0 0 31 29 27 0 20 37 28 0
0 0 0 0 0 0 0 0 0 0 26
0 0 0 0 0 0 0 0 0 0 18
Inhibition zone (mm, 140 μg/disk) M(salbsmh)2.
Biological activity In the present study, the antimicrobial activities of compounds were screened against various pathogens in vitro by disk diffusion methods. Tetracycline, trimethoprim, micanazole, and nystatin were used as positive controls against both bacteria and yeast in the disk diffusion method. The results of the antibacterial and antifungal studies of all the synthesized compounds and those of the antibiotics are depicted in Table 3. Hsalbsmh and its Pd, Pt complexes were effective against all the gram-positive, gram-negative bacteria and fungi. The presence of electron densities in the \SO2NH\ group of sulfonamides contributes positively to the increase of the activity of the ligand against tested bacteria [33], but a decrease in electron densities by the coordination of donor atoms caused a decrease of activity [34]. Perhaps for this reason the nickel complex displayed good activity against gram-negative bacteria but the Co complex displayed poor activity against gram-positive bacteria, and the Cu complex displayed no activity against any bacteria or fungi. When these complexes were compared with each other, the Pd and Pt complexes displayed more activity than the Ni and Co complexes. The Cu complex displayed no activity against the tested bacteria. Conclusions In conclusion, a series of novel aromatic sulfonamide complexes were synthesized and their antimicrobial activities were evaluated. All compounds demonstrated potent inhibition against all the strains tested. From the spectroscopic characterization, it was concluded that sulfonylhydrazones act as bidentate ligands, coordinating through \C_N and phenolic \OH via deprotonation. Further research in this area is in progress at our laboratory. Consequently, these compounds may be recommended for industrial application. Acknowledgments The authors are grateful to the TUBITAK Research Foundation for its financial support under project number 104 T 390. References [1] W. Sneader, Drug Discovery: The Evolution of Modern Medicines, Wiley, New York, 1985. [2] C. Hansch, P.G. Sammes, J.B. Taylor, Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, 1990. [3] E. Dural, Farmakoloji, Nobel Tıp Kitap, İstanbul, 2002. [4] N. Pres, V.M. Chavez, E. Ticona, M. Calderon, I.S. Apolinario, A. Culotta, et al., Clinical Infectious Diseases, Natasha Press, Society of America, 2001. [5] Internet: Nokardia, http://www.wikipedia.org/wiki/Nocardia. 2005. [6] Internet: Drug, http://www.nlm.nih.gov/medlineplus/druginformation.html. 2003.
[7] M.B. Noss, G.J. Christ, A. Melman, Sildenafil: a new oral therapy for erectile dysfunction, Drugs Today 35 (1999) 211–217. [8] G. Brock, Sildenafil citrate (Viagra(R)), Drugs Today 36 (2000) 125–134. [9] J. Adkins, D. Faulds, Amprenavir, Drugs Today 55 (1998) 837–842. [10] B. Conway, S.D. Shafran, Pharmacology and clinical experience with amprenavir, Opin. Invest. Drug. 9 (2000) 371–382. [11] T.D. Penning, J.J. Taley, S.R. Bertenshaw, Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl]benzenesulfonamide (SC58635, celecoxib), J. Med. Chem. 40 (1997) 1347–1365. [12] Y. Tamura, F. Watanabe, T. Nakatani, Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives, J. Med. Chem. 41 (1998) 640–649. [13] P. Dauban, R.H. Dodd, Synthesis and GABA(A) receptor activity of 6-oxa-analogs of neurosteroids, Org. Lett. 2 (2000) 2327–2329. [14] A.G. Newcombe, Mesyl derivatives of hydrazine, Can. J. Chem. 33 (1955) 1250–1255. [15] H. Kloes, Farbenfabriken Bayer Akt.-Ges. 9 (1959) 411. [16] N.R. Lomax, V.L. Narayanan, Chemical structures of interest to the division of cancer treatment, Developmental Therapeutics Program, VI, National Cancer Institute, Bethesta, MD, 1988. [17] P.B. Jensen, B.S. Soerensen, J.F.E. Demant, M. Sehested, P.S. Jensen, L. Vindeloey, et al., In vitro evaluation of the potential aclarubcin in the treatment of small cell carcinoma of the lung, Cancer Res. 50 (1990) 3311. [18] G.J. Finlay, B.C. Baguley, K. Snow, W. Judd, Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues, Natl. Cancer Inst. 82 (1990) 662. [19] H. Rutner, N. Lewin, E.C. Woodburry, T.J. McBride, K.V. Rao, Cancer Chemother. Rep. 58 (1974) 803. [20] R.P. Baumann, K. Shyam, P.G. Penketh, J.S. Remack, T.P. Brent, A.C. Sartorelli, -1,2Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (VNP40101M): II. Role of O6 -alkylguanine-DNA alkyltransferase in cytotoxicity, Cancer Chemother. Pharmacol. 53 (4) (2004) 288–295. [21] L.L. Silva, K.N. Oliveira, R.J. Nunes, Synthesis and characterization of chloromaleimidobenzenesulfonylhydrazones, ARKIVOC 13 (2006) 124–129. [22] L.M. Lima, E.G. Amarante, A.L.P. Miranda, C.A.M. Fraga, E.J. Barreiro, Synthesis and antinociceptive profile of novel acidic sulfonylhydrazone derivatives, from natural safrole, Pharm. Common. 5 (1999) 673–678. [23] X.P. Gou, Y. Xu, L. Tang, F. Yan, F. Chen, Representative cDNA library from isolated rice sperm cells, Acta. Bot. Sin. 43 (2001) 1093–1096. [24] H. Zimmer, B.H. Benjamin, E.H. Gerlach, K. Fry, A.C. Pronay, H. Schmank, Synthesis of trisubstituted vinyl chlorides, J. Org. Chem. 24 (1959) 1667–1669. [25] C.E. Brown, J.L. Towle, N1-Silver derivatives of sulfonamide and some related compounds, Am. Chem. Soc. 63 (1941) 3523. [26] H.G. Aslan, Ph.D. Thesis, Gazi University, Ankara, (2008). [27] K.K. Anderson, in: D.N. Jones (Ed.), Comprehensive Organic Chemistry, 3, Pergamon Press, Oxford, 1979, p. 345. [28] S.L. Graham, T.H. Scholz, The reaction of sulfinic acid salts with hydroxylamine-Osulfonic acid. A useful synthesis of primary sulfonamides, Synthesis 12 (1986) 1031–1032. [29] A. Boruah, M. Boruah, D. Prajapati, J.S. Sandhu, The efficient chemoselective reduction of azides to primary amines, Synlett (1997) 1253. [30] S. Iyer, A.K. Sattar, Ni[P(OPh)3]4 catalyzed transfer hydrogenation using HCOONH4, Synth. Commun. 28 (1998) 1721. [31] W.Y. Chan, C. Berthelette, A mild, efficient method for the synthesis of aromatic and aliphatic sulfonamides, Tetrahedron Lett. 43 (2002) 4537. [32] A.B.P. Lever, Inorg. Electronic Spectroscopy, second ed. Elsevier, Amsterdam, 1984. [33] Y.M. Al-Hıari, B.A. Sweileh, Novel synthesis and antimicrobial activity of 3,7dimethylphenoxathiin nucleus and some related analogs, Asian J. Chem. 18 (2006) 2285. [34] N. Zanatta, S.H. Alues, H.S. Coelho, et al., Synthesis, antimicrobial activity, and QSAR studies of furan-3-carboxamides, Bioorg. & Med. Chem. 15 (2007) 1947.