A cooperative hydrogen bonding system with a CH⋯O hydrogen bond in ofloxacin

Journal of Molecular Structure 1040 (2013) 122–128

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A cooperative hydrogen bonding system with a CAH  O hydrogen bond in ofloxacin Xiuxiang Gao a, Yufeng Liu a,b, Huizhen Li a,c, Jiang Bian a, Ying Zhao b, Ye Cao a, Yuezhi Mao a, Xin Li a, Yizhuang Xu a,⇑, Yukihiro Ozaki d, Jinguang Wu a a

Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, PR China Beijing National Laboratory for Molecular Sciences, Key Laboratory of Engineering Plastics, CAS, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China c College of Chemistry and Environmental Science, Henan Normal University, Xinxiang 453007, PR China d Department of Chemistry, School of Science and Technology, Kwansei-Gakuin University, Sanda 669-1337, Japan b

h i g h l i g h t s " Intra-molecular CAHO hydrogen bond is formed between an aromatic proton and a carboxyl oxygen in ofloxacin. " The CAH  O hydrogen bond forms a cooperative hydrogen bonding system with a neighboring OAH  O hydrogen bond. " Formation/disruption of the cooperative hydrogen bonds regulates the conformation and

a r t i c l e

i n f o

Article history: Received 15 December 2012 Received in revised form 10 February 2013 Accepted 14 February 2013 Available online 7 March 2013 Keywords: NMR CAH  O hydrogen bond Ofloxacin

p–p transition of ofloxacin.

a b s t r a c t We have investigated a cooperative hydrogen bonding system with a CAH  O hydrogen bond in ofloxacin by using NMR, UV–Vis spectra together with quantum chemistry calculation. Both pH-dependent NMR experiments and DFT calculation indicate that the intra-molecular CAH  O hydrogen bond between an aromatic proton and an oxygen atom from the carboxyl group is formed. Notably, the CAH  O hydrogen bond forms a cooperative hydrogen bonding system with a neighboring OAH  O hydrogen bond between the carboxyl group and the keto oxygen. The cooperative hydrogen bonding system makes the formation and disruption of the OAH  O and CAH  O hydrogen bonds in a synergistic manner. Comparison on the pKa value of the carboxylic group in different fluoroquinolones compounds indicates that the CAH  O hydrogen bond plays a significant role in stabilizing the OAH  O hydrogen bond. In addition, the formation and disruption of the cooperative hydrogen bonding system could regulate the conformation of the carboxyl group, which affects the size of the conjugated system and spectral behavior of p–p transition of ofloxacin. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Hydrogen bonding in its various facets continues to be a topic of intense scrutiny in various chemical and biological systems, as it plays a vital role in stabilizing molecular structures, modulating specificity, speed of enzymatic reactions, and constructing supramolecular structures [1–5]. Conventional hydrogen bonds of the type XAH  Y (where X and Y are electron negative atoms such as O, N, F and Cl) have widely been studied. On the other hand, a close CAH  O contact has been observed in many chemical and biological systems [3–20]. Albeit postulated early by Huggins and Pauling, it is not until the last half of the 1990s that CAH  O inter-

⇑ Corresponding author. E-mail address: [email protected] (Y. Xu). 0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2013.02.017

action has been widely accepted as a kind of hydrogen bonding [3– 5,8]. Nowadays, CAH  O hydrogen bond has been one of the main topics of hydrogen bond research from both experimental and theoretical points of view. Evidences have been accumulating to show that weak hydrogen bond such as CAH  O, CAH  N [18], OAH   p [19] hydrogen bonds acts as an important factor of stabilizing particular structures of molecules and molecular assemblies in polymers, proteins, nuclear acids and so on. Moreover, cooperativity is an important attribute of interconnected hydrogen bonds. This effect refers to enhanced stability of a system containing two or more interconnected hydrogen bonds. In recent years, attention has been focused on investigating the existence of such effects in systems where CAH  O are involved [20]. Ofloxacin ((±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzoxacine-6-carboxylic acid) is a nalidixic acid analog with broad spectrum

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17

18 O 19

8

F

9

7

13

6'

N CH3

4'

15

10

N

1'

C

C 6

5'

OH

O

O

N

16 12

11

N4

5

F

O

2'

3

1

3'

2

7'

H

CH3 14

Scheme 1. Molecular structure of ofloxacin.

antibacterial activity (Scheme 1). It belongs to the fluoroquinolones groups, which act as specific inhibitors of the bacterial DNA-gyrase [21,22]. Ofloxacin possesses a large conjugated system, which is responsible for the absorption of UV–Vis radiation and intrinsic fluorescence of the molecule [23]. Accordingly, various analytical methods with high sensitivity have been developed to monitor the metabolism of fluoroquinolones [24–29]. However, the conjugated system makes ofloxacin be involved in cleavage of DNA under UV radiation. Consequently, ofloxacin may exhibit phototoxic behavior. Ofloxacin and its analog are even suspected to be a new class of photochemical carcinogens [30–34]. Up to now, molecular behavior of ofloxacin under UV–Vis radiation has not been fully elucidated and further investigations on the photophysical properties of fluoroquinolones are needed. Ofloxacin contains a keto oxygen at C7 and a carboxylic group at C6, both of which are known to be essential to the pharmaceutical activity of ofloxacin. Because the drug contains a carboxyl group, variation of pH value of the aqueous solution is supposed to bring about significant changes on its physicochemical behavior. Blue fluorescence is observed under UV radiation when the pH value is around 7, while green fluorescence occurs as the pH value changes to 3. Additionally, it has been reported that the in vivo behavior of fluoroquinolone antibacterials is strongly affected by their physicochemical properties, in particular their acid–base properties [35]. From the molecular structure point of view, variation of the environmental pH value will change the protonation states of carboxyl group and amino groups in ofloxacin, which will affect the hydrogen bonding, conformation and physicochemical behavior of the molecule. To our acknowledgement, no reported on this issue has been found in the literature. In our previous work, we have performed a preliminary investigation on ofloxacin by using NMR spectroscopy and assignments on 1H NMR and 13C NMR spectra have been obtained [36]. In this paper, we use pH dependent NMR spectra, pH dependent UV–Vis spectra together with quantum chemistry calculation to investigate the structural variation of ofloxacin. The investigations have led us to find some evidence of the existence of a CAH  O hydro-

Fig. 1A. Calculated structure of ofloxacin cation. Both a conventional OAH  O hydrogen bond and a CAH  O hydrogen bond are marked by dash lines.

C O N F H

Fig. 1B. Calculated structure of ofloxacin zwitterion. The disruption of the conventional OAH  O hydrogen bond weakens or breaks the CAH  O hydrogen bond.

gen bond in ofloxacin. Furthermore, the CAH  O hydrogen bond together with a conventional OAH  O hydrogen bond form a cooperative hydrogen bonding system. The cooperative effect causes the formation and disruption of the CAH  O and OAH  O hydrogen bond in a synchronous manner. Such phenomena may play an important role in controlling the electronic spectroscopic behavior via modulating the conformation of ofloxacin. 2. Experimental 2.1. Reagents Ofloxacin was obtained from Kunshan pharmaceutical cooperation and used without further purification. D2O, DCl and NaOD were purchased from Beijing Chemical Factory.

O

D O

O

F

COO

F O H

N

N

OD N

D ND

ND CH 3

O CH3

H

N

O

CH3

Scheme 2. Inter-conversion between cation form and zwitterion form of ofloxacin.

CH 3

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O

pD=9.0 pD=8.0

COOH

O

pD=7.0 pD=6.7

O

pD=6.4

N N

pD=6.0 pD=5.0 Scheme 3. Molecular structure of cinoxacin.

pD=4.0 pD=3.0 8.5

8.0

7.5

H2O peak (PRESAT.AUR) was utilized. A 30° pulse with pulse width of 3.2 ls and 128 accumulations were used to generate NMR spectra with 16 K data points. A standard inversion–recovery pulse sequence (INVREC.AUR) was used to measure T1 time. The experimental parameters were as follows: a 90° pulse with 9.6 ls pulse width was used, ns = 16, D1 = 5 s.

7.0

δH(ppm) Fig. 2. pD dependent 1H NMR spectra of ofloxacin.

2.4. UV–Vis spectroscopy

8.50

UV–Vis spectra of the ofloxacin solutions were recorded on a Varian Cary 1E UV–Vis spectrophotometer and the spectra were measured at a scanning rate of 60 nm/min. To make the maximum absorbance be within 1.4, the solution was sandwiched by a pair of BaF2 windows using a PE film (25 lm) as a spacer during the spectral measurement.

Chemical Shift/ppm

8.40

8.30

8.20

2.5. Quantum chemistry calculation 8.10

8.00

7.90

2.5

3.5

4.5

5.5

6.5

7.5

8.5

9.5

pD Fig. 3. Variation of the chemical shift of 5H atom in ofloxacin as a function of the pD value of the solutions.

The geometry optimization of two molecular structures (ofloxacin cation: the carboxylic group exists as COOH and the N40 occurs as ammonium; zwitterion: a proton is removed from the carboxyl group (Scheme 2)) was carried out using DFT method with the hybrid functional B3LYP [37,38] and the triple-zeta basis set 6-311++g(d,p) was employed. A solvent effect was also considered by applying the polarizable continuum model (PCM) in geometry optimization with epsilon = 78.25 (the dielectric constant of the solvent, D2O) [39]. All the calculations were carried out using Gaussian 09 package [40]. 3. Results and discussions

2.2. Preparation of the D2O solution of ofloxacin A mixture of ofloxacin (1.0 g) and D2O (40 mL) was boiled under stirring and then cooled to room temperature. Subsequently, insoluble substances were removed by filtering and then a saturated D2O solution of ofloxacin was obtained and used as a stock solution. The concentration of the stock solution was measured to be 7.4  103 mol/L by using UV–Vis spectrometry (please see the Supporting information). The stock solution of ofloxacin was diluted by D2O and the pD value of the solution was adjusted by DCl or NaOD. To remove a concentration effect on the spectral behavior, the concentration of ofloxacin was kept as 5.9  103 mol/L. 2.3. NMR spectroscopy 1 H NMR spectra of the ofloxacin solutions were obtained on a Bruker AM-300 NMR spectrometer operating at 300.13 MHz in Fourier transform mode. Capillaries filled with dioxane were used as external references for 1H (d = 3.70 ppm). NMR spectra whose spectral widths were 2994 Hz were obtained in the range of pD 3–9 and a pulse sequence to suppress

In our previous work, we carried out NMR spectroscopic investigation of ofloxacin dissolved in acidic and alkaline aqueous solutions. Assignments of all the 1H and 13C signals have been obtained [36]. The work left an unexplained phenomenon: Ofloxacin possesses two protons attached to conjugated carbon atoms, namely H5 and H8. The two protons exhibit dramatically different spectral behavior. When the D2O solution of ofloxacin changes from alkaline to acidic, the H5 signal undergoes a remarkable down-field shift while the variation of H8 signal is insignificant. Recently, we notice that the structural feature of ofloxacin is helpful to understand why H5, which is supposed to be a hydrophobic proton, exhibits such a high sensitivity to the variation of pD of its aqueous solution. The H5 proton is at one ortho-position of a carboxyl group whose another ortho-position is occupied by a keto oxygen atom. In an acidic solution, the carboxyl group exists as COOD (Scheme 2). Such a structural feature makes it possible to form an intra-molecular OAD  O hydrogen bond between the carboxyl group and the neighboring keto oxygen. This intra-molecular hydrogen bonding is favorable since a six-member ring is formed. The intra-molecular OAD  O hydrogen bond renders the oxygen atom from the C@O of carboxyl group to be closed to the H5

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X. Gao et al. / Journal of Molecular Structure 1040 (2013) 122–128 Table 1 The molecular structure and pKa value of a series of quinolone compounds. Quinonlone compounds

Molecular Structure

pKa (COOH)

O

Nalidixic acid

6.04

COOH

N

N

O

Oxolinic acid

6.92

COOH

O

O

N

O

Lomefloxacin

F

5.82

COOH

N

N

NH

F

O

Flumequine

F

6.3

COOH

N

O

Norfloxacin

F

N

6.3

COOH

N

NH

O

Ciprofloxacin

F

N

6.09

COOH

N

HN

(continued on next page)

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Table 1 (continued) Quinonlone compounds

Molecular Structure

pKa (COOH)

O

Enoxacin

F

N

6.31

COOH

N

N

NH

pD=9.0 pD=8.0 pD=7.0 pD=6.7 pD=6.4 pD=6.0 pD=5.0 pD=4.0 pD=3.0 280

260

300

Wavelength/nm

320

Fig. 4. pD dependent UV–Vis spectra of ofloxacin.

295 294

λmax/nm

293 292 291 290 289 288 287 286 2.5

3.5

4.5

5.5

6.5

7.5

8.5

9.5

pD Fig. 5. Diagram of the peak position of the absorption band of ofloxacin vs the pD value of the solutions.

proton. Thus, we hypothesized that an intra-molecular CAH  O hydrogen bond is formed between the H5 proton and the C@O of the carboxyl group. The CAH  O hydrogen bonding is possible since a five-member ring is involved (Scheme 2). In an alkaline solution, the carboxyl group changes into COO, breaking the OAD  O hydrogen bond. Consequently, the CAH  O hydrogen bond also breaks. Quantum chemistry calculated results support the above hypothesis. Fig. 1A illustrates the structure of ofloxacin cation obtained after structural optimization. The OAH  O hydrogen bond occurs between the OH group (O17AH17) of the carboxyl group

and the carbonyl oxygen (O18) attached to C7. The hydrogen bond makes the COOH group be co-planar with the aromatic rings. As a result, the O16AH5 distance (DO16  H5) and the C5AO16 distance (DO16  C5) become 2.48 Å and 2.81 Å, respectively. According to the literature [41], the Van der Waals radius of oxygen atom is 1.50 Å. The Van der Waals radii of hydrogen and carbon atoms are in the range of 1.20–1.45 Å and 1.65–1.70 Å, respectively. Thus, the summation of the Van der Waals radii RO  H and RC  O are in the range of 2.70–2.95 Å and 3.15–3.20 Å. The fact that the DO16  H5 and DO16  C5 are smaller than the corresponding summation of the Van der Waals radii provides an evidence for the formation of CAH  O hydrogen bond. Fig. 1B shows the molecular structure of ofloxacin zwitterion where the carboxyl group changes into the carboxylate group. The carboxylate group and the aromatic ring are not co-planar any more. The angle between the carboxylate group and the aromatic ring can be characterized by a dihedral angle xC5AC6AC15AO16 whose value turns out to be 63.63°. As a result, the corresponding DO16  H5 and DO16  C5 become 2.879 Å and 3.006 Å, respectively. In comparison with ofloxacin cation, both DO16  H5 and DO16  C5 in ofloxacin zwitterion increase significantly. The increasing of DO16  H5 and DO16  C5 implies that the CAH  O hydrogen bond is weakened remarkably or even disrupted when COOD changes into COO. If the H5 proton is involved in a hydrogen bond, the resultant longitude relaxation time (T1) of H5 is anticipated to undergo significant variations upon the formation and disruption of the CAH  O hydrogen bond. When the CAH  O hydrogen bond occurs, additional restriction causes the proton to be less mobile and relax much faster. Therefore, T1 is expected to exhibit a smaller value. The disruption of the hydrogen bond removes the restriction so that the proton becomes more mobile. Thus, T1 increases considerably. Herein, T1 of the H5 proton was measured in both acidic and alkaline D2O solutions. The result demonstrates that the T1 value of the H5 proton of ofloxacin in the acidic solution is around 0.5 ms, while the corresponding T1 value is around 0.65 ms in the alkaline solution. Therefore, the variation of the longitude relaxation time (T1) of H5 provides another evidence to support the hypothesis that the C5AH5  O16 hydrogen bond exists in the acidic solution, while the CAH  O hydrogen bond is disrupted in the alkaline solution. Based on the above results, we suggest that the formation and disruption of the CAH  O hydrogen bond are triggered by interconversion of protonation states of the carboxyl group. In the acidic solution, the formation of O17AH17  O18 hydrogen bond favors the formation of C5AH5  O16 hydrogen bond. The CAH  O hydrogen bond makes the chemical shift of H5 stay in down field region in the 1H NMR spectrum. In the alkaline solution, the removal of the H17 proton from the carboxyl group disrupts the O17AH17  O18 hydrogen bond. As a result, the CAH  O hydrogen bond is also disrupted and the chemical shift of H5 moves

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up-field in 1H NMR spectrum. It is thus expected that the chemical shift of H5 undergoes remarkable variation when the pD values of D2O solutions crosses the pKa of the carboxyl group of ofloxacin. Thus, a pD-dependent 1H NMR spectroscopic experiment was conducted and the value of dH5 is plotted against pD (Figs. 2 and 3). The shape of the plot showed a step curve with a sudden drop between two plateau regions. The H5 proton stays in one state with the chemical shift around 8.4 ppm when pD is between 3 and 5. On the other hand, the H5 proton stays in another state with dH5 around 8.0 ppm when pD is between 7 and 9. Transition from one state to another occurs in a quite narrow pD region and the dH5 undergoes a steep drop when pD is around 6.0. We denote the pD value for the steep drop of dH5 as pDC. According to the literature [24,42], the pKa of the carboxyl group of ofloxacin is about 6.05. In another reference, the pKa value is reported to be 6.10 [23]. The above facts that the value of pDc is quite close to the pKa of ofloxacin indicates that variation of the chemical shift is closely related to the inter-conversion of protonation state of carboxyl group. This result supports the hypothesis that the formation and disruption of the CAH  O hydrogen bond are closely related to the inter-conversion of COOH group. The above results demonstrate that a conventional OAH  O hydrogen bond and a proposed CAH  O hydrogen bond constitute a cooperative hydrogen bonding system. On one hand, the OAH  O hydrogen bond may play a decisive role so that the formation and disruption of the OAH  O hydrogen bond and CAH  O hydrogen bond are in a synergistic fashion. On the other hand, the CAH  O hydrogen bond may also contribute to the stabilization to the OAH  O hydrogen bonding by affecting the deprotonation of COOH. Scheme 3 depicts the molecular structure of another quinolone compound, cinoxacin. The CAH at the orthoposition of carboxyl group is replaced by a nitrogen atom, thereby precluding the possibility of the formation of CAH  O hydrogen bonding. The lack of the CAH  O hydrogen bonding may account for the low pKa of cinoxacin (pKa = 5.32). For comparison, Table 1 lists a series of quinolone compounds that have a proton at one ortho-position of a carboxyl group. Their pKa values range from 5.8 to 6.3 [24]. The structural feature of ofloxacin suggests that the electronic spectral behavior should also be affected by the cooperative hydrogen bonding system. In the acidic solutions, both the conventional OAH  O hydrogen bond and the CAH  O hydrogen bond occur. The cooperative hydrogen bonding system plays a stabilizing role to maintain ofloxacin in such a conformation that the carboxyl group is co-planar with the aromatic rings. Thus, the carboxyl group is expected to take part in the conjugated system of the molecule. The conjugated system with a larger size is anticipated to cause the p–p transition band to occur in a longer wavelength region. In the alkaline solutions, the removal of proton from carboxyl group results in the disruption of the cooperative hydrogen bonding system. Thus, the carboxylate group rotates out of the aromatic plane and does not take part in the conjugated system any more since the carboxylate group and the aromatic ring are not coplanar. The conjugated system with a smaller scale is anticipated to cause the p–p transition band to appear in a short wavelength region. Experimental results confirm the above expectation. The UV– Vis of ofloxacin in different pD values are shown in Fig. 4. The main peaks in both UV–Vis spectra of ofloxacin can be assigned to the p– p transition. In the alkaline solutions, the p–p transition band of ofloxacin is located at ca 287 nm in the UV–Vis spectra. Upon acidification, the bands show a red-shift. Fig. 5 shows the peak position in the UV–Vis spectra as a function of pD of the D2O solutions. The shape is a downward step with a drop when pD is between 5 and 8. The pKa of carboxyl group is again just within the drop region. Therefore, these results further support that change of the

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electronic spectral behavior is related to the formation and disruption of the cooperative hydrogen bond system. 4. Conclusion In this work, an intra-molecular CAH  O hydrogen bond which accounts for down-filed shift of 1H NMR signal and decreasing of T1 was observed in acidic ofloxacin. The CAH  O hydrogen bond forms a cooperative hydrogen bond system with the conventional OAH  O hydrogen bond. Thus formation and disruption of the two hydrogen bonds can be adjusted by pD in a synergistic manner. The cooperative hydrogen bond system plays an important role in modulating the electronic spectral behavior by controlling the conformation of the molecule. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant Nos. 50973003 and 50673005), National High-tech R&D Program of China (863 Program) of MOST (No. 2010AA03A406) and A Program of Advanced Technology Institute, Peking University. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.molstruc.2013. 02.017. References [1] G.A. Jeffrey, W. Saenger, Hydrogen Bonding in Biological Structure, SpringerVerlag, Berlin, New York, 1991. [2] G.C. Pimentel, A.L. McClellan, The Hydrogen Bond, W.H. Freeman and Company, London, 1960. [3] K.C.K. Swamy, S. Kumaraswamy, P. Kommana, JACS 123 (2001) 12642–12649. [4] Q.Z. Li, G.S. Wu, Z.W. Yu, JACS 128 (2006) 1438–1439. [5] F. Cordier, M. Barfield, S. Grzesiek, JACS 125 (2003) 15750–15751. [6] H. Matsuura, H.I. Yoshida, M. Hieda, S. Yamanaka, T. Harada, K. Shin-ya, K. Ohno, JACS 125 (2003) 13910–13911. [7] P.J.A. Ribeiro-Claro, M.P.M. Marques, A.M. Amado, Chemphyschem 3 (2002) 599–606. [8] P.D. Vaz, P.J.A. Ribeiro-Claro, J. Raman Spectrosc. 34 (2003) 863–867. [9] E. Arbely, I.T. Arkin, JACS 126 (2004) 5362–5363. [10] H. Sato, R. Murakami, A. Padermshoke, F. Hirose, K. Senda, I. Noda, Y. Ozaki, Macromolecules 37 (2004) 7203–7213. [11] H. Sato, J. Dybal, R. Murakami, I. Noda, Y. Ozaki, J. Mol. Struct. 744–747 (2005) 35–46. [12] H. Sato, R. Murakami, J. Zhang, K. Mori, I. Takahashi, H. Terauchi, I. Noda, Y. Ozaki, Macromol. Symp. 230 (2005) 158–166. [13] H. Sato, K. Mori, R. Murakami, Y. Ando, I. Takahashi, J. Zhang, H. Terauchi, F. Hirose, K. Senda, K. Tashiro, I. Noda, Y. Ozaki, Macromolecules 39 (2006) 1525– 1531. [14] Y. Hu, J. Zhang, H. Sato, Y. Futami, I. Noda, Y. Ozaki, Macromolecules 39 (2006) 3841–3847. [15] H. Sato, R. Murakami, J. Zhang, Y. Ozaki, K. Mori, I. Takahashi, H. Terauchi, I. Noda, Macromol. Res. 14 (2006) 408–415. [16] J.G. Wu, X.X. Liang, Y.Z. Lin, H. Guo, G.X. Xu, Chem. J. Chin. Univ. 6 (8) (1985) 724–728. [17] N. Shi, J.G. Wu, X.H. Xu, G.X. Xu, Chem. J. Chin. Univ. 5 (2) (1984) 210–214. [18] M. Salamone, G. Anastasi, M. Bietti, G.A. DiLabio, Org. Lett. 13 (2) (2011) 260– 263. [19] K. Subramanian, S. Lakshmi, K. Rajagopalan, G. Koellner, T. Steiner, J. Mol. Struct. 384 (1996) 121–126. [20] A.K. Samanta, P. Pandey, B. Bandyopadhyay, T. Chakraborty, J. Phys. Chem. A 114 (2010) 1650–1656. [21] I. Turel, Coordin. Chem. Rev. 232 (2002) 27–47. [22] L.J. Ming, Med. Res. Rev. 23 (6) (2003) 697–762. [23] H.R. Park, T.H. Kim, K.M. Bark, Eur. J. Med. Chem. 37 (2002) 443–460. [24] U. Neugebauer, A. Szeghalmi, M. Schmitt, W. Kiefer, J. Popp, U. Holzgrabe, Spectrochim. Acta Part A 61 (2005) 1505–1517. [25] J.X. Du, Y.H. Li, J.R. Lu, Luminescence 20 (2005) 30–35. [26] A.M. de la Peña, A.E. Mansilla, D.G. Gómez, A.C. Olivieri, H.C. Goicoechea, Anal. Chem. 75 (2003) 2640–2646. [27] H.W. Sun, L.Q. Li, X.Y. Chen, Anal. Chim. Acta 576 (2006) 192–199.

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