Molecular docking, geometrical structure, potentiometric and thermodynamic studies of moxifloxacin and its metal complexes

Journal of Molecular Liquids 220 (2016) 802–812

Contents lists available at ScienceDirect

Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq

Molecular docking, geometrical structure, potentiometric and thermodynamic studies of moxifloxacin and its metal complexes Heba M. Refaat a, Hemmat A. El-Badway a,1, Sh.M. Morgan b,⁎ a b

Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt Environmental Monitoring Laboratory, Ministry of Health, Port Said, Egypt

a r t i c l e

i n f o

Article history: Received 16 April 2016 Received in revised form 24 April 2016 Accepted 29 April 2016 Available online xxxx Keywords: Molecular docking Moxifloxacin Geometrical structure Potentiometry study Thermodynamics parameters

a b s t r a c t Molecular docking was used to predict the binding between moxifloxacin (H2L) and the receptors of breast cancer mutant (3hb5), prostate cancer mutant (2q7k), crystal structure E. coli (3t88) and crystal structure of S. aureus (3q8u) and it was found that the moxifloxacin shows best interaction with 3hb5 receptor other than receptors. The geometrical structure of moxifloxacin is discussed. The proton-ligand dissociation constant of moxifloxacin (H2L) and metal-ligand stability constants of its complexes with metal ions (Mn2+, Co2+, Ni2+ and Cu2+) have been determined potentiometrically in 0.1 M KCl and 10% (by volume) ethanol–water mixture. At constant temperature, the stability constants of the formed complexes increase in the order of Mn2+ b Co2+ b Ni2+ b Cu2+. The effect of temperature was studied at 298, 308 and 318 K and the corresponding thermodynamic parameters (ΔG, ΔH and ΔS) were derived and discussed. The dissociation process is non-spontaneous, endothermic and entropically unfavorable. The formation of the metal complexes has been found to be spontaneous, endothermic and entropically favorable. The predicted pKa obtained by docking measurements for moxifloxacin (H2L) are in agreement with experimental values. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Development of metal complexes as artificial nucleases is an area of interest. Floroquinolone derivatives possess a broad spectrum of activity against various pathogenic microorganisms, which are resistant to aminoglycosides, penicillins, cephalosporins, tetracyclines and other antibiotics. This class of compounds, when compared to existing bactericidal drugs, shows improved pharmacokinetic properties and a broad spectrum of activity against parasites, bacteria, and mycobacteria, including resistant strains. The quinolone compounds were effectives against Gram-positive and Gram-negative bacteria [1] that can be used in a wide range of gastrointestinal, urinary and respiratory tract infections; ocular and skin infections as well as in patients with intra abdominal infections in combination with anti an aerobic agents. Various biological studies of quinolones have been focused on their interaction with DNA [2] and potential antitumor activity [3]. Several reports have also pointed out several examples of complexes due to their vast potential utilities through their interactions against microorganisms and tumour activity [4,5]. The moxifloxacin is a third-generation fluoroquinolone, with markedly improved gram-positive activity that is commonly

⁎ Corresponding author. E-mail address: [email protected] (S.M. Morgan). 1 Present address: Chemistry department, Faculty of Science, Tabuk University, KSA.

http://dx.doi.org/10.1016/j.molliq.2016.04.124 0167-7322/© 2016 Elsevier B.V. All rights reserved.

prescribed for respiratory tract infections [6]. Other advantages include a lower resistance rate compared to levofloxacin and a lower risk of adverse effects, including a lower propensity for inducing phototoxic reactions and CNS adverse effects compared to other fluoroquinolones [7,8]. Determination of pK a as physicochemical parameter may be essential for the interpretation of structure-activity relationships of this drug [9]. The aim of the present work is to investigate the molecular structure, molecular docking, potentiometry study and thermodynamics parameters. The structure and the ground-state energy of the moxifloxacin under investigation have been analyzed employing density functional theory with 3-21G basis set. The reported optimized geometries, molecular properties such as highest occupied molecular orbital energy (EHOMO), the lowest unoccupied molecular orbital energy (ELUMO) and HOMO–LUMO energy gap (ΔE) as well as essential free energy of binding have also been used to understand the activity of moxifloxacin.

2. Materials and methods 2.1. Material Moxifloxacin hydrochloride (Fig. 1), chemically known as [1cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-pyrrolo[34-b]pyridin6-yl)-4-oxo-1.4-dihydroquinoline-3-carbox-ylic acid] hydrochloride, Mr = 437.90, was obtained from Bayer Pharma AG (Germany). The

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803

the temperatures of 308 and 318 K. All titrations have been carried out between pH 3.5–11.5 and under nitrogen atmosphere. 3. Results and discussion 3.1. Molecular structure study

Fig. 1. Structure of moxifloxacin hydrochloride (H2L).

compound and solvents used were purchased from Aldrich and Sigma and used as received without further purification. 2.2. Measurements The molecular structure of moxifloxacin was optimized by HF method with 3-21G basis set. The molecule was built with the Perkin Elmer Chem Bio Draw and optimized using Perkin Elmer Chem Bio 3D software [10,11]. Quantum chemical parameters such as the highest occupied molecular orbital energy (EHOMO), the lowest unoccupied molecular orbital energy (ELUMO) and HOMO–LUMO energy gap (ΔE) for ligand are calculated. In the study simulates the actual docking process in which the ligand–protein pair-wise interaction energies are calculated using Docking Server [12]. The MMFF94 Force field was for used energy minimization of ligand molecule using Docking Server. Gasteiger partial charges were added to the moxifloxacin atoms. Docking calculations were carried out on moxifloxacin protein model. Essential hydrogen atoms, Kollman united atom type charges and solvation parameters were added with the aid of AutoDock tools [13,14]. Auto Dock parameter set- and distance-dependent dielectric functions were used in the calculation of the van der Waals and the electrostatic terms, respectively. 2.3. Potentiometric studies The pH measurements were carried out using VWR Scientific Instruments Model 8000 pH-meter accurate to ±0.01 units. Titrations were performed in a double walled glass cell in an inert atmosphere (nitrogen) at ionic strength of 0.1 M KCl. Potentiometric measurements were carried out at different temperature [15,16]. The temperature was controlled to within ±0.05 K by circulating thermo-stated water (Neslab 2 RTE 220) through the outer jacket of the vessel. A ligand solution (0.01 M) was prepared by dissolving an accurately weighted amount of the solid in ethanol. Metal ion solutions (0.001 M) were prepared from metal chlorides in double distilled water and standardized with EDTA [17]. Solutions of 0.005 M HCl and 1 M KCl were also prepared in double distilled water. A carbonate-free NaOH solution in 10% (by volume) ethanol-water mixture was used as titrant and standardized against oxalic acid. The apparatus, general conditions and methods of calculation were the same as in previous work [18]. The following mixtures (i)–(iii) were prepared and titrated potentiometrically at 298 K against standard 0.02 M NaOH in a 10% (by volume) ethanol-water mixture:

The optimized structure, bond length and bond angles of moxifloxacin (H2L) are presented in Fig. 2 and Table 1. Both the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are the main orbital takes part in chemical stability [19]. The HOMO represents the ability to donate an electron, LUMO as an electron acceptor represents the ability to obtain an electron as shown in Fig. 3. Quantum chemical parameters of moxifloxacin are obtained from calculations such as energies of the highest occupied molecular orbital (EHOMO) and the lowest unoccupied molecular orbital (ELUMO) as listed in Table 2. Additional parameters such as HOMO–LUMO energy gap, ΔE, absolute electro-negativities, χ, chemical potentials, Pi, absolute hardness, η, absolute softness, σ, global electro-philicity, ω, global softness, S, and additional electronic charge, ΔNmax, are calculated using the following Eqs. (1)–(8): ΔE ¼ ELUMO −EHOMO χ¼

−ðEHOMO þ ELUMO Þ 2

ð2Þ

η¼

ELUMO −EHOMO 2

ð3Þ

σ¼

1 η

ð4Þ

Pi ¼ −x S¼

ð5Þ

1 2η

ð6Þ

Pi2 2η

ð7Þ

ω¼

ΔN max ¼ −

Pi η

ð8Þ

The ligand has three rings. Out of these two are six membered and one five membered. Ring R1 and R2 are in a plane while rings R3 and R4 deviates from the given plane due to stric handrance of attached at N(1) of ring R1 and the other ring R4 attached to ring R3. The optimized

1) 5 cm3 0.005 M HCl + 5 cm3 1 M KCl + 5 cm3 ethanol. 2) 5 cm3 0.005 M HCl + 5 cm3 1 M KCl + 5 cm3 0.0l M ligand. 3) 5 cm3 0.005 M HCl + 5 cm3 l M KCl + 5 cm3 0.01 M ligand + 10 cm3 0.001 M metal chloride. For each mixture, the volume was made up to 50 cm3 with double distilled water before the titration. These titrations were repeated for

ð1Þ

Fig. 2. The geometrical structure of moxifloxacin (H2L).

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Table 1 Bond lengths and bond angles of moxifloxacin (H2L). Bond angles (o)

Bond lengths (Å) Cl(30)–H(55) C(29)–H(54) C(27)–H(50) C(25)–H(49) C(25)–H(48) C(23)–H(46) C(23)–H(45) C(22)–H(44) C(22)–H(43) N(20)–H(42) C(19)–H(41) C(18)–H(38) C(17)–H(37) C(17)–H(36) C(16)–H(35) C(15)–H(34) O(13)–H(33) C(6)–H(32) C(5)–C(10) C(9)–C(10) N(1)–C(10) C(2)-N(1) C(3)–C(2) C(4)–C(3) C(5)–C(4) C(6)–C(5) C(7)–C(6) C(8)–C(7) C(9)–C(8) C(27)–C(29) C(28)–C(29) C(27)–C(28) N(1)–C(27) C(7)-F(26) C(9)–O(24) O(24)–C(25) C(8)-N(21) C(23)–C(16) C(22)–C(15) N(21)–C(23) N(21)–C(22) C(15)-N(20) C(19)-N(20) C(18)–C(19) C(17)–C(18) C(16)–C(17) C(15)–C(16) C(4)–O(14) C(3)–C(11) C(11)–O(13) C(11)–O(12)

1.342 1.089 1.091 1.113 1.111 1.116 1.111 1.113 1.115 1.051 1.114 1.116 1.115 1.116 1.117 1.12 0.963 1.103 1.345 1.364 1.283 1.275 1.345 1.365 1.366 1.339 1.339 1.356 1.369 1.512 1.504 1.513 1.458 1.326 1.378 1.414 1.287 1.542 1.539 1.491 1.494 1.461 1.461 1.533 1.533 1.538 1.532 1.213 1.376 1.362 1.219

H(54)–C(29)–H(53) H(54)–C(29)–C(27) H(54)–C(29)–C(28) H(53)–C(29)–C(27) H(53)–C(29)–C(28) C(27)–C(29)–C(28) H(52)–C(28)–H(51) H(52)–C(28)–C(29) H(52)–C(28)–C(27) H(51)–C(28)–C(29) H(51)–C(28)–C(27) C(29)–C(28)–C(27) H(49)–C(25)–H(48) H(49)–C(25)–H(47) H(49)–C(25)–O(24) H(48)–C(25)–H(47) H(48)–C(25)–O(24) H(41)–C(19)–H(40) H(41)–C(19)-N(20) H(41)–C(19)–C(18) H(40)–C(19)-N(20) H(40)–C(19)–C(18) N(20)–C(19)–C(18) H(39)–C(18)–H(38) H(39)–C(18)–C(19) H(39)–C(18)–C(17) H(38)–C(18)–C(19) H(38)–C(18)–C(17) C(19)–C(18)–C(17) H(42)-N(20)–C(19) C(15)-N(20)–C(19) H(37)–C(17)–H(36) H(37)–C(17)–C(18) H(37)–C(17)–C(16) H(36)–C(17)–C(18) H(36)–C(17)–C(16) C(18)–C(17)–C(16) H(35)–C(16)–C(17) H(35)–C(16)–C(15) C(23)–C(16)–C(17) C(23)–C(16)–C(15) C(17)–C(16)–C(15) H(34)–C(15)–C(22) H(34)–C(15)-N(20) C(22)–C(15)-N(20) C(22)–C(15)–C(16) N(20)–C(15)–C(16) H(46)–C(23)–H(45) H(46)–C(23)–C(16) H(46)–C(23)-N(21) H(45)–C(23)–C(16)

114.5 116.23 118.04 121.08 116.19 60.241 114.63 116.36 120.64 117.88 116.52 60.14 108.63 109.4 108.07 109.16 111.15 106.46 110.13 110.36 108.68 109.8 111.28 107.33 109.71 109.65 110.08 110.13 109.9 108.61 115.37 106.88 109.04 110.53 110.1 110 110.23 108.37 111.11 112.02 102.26 111.74 108.05 107.22 115.24 103.95 114.24 112.4 109.31 110.18 106.17

Fig. 3. HOMO and LUMO molecular orbital of moxifloxacin (H2L).

H(45)–C(23)-N(21) C(16)–C(23)-N(21) H(44)–C(22)–H(43) H(44)–C(22)–C(15) H(44)–C(22)-N(21) H(43)–C(22)–C(15) H(43)–C(22)-N(21) C(15)–C(22)-N(21) H(33)–O(13)–C(11) H(50)–C(27)–C(29) H(50)–C(27)–C(28) H(50)–C(27)-N(1) C(29)–C(27)–C(28) C(29)–C(27)-N(1) C(28)–C(27)-N(1) C(9)–O(24)–C(25) C(8)-N(21)–C(23) C(8)-N(21)–C(22) C(23)-N(21)–C(22) C(7)–C(8)–C(9) C(7)–C(8)-N(21) C(9)–C(8)-N(21) C(6)–C(7)–C(8) C(6)–C(7)-F(26) C(8)–C(7)-F(26) C(10)–C(9)–C(8) C(10)–C(9)–O(24) C(8)–C(9)–O(24) C(5)–C(10)–C(9) C(5)–C(10)-N(1) C(9)–C(10)-N(1) H(32)–C(6)–C(7) C(5)–C(6)–C(7) C(10)–C(5)–C(4) C(10)–C(5)–C(6) C(4)–C(5)–C(6) C(3)–C(11)–O(13) C(3)–C(11)–O(12) O(13)–C(11)–O(12) C(3)–C(4)–C(5) C(3)–C(4)–O(14) C(5)–C(4)–O(14) C(10)-N(1)–C(2) C(10)-N(1)–C(27) C(2)-N(1)–C(27) C(2)–C(3)–C(4) C(2)–C(3)–C(11) C(4)–C(3)–C(11) H(31)–C(2)-N(1) H(31)–C(2)–C(3) N(1)–C(2)–C(3)

114.27 103.99 112.13 111.02 110.36 106.33 113.63 102.91 116.85 124.23 121.99 109.41 59.619 117.9 115.95 114.32 125.58 123.46 110.91 115.8 119.29 124.91 122.35 112.94 124.66 120.99 117.32 121.49 121.11 117.3 121.55 116.67 121.78 122.35 117.47 120.18 124.88 119.45 115.66 117.63 120.42 121.94 122 116.37 109.42 115.71 119.94 124.35 112.65 122.85 124.5

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Table 2 The calculated quantum chemical parameters for moxifloxacin. EHOMO (eV)

ELUMO (eV)

ΔE (eV)

χ (eV)

η (eV)

σ (eV)−1

Pi (eV)

S (eV)−1

ω (eV)

ΔNmax (eV)

−7.807

−1.707

6.100

4.757

3.05

0.3279

−4.757

0.1639

3.709

1.559

bond length of C\\C in six-membered pyridine ring R1 ranges between 1.345 Å and 1.366 Å, while, for another phenyl ring R2, this ranges between 1.339 Å and 1.369 Å. For five-membered pyrrole ring R3, C\\C bond lengths are quite high and range between 1.491 Å and 1.542 Å. The optimized value of C3–C11 bond length adjacent to pyridine ring R1 is found to be 1.376 Å, which is also high in comparison to the C\\C bond length in R1. The optimized value of C\\C bond length of six-membered ring R4 ranges between 1.461 Å and 1.538 Å. Another important C\\C bond length in cyclopropane attached to pyridine ring R1 is found in the range 1.504 Å–1.513 Å. The optimized C\\N bond lengths in pyridine ring R1 are found to be 1.257 Å and 1.283 Å, while, in pyrrole ring R3, the optimized C\\N bond lengths are found to be 1.491 Å and 1.494 Å. On the other hand the optimized C\\N bond

lengths in ring R4 are calculated as 1.461 Å. The rings R3 and R4 hve quite high in comparison to C\\N bond length in ring R1 because C\\N bond in R1 has double bond character due to delocalization of lone pair electrons of nitrogen. 3.2. Molecular docking study Molecular docking is a key tool in computer drug design [16,20–22]. The focus of molecular docking is to simulate the molecular recognition process. Molecular docking aims to achieve an optimized conformation for both the protein and drug with relative orientation between them such that the free energy of the overall system is minimized. In this context, we used molecular docking between moxifloxacin (H2L) and

Fig. 4. The moxifloxacin (green in (a) and gray in (b)) in interaction with receptors of breast cancer mutant (3hb5), prostate cancer mutant (2q7k), crystal structure of E. coli (3t88) and crystal structure of S. aureus (3q8u). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).

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H.M. Refaat et al. / Journal of Molecular Liquids 220 (2016) 802–812

Fig. 4 (continued).

receptors of breast cancer mutant (3hb5), prostate cancer mutant (2q7k), crystal structure of E. coli (3t88) and crystal structure of S. aureus (3q8u). The results showed a possible arrangement between moxifloxacin and 3hb5, 2q7k, 3t88 and 3q8u receptors. The docking study showed a favorable interaction between moxifloxacin and the receptors (3hb5, 2q7k, 3t88 and 3q8u) as shown in Fig. 4 and the calculated energy is listed in Table 3. According to the results obtained in this study, HB plot curve indicates that the moxifloxacin binds to the proteins with hydrogen bond interactions and decomposed interaction energies in

kcal/mol were exist between moxifloxacin with 3hb5, 2q7k, 3t88 and 3q8u receptors as shown in Fig. 5. 2D plot curves of docking with moxifloxacin are shown in Fig. 6. The moxifloxacin (H2L) shows the best interaction with 3hb5 receptor other than the receptors. Docking measurements can be used as a new technique for prediction of the dissociation constants (pKa). From microspecies distribution curves obtained by docking measurements for moxifloxacin (H 2 L), it was found that, there are two dissociable protons nearly equal to 9.4 and 5.6 H corresponding to pKH 1 and pK2 , respectively.

Table 3 Energy values obtained in docking calculations of moxifloxacin (H2L) with receptors of breast cancer mutant (3hb5), prostate cancer mutant (2q7k), crystal structure of E. coli (3t88) and crystal structure of S. aureus (3q8u). Receptors

Est. free energy of binding (kcal/mol)

Est. inhibition constant (Ki) (μM)

vdW + bond + desolv energy (kcal/mol)

Electrostatic energy (kcal/mol)

Total intercooled energy (kcal/mol)

Interact surface

3hb5 2q7k 3t88 3q8u

−7.45 −3.08 −3.90 −6.63

3.44 5.54 1.39 13.80

−9.16 −5.67 −5.43 −5.68

+0.22 −0.26 +0.28 −2.19

−8.94 −5.93 −5.15 −7.87

883.134 576.643 664.817 849.097

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3.3. Potentiometric studies The interaction of a metal with an electron donor atom of moxifloxacin (H2L) is usually followed by the release of H+. Alkaline potentiometric titrations are based on the detection of the protons released upon complexation. The main advantage of this technique, compared to other methods is that from the titration curves it is possible to follow complexation continuously as a function of pH and to detect exactly at which pH complexation takes place. Furthermore, it

807

is possible to calculate the dissociation constants and the stability constants of its complexes from the potentiometric titration curve (Fig. 7). The following equilibria were used for the determination of the pKa values of moxifloxacin (H2L) (Eqs. (9) and (10)) and its metal stability constants (Eqs. (11) and (12)):

H2 L

¼

HL−

þ

Hþ

ð9Þ

Fig. 5. HB plot of interaction between moxifloxacin and receptors (a) breast cancer mutant (3hb5), (b) prostate cancer mutant (2q7k), (c) crystal structure of E. coli (3t88) and (d) crystal structure of S. aureus (3q8u).

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Fig. 5 (continued).

HL−

H2 L H2 L

L2−

¼ þ þ

M2þ ML

¼ ¼

þ þ

ML ML2

2−

þ

Hþ

ð10Þ

of the acid in the absence and presence of moxifloxacin by applying the following equation:

2Hþ

ð11Þ

nA ¼ Y 

2Hþ

ð12Þ

The average number of the protons associated with moxifloxacin (H2L) at different pH values,‾nA, was calculated from the titration curves


 ðV1 −V2 Þ No þ Eo
o  o V −V1 TCL

ð13Þ

where Y is the number of available protons in ligands (Y = 2) and V1 and V2 are the volumes of alkali required to reach the same pH on the titration curve of hydrochloric acid and reagent, respectively, V° is the

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809

Fig. 6. 2D plot of interaction between moxifloxacin and receptors (a) breast cancer mutant (3hb5), (b) prostate cancer mutant (2q7k), (c) crystal structure of E. coli (3t88) and (d) crystal structure of S. aureus (3q8u).

initial volume (50 cm3) of the mixture, TC°L is the total concentration of the reagent, N° is the normality of sodium hydroxide solution and E° is the initial concentration of the free acid. Thus, the formation curves (‾nA vs. pH) for the proton-ligand systems were constructed and found to extend between 0 and ~ 2 in the‾nA scale (Fig. 8). This means that moxifloxacin (H2L) has two dissociable protons (the hydrogen atom of the amine (NH group), pKH 1 and the weaker acid (COOH group), pKH 2 ). Three replicate titrations were performed; the average values obtained are listed in Tables 4 and 5. The completely protonated form

of moxifloxacin (H2L) has two dissociable protons, that dissociates in the measurable pH range. The deprotonation of the carboxyl group most probably results in the formation of stable intramolecular H-bonding with keto group in the quinoline ring contributes to lowering acidic character for fluoroquinolones [23]. The formation curves for the metal complexes were obtained by plotting the average number of moxifloxacin attached per metal ion (‾nA) vs. the free moxifloxacin exponent (pL), according to Irving and Rossotti [24]. The average number of the reagent molecules attached

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and !n 1   βH n Hþ Vo þ V3 n¼o pL ¼ log10 : o o Vo TCL −n:TCM n¼ J X

ð15Þ

where TC°M is the total concentration of the metal ion present in the solution, βHn is the overall proton-reagent stability constant. V1, V2 and V3 are the volumes of alkali required to reach the same pH on the titration curves of hydrochloric acid, organic ligand and complex, respectively. These curves were analyzed and the successive metalligand stability constants were determined [25,26]. The values of the stability constants (log K1 and log K2) are given in Table 5. The following general remarks can be pointed out: (i) The maximum value of‾n was ~2 indicating the formation of 1:1 and 1:2 (metal: ligand) complexes [27]. (ii) The metal ion solution used in the present study was very dilute (2 × 10−4 M), hence there was no possibility of formation of polynuclear complexes [28,29]. (iii) The metal titration curves were displaced to the right-hand side of the ligand titration curves along the volume axis, indicating proton release upon complex formation of the metal ion with moxifloxacin. The large decrease in pH for the metal titration curves relative to ligand titration curves point to the formation of strong metal complexes [30,31]. (iv) At constant temperature, the stability of the chelates increases in the order: Mn2+ b Co2+ b Ni2+ b Cu2+ [32–35]. This order largely reflects that the stability of Cu2 + complex is considerably larger than those of other metals of the 3d series. The greater stability of Cu2 + complex is produced by the well known Jahn–Teller effect [36].Stepwise dissociation constants for moxifloxacin (H2 L) and the stepwise stability constants of its complexes with Mn2 +, Co2 +, Ni2 + and Cu2 + have been calculated at 298, 308 and 318 K. The corresponding thermodynamic parameters (ΔG, ΔH and ΔS) were evaluated.

Fig. 7. Potentiometric titration curves of moxifloxacin (H2L) and its metal complexes.

Fig. 8. The relation between nA vs. pH for moxifloxacin (H2L).

per metal ion, ‾n, and free ligands exponent, pL, can be calculated using Eqs. (14) and (15):
 ðV3 −V2 Þ No þ Eo  n¼
o V −V2 :nA :TCoM

ð14Þ

The dissociation constants (pKH) for moxifloxacin (H2L), as well as the stability constants of its complexes with Mn2 +, Co2 +, Ni2 + and Cu2 + have been evaluated at 298, 308 and 318 K, and given in Tables 4 and 5, respectively. The enthalpy (ΔH) for the dissociation and complexation process was calculated from the slope of the plot

Table 4 Thermodynamic functions for the dissocation of moxifloxacin in 10% (by volume) ethanol-water mixtures and 0.1 M KCl at different temperatures. Temp. (K)

298 308 318

Dissociation constant

Gibbs energy kJ mol−1

Enthalpy changekJ mol−1

Entropy change J mol−1K−1

pKH 1

pKH 2

ΔG1

ΔG2

ΔH1

ΔH2

- ΔS1

- ΔS2

8.91 ± 0.09 8.65 ± 0.11 8.42 ± 0.12

5.90 ± 0.13 5.78 ± 0.10 5.61 ± 0.10

50.84 ± 0.51 51.01 ± 0.65 51.27 ± 0.73

33.66 ± 0.75 34.09 ± 0.59 34.16 ± 0.61

44.47 ± 2.73

26.25 ± 0.11

21.38 ± 10.89 21.25 ± 10.97 21.37 ± 10.88

24.88 ± 2.12 25.44 ± 1.56 24.86 ± 1.57

Table 5 Stepwise stability constants for complexes of moxifloxacin in 10% (by volume) ethanol-water mixtures and 0.1 M KCl at different temperatures. log K2

4.33 ± 0.09 4.47 ± 0.10 4.63 ± 0.10 4.78 ± 0.13

318 K

308 K

298 K

log K1

log K2

log K1

log K2

log K1

Mn+

5.40 ± 0.11 5.56 ± 0.13 5.69 ± 0.12 5.86 ± 0.11

4.21 ± 0.10 4.35 ± 0.12 4.51 ± 0.11 4.66 ± 0.09

5.30 ± 0.12 5.43 ± 0.11 5.58 ± 0.09 5.72 ± 0.10

4.08 ± 0.10 4.24 ± 0.09 4.39 ± 0.10 4.54 ± 0.12

5.16 ± 0.09 5.30 ± 0.10 5.45 ± 0.11 5.61 ± 0.09

Mn2+ Co2+ Ni2+ Cu2+

H.M. Refaat et al. / Journal of Molecular Liquids 220 (2016) 802–812

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Table 6 Thermodynamic functions for ML and ML2 complexes of moxifloxacin in 10% (by volume) ethanol-water mixtures and 0.1 M KCl. Mn+

T/K

Mn2+

298 308 318 298 308 318 298 308 318 298 308 318

Co2+

Ni2+

Cu2+

Gibbs energy (kJ mol−1)

Enthalpy change (kJ mol−1)

Entropy change (J mol−1 K−1)

−ΔG1

−ΔG2

ΔH1

ΔH2

ΔS1

ΔS2

29.44 ± 0.52 31.26 ± 0.70 32.88 ± 0.67 30.24 ± 0.57 32.02 ± 0.65 33.85 ± 0.80 31.10 ± 0.62 32.91 ± 0.53 34.65 ± 0.73 32.01 ± 0.51 33.73 ± 0.59 35.68 ± 0.67

23.28 ± 0.57 24.83 ± 0.59 26.49 ± 0.42 24.19 ± 0.52 25.65 ± 0.71 27.22 ± 0.61 25.05 ± 0.57 26.60 ± 0.65 28.19 ± 0.61 25.90 ± 0.69 27.48 ± 0.53 29.10 ± 0.80

21.81 ± 1.85

24.48 ± 2.69

23.58 ± 2.71

20.85 ± 0.96

21.79 ± 0.85

21.77 ± 0.02

22.64 ± 0.81

21.77 ± 0.83

171.97 ± 7.94 172.28 ± 8.31 171.96 ± 7.94 180.61 ± 11.01 180.53 ± 10.90 180.61 ± 11.01 177.46 ± 4.98 177.57 ± 4.51 177.45 ± 5.00 183.40 ± 7.81 183.04 ± 7.80 183.41 ± 7.81

160.26 ± 7.12 160.08 ± 6.82 160.26 ± 7.12 151.15 ± 4.93 150.98 ± 5.40 151.15 ± 4.92 157.10 ± 1.98 157.02 ± 2.17 157.10 ± 1.97 159.97 ± 5.11 159.89 ± 4.45 159.97 ± 5.12

pKH or log K vs. 1/T using the graphical representation of Van't Hoff Eqs. (16) and (17): ΔG ¼ −2:303 RT logK ¼ ΔH–TΔS

ð16Þ

or  logK ¼

−ΔH 2:303R

  1 ΔS þ T 2:303R

ð17Þ

where R is the gas constant = 8.314 J mol−1. K−1, K is the dissociation constant for the ligand stability and T is the temperature (K). From the ΔG and ΔH values, one can deduce the entropy ΔS using the well known relationships 16 and 18: ΔS ¼ ðΔH−ΔGÞ=T

ð18Þ

The thermodynamic parameters of the dissociation process of moxifloxacin (H2L) are recorded in Table 4. From these results the following can be made: (i) The pKH values decrease with increasing temperature, i.e. the acidity of moxifloxacin increases with increasing temperature [37]. (ii) Positive values of ΔH indicate that dissociation is accompanied by absorption of heat and the process is endothermic. (iii) Large positive values of ΔG indicate that the dissociation process is not spontaneous [38]. (iv) Negative values of ΔS are due to increased order as result of the solvation processes. All the thermodynamic parameters of stepwise stability constants for the complexes of moxifloxacin are recorded in Table 6. The obtained values ΔH and ΔS can then be considered as sum of two contributions: (a) Release of H2O molecules and (b) Metal-ligand bond formation. Examination of these values shows that:

Fig. 9. The relation between stability constants (log K1 and log K2) and ionic radius of metal complexes at different temperatures.

(i) The stability constants (log K1 and log K2) for the moxifloxacin complexes increase with increasing temperature [15,39]. The stability constants of Mn2 +, Co2 +, Ni2 + and Cu2 + complexes were increased with decreasing ionic radius in the order: Cu 2+ N Ni 2+ N Co2+ N Mn2+ at constant temperature as shown in Fig. 9. (ii) The negative values of ΔG for the complexes formation suggest a spontaneous nature of such process [15]. (iii) The positive values of ΔH mean that the complex formation processes is endothermic and favored at higher temperature. (iv) The positive values of ΔS confirming that the complex formation processes is entropically favorable [15].

812

H.M. Refaat et al. / Journal of Molecular Liquids 220 (2016) 802–812

4. Conclusion The proton-ligand dissociation constant of moxifloxacin (H2 L) and metal-ligand stability constants of its complexes with metal ions (Mn 2 +, Co 2 +, Ni 2 + and Cu 2 +) have been determined and it was found that the stability of the chelates increases in the order: Mn2+ b Co2+ b Ni2+ b Cu2+ at constant temperature. The dissociation process is non-spontaneous, endothermic and entropically unfavorable. The formation of the metal complexes has been found to be spontaneous, endothermic and entropically favorable. The stability constants (log K1 and log K2) for the moxifloxacin complexes increase with increasing temperature. Geometrical structure and molecular docking of moxifloxacin (H2L) were studied. Molecular docking was used to predict the binding between moxifloxacin and the receptors of breast cancer mutant (3hb5), prostate cancer mutant (2q7k), crystal structure E. coli (3t88) and crystal structure of S. aureus (3q8u) and it was found that the moxifloxacin shows best interaction with 3hb5 receptor other than receptors. The potentiometrically measured pKa for moxifloxacin are in agreement with predicted values obtained by docking measurements. References [1] K. Drlica, X. Zhao, Microbiol. Mol. Biol. Rev. 61 (1997) 377–392. [2] K. Sandstrom, S. Warmlander, M. Leijon, A. Graslund, Biochem. Biophys. Res. Commun. 304 (2003) 55–59. [3] Y. Xia, Z.Y. Yang, P. Xia, K.F. Bastow, Y. Tachibana, S.C. Kuo, E. Hamel, T. Hackl, K.H. Lee, J. Med. Chem. 41 (1998) 1155–1162. [4] D.K. Saha, U. Sandbhor, K. Shirisha, S. Padhye, D. Deobagkar, C.E. Anson, A.K. Powell, Bioorg. Med. Chem. Lett. 14 (2004) 3027–3032. [5] I. Turel, A. Golobic, A. Klavzar, B. Pihlar, P. Buglyo, E. Tolis, D. Rehder, J. Inorg. Biochem. 95 (2003) 199–207. [6] P. Ball, J. Antimicrob. Chemother. 51 (2003) 21–27. [7] A.D. Sarro, G.D. Sarro, Curr. Med. Chem. 8 (2001) 371–384. [8] F.V. Bambeke, P.M. Tulkens, Drug Saf. 32 (2009) 359–378. [9] K. Takacs-Novak, B. Noszal, I. Hermeez, G. Kereszturi, B. Podanyi, G. Szasz, J. Pharm. Sci. 79 (1990) 1023–1028. [10] A.A. El-Bindary, A.Z. El-Sonbati, M.A. Diab, Sh.M. Morgan, J. Mol. Liq. 201 (2015) 36–42. [11] N.A. El-Ghamaz, A.Z. El-Sonbati, M.A. Diab, A.A. El-Bindary, G.G. Mohamed, Sh.M. Morgan, Spectrochim. Acta A 147 (2015) 200–211.

[12] A.Z. El-Sonbati, G.G. Mohamed, A.A. El-Bindary, W.M.I. Hassan, A.K. Elkholy, J. Mol. Liq. 209 (2015) 625–634. [13] T.A. Halgren, J. Comput. Chem. 17 (1998) 490–519. [14] G.M. Morris, D.S. Goodsell, J. Comput. Chem. 19 (1998) 1639–1662. [15] R.G. Bates, Determination of pH, Theory and Practice, John Wiley and Sons, New York, 1973. [16] A.A. El-Bindary, G.G. Mohamed, A.Z. El-Sonbati, M.A. Diab, W.M.I. Hassan, Sh.M. Morgan, A.K. Elkholy, J. Mol. Liq. 218 (2016) 138–149. [17] G.H. Jeffery, J. Bassett, J. Mendham, R.C. Deney, Vogel's Textbook of Quantitative Chemical Analysis, fifth ed. Longman, London, 1989. [18] K.D. Bhesaniya, S. Baluja, J. Mol. Liq. 190 (2014) 190–195. [19] A.Z. El-Sonbati, M.A. Diab, A.A. El-Bindary, A.M. Eldesoky, Sh.M. Morgan, Spectrochim. Acta A 135 (2015) 774–791. [20] A.Z. El-Sonbati, G.G. Mohamed, A.A. El-Bindary, W.M.I. Hassan, M.A. Diab, Sh.M. Morgan, A.K. Elkholy, J. Mol. Liq. 212 (2015) 487–502. [21] A.Z. El-Sonbati, A.A. El-Bindary, G.G. Mohamed, Sh.M. Morgan, W.M.I. Hassan, A.K. Elkholy, J. Mol. Liq. 218 (2016) 16–34. [22] M.A. Diab, A.Z. El-Sonbati, A.A. El-Bindary, Sh.M. Morgan, M.K. Abd El-Kader, J. Mol. Liq. 218 (2016) 571–585. [23] M.H. Langlois, M. Montagut, J.P. Dubost, J. Grellet, M.C. Saux, J. Pharm. Biomed. Anal. 37 (2005) 389–393. [24] H. Irving, H.S. Rossotti, J. Chem. Soc. 74 (1953) 3397–3405. [25] F.J.C. Rossotti, H.S. Rossotti, Acta Chem. Scand. 9 (1955) 1166–1176. [26] M.T. Beck, I. Nagybal, Chemistry of Complex Equilibrium, Wiley, New York, 1990. [27] M.M. Khalil, A.M. Radalla, A.G. Mohamed, Potentiometric investigation on complexation of divalent transition metal ions with some zwitterionic buffers and triazoles, J. Chem. Eng. Data 54 (12) (2009) 3261–3272. [28] P. Sanyal, G.P. Sengupta, J. Indian Chem. Soc. 67 (1990) 342–344. [29] S. Sridhar, P. Kulanthaip, P. Thillaiarasu, V. Thanikachalam, G.J. Manikandan, World J. Chem. 4 (2009) 133–140. [30] V.D. Athawale, V.J. Lele, Chem. Eng. Data 41 (1996) 1015–1019. [31] V.D. Athawale, S.S. Nerkar, Monatsh. Chem. 131 (2000) 267–276. [32] G.A. Ibañez, G.M. Escandar, Polyhedron 17 (1998) 4433–4441. [33] W.U. Malik, G.D. Tuli, R.D. Madan, Selected Topics in Inorganic Chemistry, third ed. S. Chand & Company LTD, New Delhi, 1984. [34] G.G. Mohamed, M.M. Omar, A. Ibrahim, Eur. J. Med. Chem. 44 (2009) 4801–4812. [35] F.R. Harlly, R.M. Burgess, R.M. Alcock, Solution Equilibria, Ellis Harwood, Chichester, 1980 257. [36] L.E. Orgel, An Introduction to Transition Metal Chemistry Ligand Field Theory, Methuen, London, UK, 1966 55. [37] A.Z. El-Sonbati, G.G. Mohamed, A.A. El-Bindary, W.M.I. Hassan, A.K. Elkholy, J. Mol. Liq. 209 (2015) 625–634. [38] A. Bebot-Bringaud, C. Dange, N. Fauconnier, C. Gerard, J. Inorg. Biochem. 75 (1999) 71–78. [39] A.F. Shoair, A.A. El-Bindary, A.Z. El-Sonbati, N.M. Beshry, J. Mol. Liq. 215 (2016) 740–748.