Docking studies on an N 4 -donor Schiff base ligand and its Cu(II) complex supported by structural,spectral and theoretical studies

Abstract

A new asymmetrical Schiff base ligand, N¹-(3-((pyridin-2-ylmethylene)amino)propyl)ethane-1,2-diamine, and its copper(II) complex, [Cu(PPEA)Br]Br·H₂O (1), have been prepared. The copper complex has an elongated square pyramidal geometry with a CuN₄Br environment. The thermodynamic stability of the compounds and their charge distribution patterns were studied by Density Functional Theory and natural bond orbital analysis. The ability of the ligand and its copper complex to interact with 10 selected biomacromolecules (BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS, Top II and B-DNA) was investigated by docking studies and compared with that of doxorubicin.

Keywords

copper Density Functional Theory calculations docking studies Schiff base

Introduction

Schiff base compounds and their metal complexes have been extensively investigated due to their wide range of applications including catalysts,^1–3 medicine,⁴ anticorrosion agents,⁵ photovoltaic materials,⁶ chemosensors,^7,8 anode materials in sodium ion batteries,^9,10 organic light-emitting diode (OLEDs)¹¹ and polymer light-emitting diode (PLED) materials.^12,13 These compounds serve as the photosensitizers, electrolytes or redox mediators in DSSCs (dye-sensitized solar cells).¹² Metal Schiff base complexes can be exploited to act as the antenna for lanthanide ion sensitization.¹⁴ Schiff bases are known to be good ligands for metal ions.^15,16 Schiff base ligands and their complexes show interesting pharmacological effects such as antimicrobial,¹⁷ antitumor,^18,19 antibacterial,²⁰ antifungal,²⁰ antioxidative²¹ and urease inhibitory^22,23 activities. The cleavage of plasmid DNA by Schiff base complexes has also been reported.^24,25

In the following paper, we report the synthesis, characterization (Fourier-transform infrared spectroscopy (FT-IR), Raman, X-ray) and coordination of new pyridine-based asymmetrical Schiff base ligand, N¹-(3-((pyridin-2-ylmethylene)amino)propyl)ethane-1,2-diamine (PPEA; Scheme 1), towards copper(II), [Cu(PPEA)Br]Br·H₂O (1). The thermodynamic stability of the compounds and their charge distribution patterns were studied by Density Functional Theory (DFT) and natural bond orbital (NBO) analysis.

Scheme 1.

Structure of N¹-(3-((pyridin-2-ylmethylene)amino)propyl)ethane-1,2-diamine (PPEA).

Schiff-base ligands are potential anticancer, antibacterial and antiviral agents, and their activities tend to increase in binding to metal centres.^26,27 In addition to the expected biological properties of the PPEA ligand, binding it to the copper(II) ion makes the resulting complex a good choice as a biologically active compound. Many copper(II) complexes have been reported as potential antitumour agents and they have been found to be active both in vitro and in vivo.^28–31

For the study of the biological activities of the ligand and its copper complex, docking calculations were run to investigate the possibility of an interaction between these compounds with 10 biomacromolecule targets:^32–34 BRAF kinase, cathepsin B (CatB), DNA gyrase, histone deacetylase (HDAC7), recombinant human albumin (rHA), ribonucleotide reductases (RNR), thioredoxin reductase (TrxR), thymidylate synthase (TS), topoisomerase II (Top II) along with B-DNA. These proteins were selected either due to their reported roles in cancer growth or as transport agents that affect drug pharmacokinetic properties (e.g. rHA). The DNA gyrase was included to study the possibility of anticancer properties and their activity as antimalarial agents.³⁵ The knowledge gained from docking on the B-DNA should be useful for the development of potential probes for DNA structure and new therapeutic reagents for tumours and other diseases.³⁶

Experiment

Materials and instrumentation

All chemicals and solvents (Merck, Aldrich) were used as received without further purification. Infrared (IR) spectra (as KBr pellets) in the range 4000–400 cm⁻¹ were recorded on a FT-IR 8400-Shimadzu spectrometer. The carbon, hydrogen and nitrogen contents were determined using a Thermo Finnigan Flash Elemental Analyzer 1112 EA. The melting points were measured with a Barnsted Electrothermal 9200 electrically heated apparatus. Raman spectra were obtained using a Nicolet Model 910 Fourier transform spectrometer. The microwave-assisted reactions for the synthesis of the ligand were carried out using a Microwave Laboratory Systems MicroSYNTH reactor from Milestone S.r.l.

PPEA

A mixture of N¹-(2-aminoethyl)propane-1,3-diamine (0.11 g, 0.94 mmol) and pyridine-2-carboxaldehyde (0.10 g, 0.93 mmol) was irradiated inside a microwave reactor for 30 min with power up to 300 W. After microwave irradiation, an oily liquid was obtained. Excess precursors were removed using a rotary evaporator and a brown oil was obtained. Several attempts to crystallize the compound were unsuccessful. Yield: 0.14 g, 72%. Anal. calcd for C₁₁H₁₈N₄: C, 64.05; H, 8.80; N, 27.16; found: C, 64.73; H, 8.43; N, 26.84%. IR (KBr disc, cm⁻¹): 3400 m (ν_as NH₂), 3306 m (ν_s NH₂ and/or ν N−H), 3100 m (ν C−H^ar and/or C−H^imine), 2936 s (ν_as CH₂), 2858 m (ν_s CH₂), 1660 m (ν C=N)^imine, 1590 s (δ NH₂), 1570 s (ν C=N)^py, 1470 s (ν C=C)^ar, 1435 s (δ_as CH₂), 1338 m (δ_s CH₂), 1049 m (ν C−N), 779 m and 621 m (γ py).

[Cu(PPEA)Br]Br H₂O (1)

A solution of PPEA (0.08 g, 0.39 mmol) in ethanol (15 mL) was added with stirring of CuBr₂ (0.09 g, 0.39 mmol) in the same solvent (15 mL). The reaction mixture was then heated to reflux for 1 h. Blue crystals suitable for X-ray diffraction were obtained by slow evaporation of the solution for 3 days and collected by filtration. Yield: 0.09 g, 52%; m.p. 169 °C. Anal. calcd for C₁₁H₂₀Br₂CuN₄O: C, 29.51; H, 4.50; N, 12.52; found: C, 29.37; H, 4.66; N, 12.03%. IR (KBr disc, cm⁻¹): 3383 s (ν_as NH₂), 3213 s (ν_s NH₂ and/or ν N−H), 3136 m (ν C−H^ar and/or C−H^imine), 2936 s (ν_as CH₂), 2862 m (ν_s CH₂), 1643 m (ν C=N^imine and/or δ H₂O), 1597 m (δ NH₂ and/or C=N^py), 1470 m (ν C=C)^ar, 1454 m (δ_as CH₂), 1325 w (δ_s CH₂), 1061 m (ν C−N), 783 m and 629 m (γ py and/or ρ_r H₂O), ρ_w = 536 w (H₂O). Raman (cm⁻¹): 1601 m (δ NH₂ and/or C=N^py), 1522 m (ν C=C)^ar, 709 m and 616 m (γ py and/or ρ_r H₂O), 461 m (ν Cu−N), 309 s (ν Cu−Br).

Crystal structure determination

Diffraction data were collected at 170 K on a Rigaku XtaLAb mini diffractometer. Data processing and absorption correction were carried out using CrystalClear-SM Expert.³⁷ The structures were solved with direct methods and refined with least squares using the OLEX-II package.³⁸ All hydrogen atoms were placed at their calculated positions. Diagrams of the molecular structure and unit cell were created using Ortep-III^39,40 and Diamond.⁴¹ Crystallographic data and details of the data collection and structure refinement are listed in Table 1, selected bond lengths and angles in Table 2 and hydrogen bond geometries in Table 3.

Table 1.

Crystal data and structure refinement for complex 1.

Empirical formula	C₁₁H₁₈BrCuN₄·Br·H₂O
Formula weight (g mol⁻¹)	447.67
Crystal size (mm³)	0.09 × 0.06 × 0.06
Temperature (K)	170
Crystal system	Triclinic
Space group	P $\bar{1}$
Unit cell dimensions
a (Å)	7.8548 (3)
b (Å)	9.9048 (5)
c (Å)	11.1284 (5)
α (°)	88.523 (4)
β (°)	70.093 (4)
γ (°)	79.557 (4)
Volume (Å³)	799.96 (7)
Z	2
Calculated density (g cm⁻³)	1.859
Absorption coefficient (mm^–1)	6.36
F(000) (e)	442
θ range for data collection (°)	2.1−29.1
h, k, l ranges	−10 ⩽ h ⩽ 10, –13 ⩽ k ⩽ 12, –15 ⩽ l ⩽ 15
Reflections collected/independent/R_int	6907/3691/0.017
Data/restraints/parameters	3691/0/180
Goodness-of-fit on F²	1.02
R1/wR2 (I ⩾ 2 σ(I))	0.0259/0.0563
R1/wR2 (all data)	0.0336/0.0590
Largest diff. peak/hole (e Å⁻³)	0.55/−0.64

Table 2.

Selected bond length (Å) and angles (°) for complex 1 with estimated standard deviations in parentheses.

Distances		Angles
Cu1–N1	2.035 (2)	N1–Cu1–N2	81.28 (9)
Cu1–N2	1.991 (2)	N2–Cu1–N3	93.56 (9)
Cu1–N3	2.017 (2)	N3–Cu1–N4	85.50 (9)
Cu1–N4	2.006 (2)	N4–Cu1–Br1	94.82 (6)
Cu1–Br1	2.7910 (5)	Br1–Cu1–N3	94.08 (6)

Table 3.

Hydrogen bonds and short contacts dimensions (Å and °) in complex 1.

D–H···A	d(D–H)	d(H···A)	<(DHA)	d(D···A)	Symmetry code on A atom
O(1)–H(1A)···Br(1)	0.78	2.49	173	3.268(3)	x, y, z
O(1)–H(1B)···Br(2)	0.80	2.52	158	3.281(3)	−1 + x, y, z
N(3)–H(3)···Br(2)	0.98	2.85	125.9	3.514(2)	x, y, z
N(3)–H(3)···O(1)	0.98	2.53	154.7	3.442(4)	−1 + x, y, z
N(4)–H(4A)···Br(2)	0.89	2.60	152.8	3.410(2)	1 − x, 1 − y, 1 − z
N(4)–H(4B)···O(1)	0.89	2.27	164.4	3.140(4)	x, y, z
C(2)–H(2)···O(1)	0.93	2.56	140.3	3.330(4)	−x, 1 − y, 1 − z
C(3)–H(3A)···Br(1)	0.93	2.98	141.4	3.758(3)	−x, 2 − y, 1 − z
C(6)–H(6)···Br(2)	0.93	2.83	155.1	3.699(2)	1 − x, 2 − y, 1 − z

Computational details

All structures were optimized with the Gaussian 09 software⁴² and calculated for an isolated molecule using DFT⁴³ at the B3LYP⁴⁴/6-31G⁴⁵ (d,p) level of theory for ligand and B3LYP/LanL2DZ⁴⁶ for complex as well as for NBO analysis. The X-ray structural data of complex 1 were used as input for the theoretical calculations. The structure of the ligand was extracted from the cif file of complex 1 and used for DFT studies.

Docking studies

The pdb files 4r5y, 3ai8, 5cdn, 3c0z, 2bx8, 1peo, 3qfa, 1njb, 4gfh and 1bna for the 10 receptors, BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS, Top II and B-DNA, respectively, used in this research were obtained from the Protein Data Bank (pdb).⁴⁷ The full version of Genetic Optimisation for Ligand Docking (GOLD) 5.5⁴⁸ was used for the docking studies. The Hermes visualizer in the GOLD Suite was used to further prepare the ligand, complex and the receptors for docking. The cif file of the complex and optimized structure of ligand was used for the docking studies. The region of interest used for GOLD docking was defined as all the protein residues within 6 Å of the reference ligand ‘A’ that accompanied the downloaded protein. For B-DNA, the region of interest was defined on the DNA backbone within 10 Å of the O4, DT19 and O2, DT19 atoms for major and minor graves, respectively. All free water molecules in the structure of the proteins were deleted before docking. Default values of all other parameters were used and the compounds were submitted to 10 genetic algorithm runs using the GOLDScore fitness function.

Results and discussion

Spectroscopic characterization

In the IR spectra of PPEA and 1, the frequencies around 3000 cm⁻¹ confirm the presence of the aromatic and aliphatic moieties in these compounds, respectively. In the vibrational spectrum of the ligand, two sharp peaks at ca. 3300−3400 cm⁻¹ can be assigned to the asymmetric and symmetric stretching vibrations of the NH₂ group which are shifted by 17 and 93 cm⁻¹, respectively, to lower frequencies, confirming coordination through this unit. A similar shift (17 cm⁻¹) was also observed in ν (C=N) of the imine group.

The presence of the water molecule in 1 affects its IR spectrum in three regions^49,50 including the following: 3200–3400 cm⁻¹ for asymmetric and symmetric OH stretches, 1643 cm⁻¹ for H₂O bending and 200–600 cm⁻¹ for librational modes. These modes are due to rotational oscillations of the water molecules restricted by interactions with neighbouring atoms and they are classified into three types (wagging (ρ_w), twisting (ρ_t) and rocking (ρ_r)) depending upon the direction of the principal axis of rotation.^51,52 The asymmetric and symmetric vibrational and also bending modes of the water molecule are overlapped with the sharp peaks of the amine group and ν (C=N)^imine, respectively.

Information regarding the low frequency metal-ligand vibrations was obtained by Raman spectroscopy. In the Raman spectrum of 1, a band at 461 cm⁻¹ was assigned to the Cu−N stretching vibration. The Cu–Br^terminal stretching vibration was assigned to the strong band at 309 cm⁻¹, consistent with the values reported in the literature (200−300 cm⁻¹ for M−Br^terminal).^53,54

Crystal structure of [Cu(PPEA)Br]Br·H₂O (1)

X-ray analysis of 1 (Figure 1) revealed an ionic copper(II) compound. In this structure, the copper atom is coordinated by one bromide ligand and one N₄-donor PPEA giving a coordination number 5. A pentacoordinate geometry may adopt either a square pyramidal or a trigonal bipyramidal structure. To determine geometry for such complexes, the formula of Addison et al.⁵⁵ was applied. The angular structural parameter (τ) value for 1 was calculated to be 0.21 indicating a distorted square pyramidal geometry around the copper atom which is the common geometry for the copper atom for the complexes with coordination number of 5.³⁴ A search of the CSD database for a Cu(N-sp³)₂(N-sp²)₂Br unit revealed that there are four examples with such an environment.^56–59 All of them are ionic compounds with formulae similar to 1 and their τ values are in the range of 0.19−0.48, confirming that the copper atom in all of them has a distorted square pyramidal geometry.

Figure 1.

Ortep diagram of the molecular structure of complex 1. The ellipsoids are drawn at the 50% probability level.

Studying the CSD database also revealed that the complexes with a Cu(N-sp³)₂(N-sp²)₂Br unit can be classified into two types (Scheme 2): the common (a) type (75%), in which the bromide ligand is located in the axial position and (b) type with the bromide ligand in the equatorial plane. The difference between the bond lengths of the axial and equatorial bromide ligands in (a) type complexes is 0.250 Å, confirming elongation along the z axis. Comparing the axial and equatorial Cu−N bond lengths in (b) type complexes also confirms this elongation; the average equatorial Cu−N bond length is 0.330 Å shorter than the axial one and is comparable with that of (a) type complexes (Scheme 2). Complex 1 belongs to the (a) type complexes; the average Cu−N bond length in 1 (2.012 Å) is comparable with the CSD average (Scheme 2) while the Cu−Br bond length (2.791 Å) is larger than that of the CSD search result set. Similar results have been observed for the CuNO₂Cl₂ environment (any type of O- and N-donor ligand with terminal chloride ions and τ value in range of 0.00−0.50).⁶⁰ In addition to five dative interactions around the copper atom, this atom interacts with one non-coordinated bromide ion at a long distance (3.199(5) Å) to complete its pseudo-octahedral geometry.

Scheme 2.

CSD average for all complexes with Cu(N-sp³)₂(N-sp²)₂Br environment. The bromo ligand can locate in the axial position (a) or on the equatorial plane (b).

In this structure, the PPEA ligand acts as an N₄-donor by forming two 5- and one 6-membered chelate rings. The five-membered chelate ring containing the imine group is planar (root mean square deviation: 0.055 for N1 atom) while the other rings are non-planar. The bond angle of the six-membered chelate ring (93.56(9)°) is larger than the two 5-membered ones (81.28(9) and 85.50(9)°). The PPEA ligand itself does not have chiral centre but a new one (N3) is formed upon coordination. Although 1 has one chiral centre, the crystals are a racemic mixture of R and S isomers in alternate layers.^50,61

Crystal network interactions

In crystal structure of 1, there are various intermolecular C–H···O, C–H···Br, N–H···O, N–H···Br and O–H···Br hydrogen bonds (Table 3, Figure 2). The bromide ions act as proton acceptors whereas the carbon and nitrogen atoms of the ligand participate in hydrogen bonding as proton donors. The oxygen atom of the water molecule acts as proton donor and acceptor at the same time. Among these hydrogen bonds, two N–H···Br hydrogen bonds participate in the formation of one $R_{4}^{2} (12)$ hydrogen bond motif (two acceptors, four donors with degree of 12)⁵² between two neighbouring units. Similarly, N–H···O and O–H···Br hydrogen bonds form a $R_{2}^{2} (6)$ motif. In addition to the hydrogen bonds, the crystal network is stabilized by π–π stacking interactions between pyridine rings of the ligands of adjacent complexes (Figure 2). The centroid–centroid distance and the perpendicular distance between the pyridine planes is 3.908 and 3.388 Å, respectively. Thus, the slippage of pyridine rings was calculated to be 1.948 Å.

Figure 2.

Packing of complex 1, showing hydrogen bonds and ··· stacking interactions. Only the hydrogen atoms involved in hydrogen bonding are shown. Each CuN₄Br unit is shown as a square pyramid.

Theoretical studies

For comparing the structure of the complex 1 in solid state with an isolated gas phase 1, DFT calculations were performed; the optimized structure is presented in Figure 3. For the optimized structure 1^opt, the τ was calculated to 0.26, showing that the square pyramidal geometry in the solid state is slightly different than in the gas phase. The average Cu−N bond lengths (2.074 Å) and Cu−Br (2.767 Å) are comparable with the experimental results (2.012 and 2.791 Å, respectively); thus, we can conclude that the z-out elongation also occurs in the gas phase structure. The Cu···Br₂ distance (3.004 Å) in the gas phase structure is shorter than in the solid state, confirming that the geometry of copper atom in the computed structure is closer to octahedral. In the optimized structure of the ligand (Figure 3), the PPEA^opt has the E configuration and all nitrogen atoms have same direction as observed in the structure of the complex, but the ethanamine arm is bent out of the molecule plane.

Figure 3.

Ortep diagram of the optimized structures of PPEA^opt and 1^opt. The ellipsoids are drawn at the 50% probability level.

For studying the charge distribution pattern of the ligand before and after coordination, an NBO analysis was performed (Table 4). The results reveal that the calculated charge on the carbon atom of the imine moiety is positive while other carbon atoms have a negative charge. Among the three nitrogen atoms, the amine nitrogen has higher electronegativity than the others. In 1^opt, the calculated charge on the copper atom (+0.70) is lower than the formal charge (+2) owing to electron donation of the ligand upon complexation. These calculations revealed that the charges on the hydrogen and carbon atoms in 1^opt are positive compared to the free ligand as well as bromides (respect to their formula charge, −1), showing that these atoms play an important role in electron donation towards the metal atom and decreasing the charge of it. The nitrogen atom of the pyridine ring and carbon of imine moiety show the highest charge variation after coordination (−0.09 and +0.09, respectively). The charge on the non-bonded bromide ion is −0.07 negative than the bonded ones.

Table 4.

The NBO analysis results (e) for PPEA ligand and complex 1.

	C^py	C^imine	C^aliph	H^amine	H^imine	H^py	H^aliph	N^py	N^amine	N^imine	Br^bonded	Br^non-bonded	Cu
PPEA	−0.11	0.07	−0.31	0.39	0.17	0.24	0.22	−0.42	−0.80	−0.40	−	−	−
Complex 1	−0.06	0.16	−0.25	0.43	0.20	0.23	0.23	−0.51	−0.83	−0.47	−0.65	−0.72	0.70

PPEA: N¹-(3-((pyridin-2-ylmethylene)amino)propyl)ethane-1,2-diamine; NBO: natural bond orbital.

The values are the average of charge on similar atoms.

In the optimized structure of ligand, the lowest unoccupied molecular orbital (LUMO) is delocalized on the aromatic and imine portions while the highest occupied molecular orbital (HOMO) is delocalized mainly on the aliphatic moiety (Table 5). In 1^opt, the LUMO has similar pattern with PPEA^opt while the HOMO mainly delocalized on the bromide ions. The copper atom does not have significant quota in the frontier orbitals of the complex.

Table 5.

HOMO and LUMO, total energy and LUMO/HOMO gap for optimized structures of PPEA ligand and complex 1.

	LUMO	HOMO	Total energy (kcal mol⁻¹)	LUMO/HOMO gap (kcal mol⁻¹)
PPEA			−407,246.21	3.70
Complex 1			−546,880.94	2.22

PPEA: N¹-(3-((pyridin-2-ylmethylene)amino)propyl)ethane-1,2-diamine; LUMO: lowest unoccupied molecular orbital; HOMO: highest occupied molecular orbital.

Docking studies

For predicting the biological activities of the PPEA ligand and its copper complex, interactions of these compounds with 10 macromolecular receptors were studied using the GOLD⁴⁸ docking software. The GOLD docking results are reported in terms of the values of fitness, which means that the higher the fitness, the better the docking interaction of the compounds.^32–35 The results of the docking presented in this work are the best binding results out of 10 favourites predicted by GOLD. Also for evaluation of the calculated fitness values, these scores were compared with those of the anticancer drug, doxorubicin (a cancer medication that interferes with the growth and spread of cancer cells in the body⁶²).

The general features from the GOLD docking prediction (Table 6) show that all studied structures can be considered as biologically active compounds.^32–34 The best predicted protein targets for PPEA and 1 are HDAC7 and TrxR, respectively. Based on the calculated fitness values, the interaction of the ligand and its complex with BRAF-Kinase, rHA and RNR macromolecules are comparable, while in other cases, the ligand can interact better than the complex. Data shown in Table 6 revealed that these compounds can place in the major and minor grooves of the DNA molecule, which make these compounds a good choice for DNA binding studies. Docking calculations revealed that the PPEA ligand has higher fitness values than doxorubicin in binding towards the CatB and its score in interaction with HDAC7 is comparable with doxorubicin. The docking results of the interaction between the ligand and its complex with B-DNA (minor groove) are shown in Figures 4 and 5, respectively.

Table 6.

The calculated fitness values for PPEA ligand and complex 1 along with the doxorubicin.

	B-DNAs/Maj	B-DNAs/Min	BRAF-Kinase	CatB	DNA-Gyrase	HDAC7	rHA	RNR	TrxR	TS	Top II
PPEA	29.68	56.09	40.81	32.64	45.64	49.08	41.28	38.19	45.93	41.58	42.36
Complex 1	17.98	37.14	39.04	22.62	36.68	34.87	40.60	36.00	41.10	35.21	37.98
Doxorubicin	33.47	83.10	54.21	25.95	52.97	50.73	50.10	49.18	66.70	53.34	59.05

PPEA: N¹-(3-((pyridin-2-ylmethylene)amino)propyl)ethane-1,2-diamine.

Figure 4.

Docking study results, showing the interaction between the PPEA and B-DNA (minor grave).

Figure 5.

Docking study results, showing the interaction between complex 1 and B-DNA (minor grave).

Conclusion

In this work, a new asymmetrical Schiff base ligand, PPEA, and its copper(II) complex, [Cu(PPEA)Br]Br·H₂O (1), were synthesized and their spectral (IR, Raman) and structural properties were investigated. The geometry of the copper atom in 1 is square pyramidal, which can be considered pseudo-octahedral geometry with one long distance Cu···Br interaction. CSD studies revealed that the geometry in the Cu(N-sp³)₂(N-sp²)₂Br environment (same as 1) is elongated along the z axis. In the crystal structures of 1, the water molecules, along with amine and bromide units, form $R_{4}^{2} (12)$ and $R_{2}^{2} (6)$ hydrogen bond motifs. In addition to the hydrogen bonds, the crystal network is further stabilized by π–π stacking interactions between pyridine rings of the ligands of adjacent complexes. A theoretical study revealed that the hydrogen and carbon atoms in 1^opt play an important role in electron donation towards the copper atom and decreasing the charge of it. Based on the DFT calculations, the LUMO/HOMO energy gap in 1^opt is 1.48 eV lower than the free ligand. Docking studies revealed that the PPEA and 1 can interact with biomacromolecules (BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS, Top II and B-DNA). In addition, the best predicted targets for PPEA and 1 are HDAC7 and TrxR, respectively. Since the fitness values of the ligand in some cases are comparable with that of doxorubicin and also these compounds can interact with the DNA, study of its anticancer activities could be interesting.

Footnotes

Acknowledgements

We are grateful to Payame Noor University and Urmia University of Iran for financial support.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental material

CCDC 1545439 contain the supplementary crystallographic data for complex 1. These data can be obtained free of charge via , or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.

References

Clercq

Lefebvre

Verpoort

Appl Catal 2003; A247: 345–364.

Gupta

Sutar

AK.

Coord Chem Rev 2008; 252: 1420–1450.

Kannappan

Matsumoto

Hallren

, et al. J Mol Catal 2011; A339: 72–78.

Zoubi

WA.

Int J Org Chem 2013; 3: 73–95.

Ahamad

Prasad

Quraishi

MA.

Corros Sci 2010; 52: 933–942.

Wesley Jeevadason

Kalidasa Murugavel

Neelakantan

. Renew Sust Energ Rev 2014; 36: 220–227.

Wang

Cao

, et al. Sensor Actuator 2017; B250: 132–138.

Xie

Chen

Chin J Chem 2006; 24: 1800–1803.

Castillo-Martínez

Carretero-González

Armand

Angew Chem Int Edit 2014; 53: 5341–5345.

10.

López-Herraiz

Castillo-Martínez

Carretero-González

, et al. Energy Environ Sci 2015; 8: 3233–3241.

11.

Che

C-M

Chan

S-C

Xiang

H-F

, et al. Chem Commun 2004; 50: 1484–1485.

12.

Zhang

Wong

W-Y.

Coord Chem Rev 2018; 355: 180–198.

13.

Ying

C-L

, et al. Adv Mater 2014; 26: 2459–2473.

14.

Eliseeva

Bünzli

J-CG

. Chem Soc Rev 2010; 39: 189–227.

15.

Raman

Johnson Raja

Sakthivel

J Coord Chem 2009; 62: 691–709.

16.

Rezaeivala

Keypour

Coord Chem Rev 2014; 280: 203–253.

17.

Zhang

Xian

D-M

H-H

, et al. Aust J Chem 2012; 65: 343–350.

18.

Altıntop

Özdemir

Turan-Zitouni

, et al. Eur J Med Chem 2012; 58: 299–307.

19.

da Silveira

Luz

Oliveira

, et al. J Inorg Biochem 2008; 102: 1090–1103.

20.

Shanker

Rohini

Ravinder

, et al. Spectrochim Acta 2009; A73: 205–211.

21.

Yang

Z-y.

Inorg Chim Acta 2009; 362: 4823–4831.

22.

Taha

Ismail

Baharudin

, et al. Med Chem Res 2015; 24: 1310–1324.

23.

Jing

Wang

Yan

, et al. Bioorg Med Chem 2016; 24: 270–276.

24.

Morrow

Kolasa

KA.

Inorg Chim Acta 1992; 195: 245–248.

25.

Tiwari

Mishra

, et al. Spectrochim Acta 2011; A79: 1050–1056.

26.

Hodnett

Dunn

WJ.

J Med Chem 1970; 13: 768–770.

27.

Hodnett

Dunn

WJ.

J Med Chem 1972; 15: 339–339.

28.

Ramakrishnan

Rajendiran

Palaniandavar

, et al. Inorg Chem 2009; 48: 1309–1322.

29.

Wang

Zhu

, et al. Dalton Trans 2011; 40: 12926–12934.

30.

Tan

Yan

Lee

, et al. Future Med Chem 2010; 2: 1591–1608.

31.

Alagesan

Bhuvanesh

NSP

Dharmaraj

Eur J Med Chem 2014; 78: 281–293.

32.

Marandi

Moeini

Alizadeh

, et al. Inorg Chim Acta 2018; 482: 717–725.

33.

Marandi

Moeini

Alizadeh

, et al. Z Naturforsch 2018; 73b: 369–375.

34.

Mardani

Kazemshoar-Duzduzani

Moeini

, et al. RSC Adv 2018; 8: 28810–28824.

35.

Adeniyi

Ajibade

PA.

Molecules 2013; 18: 3760–3778.

36.

Moghadam

Salehzadeh

Shahabadi

Nucleos Nusleot Nucl 2017; 36: 553–570.

37.

CrystalClear-SM Expert 2.0. Tokyo, Japan: Rigaku Corporation, 2014.

38.

Dolomanov

Bourhis

Gildea

, et al. J Appl Crystallogr 2009; 42: 339–341.

39.

Farrugia

J Appl Crystallogr 1997; 30: 565.

40.

Burnett

Johnson

CK.

Ortep-III. Report ORNL-6895, 1996. Oak Ridge, TN: Oak Ridge National Laboratory.

41.

Bergerhof

Berndt

Brandenburg

J Res Natl Stand Technol 1996; 101: 221–225.

42.

Frisch

Trucks

Schlegel

, et al. Gaussian 09. Wallingford, CT: Gaussian, Inc., 2009.

43.

Perdew

JP.

Phys Rev 1986; B33: 8822–8824.

44.

Becke

AD.

J Chem Phys 1993; 98: 5648–5652.

45.

Ditchfield

Hehre

Pople

JA.

J Chem Phys 1971; 54: 724–728.

46.

Hay

Wadt

WR.

J Chem Phys 1985; 82: 270–283.

47.

Gavezzotti

Acc Chem Res 1994; 27: 309–314.

48.

Jones

Willett

Glen

, et al. J Mol Biol 1997; 267: 727–748.

49.

Hakimi

Mardani

Moeini

J Korean Chem Soc 2013; 57: 447–454.

50.

Hakimi

Mardani

Moeini

, et al. Z Naturforsch 2013; 68b: 267.

51.

Hakimi

Moeini

Mardani

, et al. J Korean Chem Soc 2013; 57: 352–356.

52.

Hakimi

Moeini

Mardani

, et al. Polyhedron 2014; 70: 92–100.

53.

Nakamoto

Infrared and Raman spectra of inorganic and coordination compounds. Hoboken, NJ: John Wiley & Sons, 1986, p. 324.

54.

Hakimi

Ahmadi

Mardani

, et al. J Coord Chem 2017; 70: 3513–3522.

55.

Addison

Rao

Reedijk

, et al. Dalton Trans 1984; 7: 1349–1356.

56.

Limpke

Butenuth

Stammler

, et al. Eur J Inorg Chem 2017; 2017: 3570–3579.

57.

Singh

Copeland

Hatfield

, et al. J Phys Chem 1972; A76: 2887–2891.

58.

Driscoll

Keyes

Heeg

, et al. Inorg Chem 2008; 47: 7225–7232.

59.

Lee

Y-M

Kim

E-S

Kim

H-J

, et al. Dalton Trans 2009; 38: 126–133.

60.

Mardani

Golsanamlou

Jabbarzadeh

, et al. J Coord Chem 2018; 71: 1–37.

61.

Hakimi

Mardani

Moeini

, et al. Z Naturforsch 2013; 68b: 272–276.

62.

https://www.drugs.com/mtm/doxorubicin.html

Docking studies on an N 4 -donor Schiff base ligand and its Cu(II) complex supported by structural,spectral and theoretical studies

Abstract

Keywords

Introduction

Experiment

Materials and instrumentation

PPEA

[Cu(PPEA)Br]Br H2O (1)

Crystal structure determination

Computational details

Docking studies

Results and discussion

Spectroscopic characterization

Crystal structure of [Cu(PPEA)Br]Br·H2O (1)

Crystal network interactions

Theoretical studies

Docking studies

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

Supplemental material

References

[Cu(PPEA)Br]Br H₂O (1)

Crystal structure of [Cu(PPEA)Br]Br·H₂O (1)