Hydrothermally synthesized (N,O)-linked Cu(II)-based coordination complex as a potential antibacterial agent European Journal of Chemistry 14 (4) (2023) 429-438 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2023 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.14.4.429-438.2465 European Journal of Chemistry View Journal Online View Article Online Hydrothermally synthesized (N,O)-linked Cu(II)-based coordination complex as a potential antibacterial agent Anmol Chettri , Sudarshan Pradhan , Pritika Gurung , Sriparna Roy and Biswajit Sinha * Department of Chemistry, University of North Bengal, Darjeeling, 734013, India * Corresponding author at: Department of Chemistry, University of North Bengal, Darjeeling, 734013, India. e-mail: biswachem@nbu.ac.in (B. Sinha). 10.5155/eurjchem.14.4.429-438.2465 Received: 13 July 2023 Received in revised form: 31 August 2023 Accepted: 19 September 2023 Published online: 31 December 2023 Printed: 31 December 2023 The N,O-linked Cu(II)-based coordination complex was synthesized hydrothermally and characterized by SC-XRD, FTIR spectroscopy, and FE-SEM. Single crystal X-ray diffraction studies showed that the complex crystallizes in a square pyramidal geometry and belongs to the monoclinic crystal system with the space group P21/n. Crystal data for C14H13CuN3O6: a = 8.7355(11) Å, b = 17.646(2) Å, c = 9.8036(12) Å, β = 98.506(6)°, V = 1494.6(3) Å3, Z = 4, μ(MoKα) = 1.500 mm-1, Dcalc = 1.701 g/cm3, 5120 reflections measured (4.616° ≤ 2Θ ≤ 49.982°), 1953 unique (Rint = 0.0316, Rsigma = 0.0718) which were used in all calculations. The final R1 was 0.0380 (I > 2σ(I)) and wR2 was 0.0972 (all data). The experimental antibacterial activity studies performed using the disc diffusion method revealed that the complex is indeed acting as a good antibacterial agent against Staphylococcus aureus and Escherichia coli. A better understanding of the binding mechanisms was uncovered through comparative molecular docking investigations. The docking score for the target S. aureus glyrase complex with DNA (PDB id-2XCS) was found to be -7.1 kcal/mol, while the docking score for dialkylglycine decarboxylase (PDB id-1D7U) was -5.2 kcal/mol. The high docking score of the complex with the target protein allowed the complex to act as a potential antibacterial agent. These results were also supported by other theoretical studies such as DFT calculations and pharmacokinetic studies. The correlation between the HOMO-LUMO energy gap and antibacterial activity was studied computationally. Hirshfeld surface analysis and pharmacokinetic studies were also performed for this crystal for a better understanding of the intermolecular interactions and ADME properties. Hirshfeld surface ADME properties Molecular docking Antibacterial studies Computational studies Hydrothermal synthesis Cite this: Eur. J. Chem. 2023, 14(4), 429-438 Journal website: www.eurjchem.com 1. Introduction Due to the astounding architectures, topologies and diverse potential applications as catalysts and chemical sensors, the design and synthesis of coordination complexes has attracted tremendous attention globally [1-4]. Many factors, including the geometry of coordination preferred by a specific metal ion, pH, nature of the counterions, temperature, and ligand geometry, can influence the architecture and functions of the products [5]. The hydrothermal synthesis of metal complexes has recently received considerable attention because it is one of the greener ways of synthesizing a complex. Unlike many other advanced synthetic methods, the hydrothermal method uses relatively inexpensive instrumentation and precursors [6]. From an environmental standpoint, this method is more environmentally benign than many other synthetic methods [7- 11]. Furthermore, by this method, we can readily obtain or control the rate and uniformity of nucleation, crystal formation, and aging, all of which affect the crystal size, morphology, and aggregation. This simple method requires no catalyst, toxic and expensive surfactant, or template, making it an ideal method for large-scale manufacturing of high-quality, dislocation-free single crystals. Because Cu(II) is biologically important, the synthesis of various biologically useful Cu(II) complexes is becoming an urgent need. Cu(II) ions and their complexes have continued to catch the eye of coordination chemists because of their diverse structural features, utility as models for the active centres of various metalloenzymes, catalytic, electronic, magnetic and biological properties [12-14]. Dipicolinic acid is a good candidate for coordination with transition metals in this respect because of its ability to form chelates through its two O atoms and one N atom, which provides extra stability to the complex formed. Pyridine-2,6- dicarboxylic acid (H2dipic) is a polydentate ligand that can form stable chelates with oxo-metal cations and simple metal ions, thus exhibiting a wide variety of coordination behaviours. Dipicolinates (dipic) are often coordinated with transition metal ions through carboxylate bridges between the metal centres, forming dimeric or polymeric complexes [15-18] or by tridentate chelation (O, N, O′) to a single metal ion [17,18]. Dipicolinic acid has its applications in analytical chemistry [19], corrosion inhibition, nuclear reactor decontamination [20], and many biological activities [21]. Benzimidazole (BMZ), a heterocyclic aromatic compound, is very well known for its antimicrobial properties [22]. In this study, we report the synthesis of a Cu (II)-based coordination complex having the molecular formula C14H11Cu N3O5·H2O using Cu(NO3)·2H2O, pyridine-2,6-dicarboxylic acid and benzimidazole using the hydrothermal method. Although ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.14.4.429-438.2465 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.14.4.429-438.2465 mailto:biswachem@nbu.ac.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.14.4.429-438.2465&domain=pdf&date_stamp=2023-12-31 430 Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Table 1. Crystal data and structure refinement for complex. Empirical formula C14H13N3O6Cu Formula weight (g/mol) 382.81 Temperature (K) 296(2) Crystal system Monoclinic Space group P21/n a, (Å) 8.7355(11) b, (Å) 17.646(2) c, (Å) 9.8036(12) β (°) 98.506(6) Volume (Å3) 1494.6(3) Z 4 ρcalc (g/cm3) 1.701 μ (mm-1) 1.500 F(000) 780.0 Crystal size (mm3) 0.18 × 0.17 × 0.16 Radiation MoKα (λ = 0.71073) 2Θ range for data collection (°) 4.616 to 49.982 Index ranges -10 ≤ h ≤ 10, -16 ≤ k ≤ 20, -11 ≤ l ≤ 11 Reflections collected 5120 Independent reflections 1953 [Rint = 0.0316, Rsigma = 0.0718] Data/restraints/parameters 1953/1/223 Goodness-of-fit on F2 0.929 Final R indexes [I≥2σ (I)] R1 = 0.0380, wR2 = 0.0932 Final R indexes [all data] R1 = 0.0585, wR2 = 0.0972 Largest diff. peak/hole (e.Å-3) 0.36/-0.30 Dong et al. reported the synthesis of a similar complex (CCDC- 777866) under reflux conditions, they obtained single crystals suitable for SC-XRD only after 20 days [23]. In addition, no other experimental and theoretical studies were reported for the complex. Here, we report the synthesis of the complex in just 72 hours using the hydrothermal method [24] as an alternative time-efficient method. In addition, using the disc diffusion technique [25], antibacterial activity was examined against Gram-positive and Gram-negative bacteria strains of Staphylococcus aureus and Escherichia coli, respect-tively. Molecular docking studies were also performed against the respective protein targets to comprehend the binding activity. Computational studies were performed to find the relationship between antibacterial activity and the HOMO-LUMO energy gap. Furthermore, Hirshfeld surface analysis [26] and pharmacokinetic studies were also performed to better understand the intermolecular interactions and ADME properties [27]. 2. Experimental 2.1. Materials Copper nitrate (Cu(NO3)2·2H2O, 98% pure), 2,6-pyridine dicarboxylic acid (dipicolinic acid, 99%pure), benzimidazole (98% pure) and triply distilled deionized water (with specific conductance <1×10-6 S·cm-1 at 25 °C) were used during synthesis. All of these compounds were of A.R. grade (purchased from S.D. Fine-Chem Limited, India) and were used without additional purification. 2.2. Instrumentations The FT-IR spectrum was obtained at ambient temperature using a Perkin Elmer FT-IR spectrometer (RX-1) in the region 4000 to 400 cm-1. The sample was pressed into a pellet after being diluted with IR grade KBr (Sigma-Aldrich, Germany). The morphology of the crystal was investigated by field emission scanning electron microscopy (FESEM, JSM-IT 100). Data for single crystal X-ray diffraction were obtained using Bruker SMART CCD area-detector diffractometer and the relevant software [28]. 2.3. Synthesis of copper complex The copper complex was synthesized hydrothermally at 120 °C in a 5 mL Teflon-lined stainless-steel autoclave under autogenous pressure. A mixture of Cu(NO3)2·2H2O (241 mg, 1 mmol), dipicolinic acid (167 mg, 1 mmol), and benzimidazole (118 mg, 1 mmol) was pulverized using an agate mortar and pestle. The mixture was then poured into a 5 mL Teflon lined stainless steel autoclave and distilled water (3.0 mL) was added to it, then the mixture was stirred for about 40 min until a homogeneous suspension was obtained. The autoclave was then sealed and the reaction mixture was heated for 72 h in an automated hot air oven at 120 °C. After 72 h, the autoclave was left for approximately 10 h to cool naturally at room temperature. The initial pH of the suspension was around 3 and remained constant after the reaction was complete. The reaction mixture was filtered and washed multiple times with triply distilled deionized water and ethanol. The solid residue obtained was allowed to air dry for several hours. Yield: 379 mg (72% based on copper). Blue-colored crystals having needle- like shape, suitable for single-crystal XRD, were obtained. It was collected by hand picking under a microscope (40×). The complex obtained was completely soluble in dimethyl sulfoxide and did not melt up to 300 °C. 2.4. Single crystal structure determination The single crystal of the complex was analyzed using a Bruker Smart Apex II X-ray single crystal diffractometer equipped with Kryoflex liquid N2 attachment for crystal mounting. Radiation used was MoKα (λ = 0.71073 Å) and absorption multi-scan [28] was applied to all data and analysed with related softwares [28,29]. The structure of the complex was solved and refined using SHELX-97 software [28]. The crystal data of the C14H11CuN3O5·H2O complex (CCDC Depo- sition number: 2286899) was found to closely resemble the reported complex (CCDC Deposition number: 777866) [23]. The crystal data and structure refinement parameters are provided in Table 1 and the X-ray geometrical parameters (bond distance and angles) are provided in Table 2. Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 431 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Table 2. Bond lengths for copper complex. Atom Atom Length (Å) (Exp.) Length (Å) (Theor.) Atom Atom Length (Å) (Exp.) Length (Å) (Theor.) Cu1 O1 2.018(3) 2.010 C8 O3 1.224(5) 1.226 Cu1 N2 1.942(4) 1.985 C8 O2 1.266(5) 1.307 Cu1 N3 1.905(4) 1.925 N1 C7 1.314(5) 1.360 Cu1 O2 2.048(3) 2.055 N1 C5 1.367(5) 1.392 Cu1 O5 2.243(3) 2.391 C9 C10 1.363(6) 1.393 O1 C14 1.267(5) 1.305 C14 C13 1.530(6) 1.530 N2 C6 1.396(5) 1.394 C12 C11 1.369(6) 1.402 N2 C7 1.313(5) 1.320 C12 C13 1.378(6) 1.402 O4 C14 1.221(5) 1.226 C4 C5 1.400(6) 1.397 N3 C9 1.334(5) 1.333 C6 C1 1.397(6) 1.400 N3 C13 1.333(5) 1.332 C6 C5 1.386(6) 1.410 C3 C4 1.345(7) 1.393 C1 C2 1.382(7) 1.392 C3 C2 1.410(7) 1.413 C10 C11 1.381(6) 1.402 C8 C9 1.514(6) 1.529 Table 3. Bond angles for copper complex. Atom Atom Atom Angle (°) (Exp.) Angle (°) (Theor.) Atom Atom Atom Angle (°) (Exp.) Angle (°) (Theor.) O1 Cu1 O2 159.60(12) 158.02 N3 C9 C10 120.1(4) 121.23 O1 Cu1 O5 94.94(13) 94.91 C10 C9 C8 128.9(4) 129.36 N2 Cu1 O1 100.75(13) 101.23 C8 O2 Cu1 114.2(3) 114.56 N2 Cu1 O2 97.50(13) 96.58 O1 C14 C13 114.6(4) 114.92 N2 Cu1 O5 94.62(15) 94.89 O4 C14 O1 125.8(4) 124.90 N3 Cu1 O1 80.72(13) 81.00 O4 C14 C13 119.6(4) 119.63 N3 Cu1 N2 170.16(16) 170.26 C11 C12 C13 118.2(4) 119.79 N3 Cu1 O2 79.76(13) 79.11 C3 C4 C5 117.1(5) 117.94 N3 Cu1 O5 94.95(14) 93.99 N2 C6 C1 131.1(4) 130.56 O2 Cu1 O5 92.60(13) 92.79 C5 C6 N2 107.5(4) 107.90 C14 O1 Cu1 115.1(3) 116.22 C5 C6 C1 121.4(4) 120.53 C6 N2 Cu1 131.6(3) 131.63 C2 C1 C6 116.4(5) 114.33 C7 N2 Cu1 121.2(3) 120.99 C9 C10 C11 118.3(4) 116.96 C7 N2 C6 106.0(4) 105.53 C12 C11 C10 121.1(5) 120.79 C9 N3 Cu1 119.2(3) 119.67 N2 C7 N1 112.0(4) 111.57 C13 N3 Cu1 118.3(3) 119.00 N3 C13 C14 111.3(4) 110.99 C13 N3 C9 122.6(4) 122.34 N3 C13 C12 119.7(4) 117.79 C4 C3 C2 122.1(5) 122.12 C12 C13 C14 129.0(4) 130.23 O3 C8 C9 119.1(4) 119.37 C1 C2 C3 121.5(5) 119.99 O3 C8 O2 125.5(4) 126.33 N1 C5 C4 132.7(4) 133.63 O2 C8 C9 115.4(4) 114.34 N1 C5 C6 105.8(4) 107.33 C7 N1 C5 108.6(3) 107.57 C6 C5 C4 121.6(4) 123.63 N3 C9 C8 110.9(4) 111.00 2.5. Antibacterial activities The bacterial strains used in this investigation were E. coli (ATCC-25922) and S. aureus (ATCC-25923). Individual pure bacteria cultures were grown on nutrient agar medium at a concentration of 40 g/L. To sustain the bacterial cultures, they were subcultured on a regular basis using the same medium, then incubated at 37 °C for 24 hours before being stored at 4 °C until they were used in this experiment [30,31]. The agar well diffusion technique [30-34] was used to assess the antibacterial activity of the synthesized complex with minimal modifications [30]. Antimicrobial susceptibility was assessed using a medium made with agar (20 g/L) and Mueller Hinton (MH) broth (21 g/L) in a 1 L conical flask using the agar well diffusion technique. After preparing the medium, it was autoclaved at 120 °C for 20 minutes to sterilize it. A sterile cork borer was used to make a 6 mm hole, after which 100 µL of the solution (made by dissolving the complex in DMSO) were pipetted into triplicate wells at a concentration of 10 mg/mL. The width of the inhibition zone was measured in three different fixed directions and the mean value was obtained after incubation of the plates at 37 °C for 24-48 h. 2.6. Molecular docking The prediction of interactions between a small molecule (ligand) and a target protein can be done computationally by using molecular docking. The interactions of a compound with a particular target of bacterial proteins, such as an enzyme or receptor crucial for bacterial growth or survival, could be usefully revealed by molecular coupling to predict antibacterial activity [35]. Auto-Dock Vina software [36] was used for molecular docking studies. The RCSB PDB (https://www.rcsb.org) was used to obtain the X-ray crystallographic structure of the receptor protein, which was then used for molecular docking studies against the synthesized complex [37]. The receptor structure was described as rigid, the grid dimensions x, y and z ranged from 62, 100, 88 and 54, 68, 64 with 1 Å spacing for the proteins with PDB ID-2XCS and PDB ID-1D7U, respectively [38,39]. By removing water molecules and polar hydrogen, each protein of interest was prepared [37]. 2.7. Density functional theory studies Density functional theory (DFT) is an extremely successful approach for the description of ground state properties of metals, semiconductors, and insulators [40]. Here, the structure of the complex was fully optimized using the Gaussian 16 program package [41] using the UB3LYP hybrid functional [42] at 6-31++G(d,p) [43] level of theory 6-31++G(d,p) [43] com- bined with the LANL2DZ [44] basis set for a heavy element like Cu. EmpiricalDispersion = GD3 [45] and TightSCF [45] criteria were applied for a better result. https://www.rcsb.org/ 432 Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Figure 1. ORTEP representation of the asymmetric unit of the complex with the atom numbering scheme. All thermal ellipsoids are drawn at 50% probability level. Frequency analysis was carried out using the same functional and basis set to verify the nature of optimized molecule. No imaginary frequency was found, which signifies a stationary point of minimum and the success of geometry optimization [46]. 2.8. Pharmacokinetic analysis The pharmacokinetic properties of a substance or compound, such as its absorption, distribution, metabolism, and excretion (ADME), must be evaluated prior to clinical and animal studies because they determine the potential of the substance as a drug and its activity within the body [47]. Additionally, the pharmacokinetic parameters provide important details on drug concentrations in various locations in the body over time [48]. For any chemical to be evaluated as a drug candidate, pharmacokinetic characteristics such as gastrointestinal absorption (GI), water soluble capacity (Log S), lipophilicity (Log Po/w), CYP1A2 inhibitor, and blood-brain barrier (BBB) are crucial [49]. Therefore, the SwissADME database (http://www.sib.swiss) was used to assess the pharmacokinetic characteristics of the complex [27]. 3. Results and discussion 3.1. Structural description Single crystal X-ray diffraction studies of the complex C14H11CuN3O5.H2O revealed that it crystallizes in monoclinic form with the space group P21/n. In Figure 1, it is evident that the asymmetric unit consists of a Cu(II) ion coordinated with one N atom of benzimidazole, one N atom of dipicolinic acid, two O atoms of dipicolinic acid, and one O atom of water molecule. The geometry of the complex is distorted square pyramidal with a Cu(II) ion, dipicolinic acid, and benzimidazole in almost a single plane, thereby forming the base, and one water molecule is out of the plane forming the apex of the square pyramidal geometry. The dipicolinate ligands are linked to a Cu(II) ion in a tridentate N,N,O chelating mode, forming two 5-membered chelate rings and the benzimidazole moiety and water molecules behave as monodentate ligands, both occupying the remaining positions of a square pyramidal geometry. Both Cu-O bonds formed by the O atoms of the dipicolinic acid anion are almost of the same length (Cu1-O1 = 2.018(3) Å and Cu1-O2 = 2.048(3)Å), whereas Cu-O bond formed by the O atom of water is much higher (Cu1-O5 = 2.243(3) Å). As expected, the two Cu-N bonds (one formed using the N-atom of benzimidazole and the other formed using the N-atom of dipicolinic acid) are of different lengths (Cu1-N2 = 1.942(4) Å and Cu1-N3 = 1.905(4) Å). There is a slight distortion in the bond angles surrounding the Cu(II) ion. This may be due to the steric hindrance of the dipicolinic acid anion and the benzimidazole moiety [50]. The geometrical para- meters of the obtained complex were very close to those of the reported complex [23]. The bond parameters of the reported complex are as follows; Cu1-O1 = 2.001(3), Cu1-O2 = 2.052 (3), Cu1-O5 = 2.242(3), Cu1-N2 = 1.934(3) and Cu1-N3 = 1.898(3) Å. 3.2. FT-IR spectroscopy The broad band observed at around 3444 cm-1 in the FT-IR spectrum of the complex is due to the OH stretching vibrations of the coordinated water molecules [51]. The peaks observed at 3061 and 2925 cm-1 are due to aromatic C-H stretching vibration and C-H vibration, respectively [52]. The O-H rocking and wagging vibrations of the coordinated H2O molecules in the complex were assigned a peak of around 856 cm-1 [53]. A broad band around 471 cm-1 could be attributed to Cu-O stretching vibration [51,54]. Cu-N stretching vibrations were assigned to the peak at 447 cm-1, indicating that the N of imidazole and 2,6- pyridine dicarboxylic acid coordinate with the Cu(II) ion [55,56]. The characteristic bands of the carboxylate group appear at 1362 cm-1, suggesting coordination of the O atom of the 2,6 pyridine dicarboxylic acid moiety with the Cu(II) ion [51,54]. 3.3. Scanning electron microscope (SEM) analysis The FE-SEM image (Figure 2) of the complex shows the formation of large crystals of the complex, demonstrating its regular crystalline structure. The crystal grains are arranged in a unidirectional and regular pattern, as is seen in Figure 2. The crystal is arranged in a regular rod shape and has well- characterized regular faces. 3.4. Hirshfeld surface analysis The Hirshfeld surface analysis of the synthesized complex was performed and their associated two-dimensional fingerprint plots were used to predict possible intermolecular interactions. For mapping the Hirshfeld surface of a molecule, the descriptor dnorm was used, which includes two factors: (i) de, which represents the distance of any surface point nearest to http://www.sib.swiss/ Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 433 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Table 4. Lipinski’s properties and pharmacokinetic properties (ADME) of the title complex *. MW #RB #HBD #HBA Violation Log PO/W Log S GI BBB CYP1A2 TPSA Bioavailability score 382.82 1 3 6 0 -0.04 -3.97 High No Yes 94.61 0.55 * MW: Molecular weight (g/mol), #RB: Rotatable bond, #HBD: Hydrogen bond donor, #HBA: Hydrogen bond acceptor, Log PO/W: Lipophilicity (Octane/water), Log S: Solubility, GI: Gastro intestinal absorption, BBB: Blood brain barrier, CYP1A2: TPSA: Topological polar surface area. Figure 2. FE-SEM images of the crystal. Inset: Rod-shaped crystals with well-characterized faces. (a) (b) (c) Figure 3. Molecular Hirshfeld surface: (a) dnorm; (b) shape index, (c) curvedness. the internal atoms, and (ii) di, which represents the distance of any surface point nearest to the exterior atoms [57]. The parameter dnorm is calculated by the mathematical expression given below; dnorm = (di – rivdw)/ rivdw + (de – revdw)/ revdw (1) where rivdw and rivdw represent the van der Waals radii of atoms. On the basis of the types of intermolecular contacts, the parameter dnorm may have a negative or positive value. The intermolecular contacts are shorter than the van der Waals separation if the value is negative, and the contacts are larger than the van der Waals separation if the value is positive [57]. The dnorm shows a surface with bright red, white, and blue spots for the shortest contact, contact around the van der Waals separation, and devoid of close contacts, which appear as the primary interaction in the complex, respectively. The Hirshfeld surface is unique in crystals with spherical atomic electron densities and provides insight into the intermolecular interactions that occur in the studied molecular crystals. The surfaces have been made transparent for better visualization of the molecular moiety around which they are calculated. Figure 3 shows the molecular Hirshfeld surface for Cu(II); dnorm, curvedness and shape index for the Cu(II) complex, which is mapped over the dnorm range -0.6670 to 1.3215, curvedness range -4.0000 to 0.4000 and shape index ranges -1.0000 to 1.0000, respectively. Compared to the van der Waals sum of the two elements that share this interaction, the intense red spots in the crystal dnorm maps indicate the presence of significantly short intermolecular contacts. In the corresponding fingerprint plots (shown in Figure 4), the red spots appeared as sharp spikes and were found to be associated with the polar O···H hydrogen bonding interactions. The other less important intermolecular interactions appeared in the dnorm map as faded red spots, and the broad peaks in the fingerprint plots are attributed to the hydrophobic C···H and H···H interactions. Figure 4 shows a graphical representation of the complete quantitative determination of all possible intermolecular contacts. It is evident that the O···H (30.6%), H···H (36.4%), and C···H (12.6%) contacts contributed the most to the intermolecular interactions, indicating that these contacts are important in the molecular packing of the reported complex [58]. 3.5. Pharmacokinetic properties An in silico ADME prediction study has been performed on the copper complex. An important pharmacokinetic parameter for any compound is its bioavailability score, which was calculated using Swiss ADME software [27] and evaluated several factors such as molecular weight, hydrogen donor and acceptors, as well as rotatable bonds, lipophilicity, gastrointestinal absorption, water soluble capacity (Log S), CYP1A2 inhibitor, blood-brain barrier (BBB) [33]. It is evident from Table 4 that the complex with a bioavailability score of 55% has a consensus lipophilicity value (Log PO/W) of -0.04. There are no apparent violations of the Lipinski rule in the title complex, indicating that this compound has the potential to be exploited as a candidate medicine [47]. 3.6. Molecular docking studies The Auto Dock Vina program was used to investigate how the copper complex interacted with different protein receptors [36]. The crystal structures of the required target proteins were retrieved from the protein data bank (PDB IDS-2XCS and 1D7U) in order to evaluate the antimicrobial activity [38,39]. 434 Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Table 5. Binding affinity of the complex with different proteins. PDB ID Binding energy (Kcal/mol) Amino acid residues Molecular surface view and the molecular interactions 2XCS -7.1 PHE1480, PRO1102, ASP1096, ASP1105, ARG1127, PRO1060, LYS1130, THR1129 1D7U -5.2 ASP319, ARG323, ARG316, LEU315, ASP89, VAL67, SER66 Figure 4. 2D Fingerprint plots of the complex. Dialkylglycine decarboxylase (PDB ID: 1D7U) is one of the proteins that is frequently targeted by bacteria. Furthermore, a crystal structure of GSK299423 and the DNA-bound S. aureus gyrase complex were used [38,39]. The docking score for dialkylglycine decarboxylase (PDB identification 1D7U) was found to be -5.2 kcal/mol, while the docking score for the S. aureus gyrase complex with DNA (PDB identifier 2XCS) was determined to be -7.1 kcal/mol (Table 5). The results obtained indicate that the synthesized Cu(II) has a strong interaction with bacterial proteins. 3.7. Antibacterial activity The disc diffusion method was used to examine the complex under study for its in vitro biological screening effects on a variety of bacterial species. In terms of antibacterial species, the title complex has good activity. The complex shows anti- bacterial activity against the Gram-negative bacterial isolate E. coli with an inhibition zone diameter of 11 mm and the Gram- positive bacterial isolate S. aureus with an inhibition zone diameter of 18 mm. The MIC values for the complex were checked and it was found that it shows MIC 3 mg/mL in the case of S. aureus and 2 mg/mL in the case of E. coli. 3.8. Computational studies The optimized geometry of the Cu(II) complex is shown in Figure 5. The penta-coordinated Cu(II) complex adopts a square pyramidal structure, which is consistent with the structure obtained from a single-crystal X-ray diffraction (XRD) study. To obtain more information about the molecular structure, excitation properties, and electron transport in the studied system, frontier molecular orbitals (HOMO and LUMO) analysis has been carried out [59,60]. Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 435 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Table 6. The HOMO-LUMO orbital energies, ∆E, ionisation potential (IP), electron affinity (EA), chemical potential (μ), global hardness (η), and global electrophillicity power (ω) at the UB3LYP/6-31++G(d,p) level of theory. Parameters Energy (eV) EHOMO -0.24 eV ELUMO -0.08 eV ∆E 0.17 eV Ionization potential (IP) -0.24 eV Electron affinity (EA) 0.08 eV Chemical potential (μ) -0.16 eV Global hardness (ή) 0.08 eV Electrophilicity power (ω) 0.16 eV Table 7. Mulliken atomic charges of complex. Atoms Atomic charges Atoms Atomic charge Cu1 -0.077022 H18 0.074810 O2 -0.534952 C19 -0.160532 H3 0.396600 H20 0.085693 H4 0.399794 C21 0.263952 O5 -0.367602 C22 0.263961 O6 -0.490847 C23 0.238960 O7 -0.488507 H24 0.150328 O8 -0.330866 C25 0.409527 N9 0.114388 C26 -0.208152 N10 -0.013600 H27 0.048559 N11 -0.277779 C28 -0.146566 H12 0.277362 H29 0.046941 C13 0.415130 C30 -0.258159 C14 0.224906 H31 0.065073 C15 -0.106678 C32 -0.095730 H16 0.085934 H33 0.103078 C17 -0.122295 C34 0.014290 Figure 5. Optimized geometry of the copper complex. Frontier molecular orbital theory (FMO) can also predict the optical properties and chemical stability of the complex [61]. The energy of the HOMO and LUMO orbitals of the studied system is found to be -0.24 and -0.08 eV, respectively (Table 6). The negative energy values of the HOMO and LUMO orbitals are indicators of the stability of the complex [62]. On the other hand, when the effect of optical properties is studied, a critical analysis of the energy difference in the HOMO-LUMO gap (∆E = ELUMO-EHOMO) is an important parameter and for the complex studied it was found to be 0.17 eV (Figure 6). The smaller energy gap (E) between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) influences the molecules to absorb light in the region of higher wavelength, which is important for optoelectronic applications [63]. In addition, the HOMO-LUMO energy gap can predict the chemical hardness and softness of a molecule [64]. A low ∆E value signifies a chemically soft molecule with less stability, while a high ∆E value signifies a chemically hard molecule with high stability [65]. Polarizability increases with the increase of the softness in a molecule which facilitates to enlarge the Non linear optical (NLO) response [66]. The ionization potential (IP) and electron affinity (EA) of the organic molecule are crucial parameters that give information about the charge injection and charge transport characteristics of a molecule [61]. High EA of the conjugated molecule is used to progress the electron injection/transport and low IP of the conjugated molecule results in better hole injection/transport, which is the main parameter for the achievement of an organic light-emitting diode (OLED) [67]. The HOMO-LUMO orbital energies are directly related to the ionization potential and electron affinity of the system. To better understand, we can calculate various properties such as the chemical potential (μ), global hardness (η), and global electrophillicity power (ω) from the value of ∆E based on DFT to understand the structure and reactivity of the molecule by the following relations [62]: 𝐼𝐼𝐼𝐼 = 𝐸𝐸𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 (2) 𝐸𝐸𝐸𝐸 = −𝐸𝐸𝐿𝐿𝐿𝐿𝐻𝐻𝐻𝐻 (3) 𝜇𝜇 = 𝐸𝐸𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻+𝐸𝐸𝐿𝐿𝐿𝐿𝐻𝐻𝐻𝐻 2 (4) η = −𝐸𝐸𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻+𝐸𝐸𝐿𝐿𝐿𝐿𝐻𝐻𝐻𝐻 2 (5) ω= 𝜇𝜇2 2ή (6) From Table 7, it is evident that the Mulliken charges in the neighborhood of C13, C14, C21, C22, C23, C25, and C34 are more positive and thus this positive value indicates the direction of delocalization. 436 Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 HOMO LUMO Figure 6. Frontier molecular orbitals of the complex studied in the gas phase at the UB3LYP/6-31++G(d,p) level of theory. Figure 7. Molecular electrostatic potential surface diagram of the complex. The electrostatic potential is typically visualized as a mapped surface. An electron density isosurface is colored according to the value of the electrostatic potential at each point on it [68]. Regions of large positive and negative electrostatic potential conventionally appear red and blue, respectively. While the positive (blue) portion of Molecular Electrostatic Potential (MEP) corresponds to nucleophilic reactivity, the negative (red and yellow) region is associated with electro- philic reactivity. As can be seen in Figure 7, the carboxylic group oxygen atom is the most reactive component of the molecule. The increased reactivity of this group may be due to its more electronegative character [62]. 4. Conclusions In this study, the antibacterial activities of the copper complex were explored using an extensive approach that included molecular docking, absorption, distribution, meta- bolism, and excretion (ADME) analysis, and density functional theory (DFT) investigations. From molecular docking studies, dialylglycine decarboxylase was discovered to have a docking score of -5.2 kcal/mol (PDB: 1D7U), whereas the S. aureus gyrase complex with DNA (PDB: 2XCS) had a docking score of - 7.1 kcal/mol. The results show that the Cu(II) complex interacts strongly with bacterial proteins. From ADME studies, it was evident that the compound has the potential to be used as a candidate drug because there are no apparent violations of the Lipinski rule in the title complex. The HOMO-LUMO gap (∆E = ELUMO-EHOMO) measured using DFT calculations was found to be 0.17 eV. From antibacterial studies, the MIC values were found to be 3 mg/mL in the case of Staphylococcus sp. and 2 mg/mL in the case of E. coli. The findings of these investigations provided important information about the potential of the metal complex to be used as an antibacterial agent. Acknowledgements The authors are grateful to the Departmental Special Assistance Scheme under the University Grants Commission, New Delhi (SAP-DRS-III, NO. 540/12/DRS/2013), and University of North Bengal, Government of West Bengal for financial and instrumental support. We are also grateful to Department of Chemistry, Gauhati University, for carrying out single crystal X-ray diffraction studies. Supporting information CCDC-2286899 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compound are available from the author. CRediT authorship contribution statement Conceptualization: Anmol Chettri; Methodology: Anmol Chettri, Sudarshan Pradhan; Software: Sriparna Roy; Validation: Anmol Chettri; Formal Analysis: Anmol Chettri, Pritika Gurung; Investigation: Anmol Chettri; Resources: Anmol Chettri, Biswajit Sinha; Data Curation: Anmol Chettri; Writing - Original Draft: Anmol Chettri; Writing - Review and Editing: Anmol Chettri, Biswajit Sinha; Visualization: Anmol Chettri; Funding acquisition: Anmol Chettri, Biswajit Sinha; Supervision: Biswajit Sinha; Project Administration: Biswajit Sinha. ORCID and Email Anmol Chettri chettrianmol5@gmail.com https://orcid.org/0000-0002-7939-238X http://www.ccdc.cam.ac.uk/%20data_request/cif http://www.ccdc.cam.ac.uk/%20data_request/cif mailto:data_request@ccdc.cam.ac.uk mailto:chettrianmol5@gmail.com https://orcid.org/0000-0002-7939-238X Chettri et al. / European Journal of Chemistry 14 (4) (2023) 429-438 437 2023 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.14.4.429-438.2465 Sudarshan Pradhan sudarshanpradhan43@gmail.com https://orcid.org/0000-0002-6963-8980 Pritika Gurung pritikagurung21@gmail.com https://orcid.org/0000-0003-2074-0711 Sriparna Roy chemsriparna26@gmail.com https://orcid.org/0009-0001-0737-5767 Biswajit Sinha biswachem@gmail.com https://orcid.org/0000-0003-0468-4035 References [1]. Aakeröy, C. B.; Champness, N. R.; Janiak, C. Recent advances in crystal engineering. CrystEngComm 2010, 12, 22–43. [2]. Wong-Foy, A. G.; Matzger, A. J.; Yaghi, O. M. 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This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Materials 2.2. Instrumentations 2.3. Synthesis of copper complex 2.4. Single crystal structure determination 2.5. Antibacterial activities 2.6. Molecular docking 2.7. Density functional theory studies 2.8. Pharmacokinetic analysis 3. Results and discussion 3.1. Structural description 3.2. FT-IR spectroscopy 3.3. Scanning electron microscope (SEM) analysis 3.4. Hirshfeld surface analysis 3.5. Pharmacokinetic properties 3.6. Molecular docking studies 3.7. Antibacterial activity 3.8. Computational studies 4. Conclusions Acknowledgements Supporting information Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField18: PrintField19: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: PrintField28: PrintField29: