Synthesis, X-Ray Structure, Hirshfeld Surface Analysis, DFT Calculations, and Molecular Docking Studies of Nickel(II) Complex with Thiosemicarbazone Derivative

This article presents both experimental and computational study of a new Ni(II) complex, namely, bis{2-(2-trifluoromethylbenzylidene)hydrazine-1-carbothioamido-κ2N2, S}nickel(II) (abbreviate as NiL2). The complex was synthesized and well characterized using various spectroscopic methods. The single X-ray crystallographic study revealed a distorted square planar geometry around Ni(II) metal ion centre in which the angles deviated from ideal 90° with a maximum value of 6.57° occupied by nitrogen and sulphur donor atoms. The theoretical bond lengths and angles for the NiL2 complex were obtained by using the B3LYP level of density function theory (DFT) with LANL2DZ/6-311G (d, p) basis sets. These results showed very good agreement with the experimental X-ray values. The electrophilicity index (ω = 50.233 eV) shows that the NiL2 complex is a very strong electrophile. In addition, strong F⋯H/H⋯F interactions with 28.5% of the total Hirshfeld surface analyses in NiL2 were obtained indicating that the complex could bind with protein effectively. Furthermore, the new NiL2 complex was docked with plasma retinol-binding protein 4 (RBP4) (PDB id: 5NU7), which implied that the NiL2 complex bound to Tyrosine 133 and Aspartate 102 amino acids via N-H intermolecular hydrogen bonds.


Introduction
Recent interest in the chemistry of thiosemicarbazone ligands arises mainly from the potential from both azomethine nitrogen and thiolate sulphur donor atoms with variance coordination modes of either monodentate [1], bidentate [2], or tridentate [3].
is variance can be performed by introducing different substituents in order to form a selection of mononuclear [4] and polynuclear [5] complexes. e versatility of thiosemicarbazone derivatives and its metal complexes allows for the design and development of bioactive compounds, including anticancer [6], antioxidant [7], and antibacterial [8]. (E)-2-(1-(3-Bromophenyl)ethylidene)hydrazine-1-carbothioamide molecule shows high potential in behaving as antimalarial agents [9]. Due to these reasons, their structural details are considered useful for structure activity relationships (SAR) design for future applications.
e experimental X-ray crystallographic structure of the Ni(II) complex also has been correlated with the corresponding structure optimized at DFT/ B3LYP/LANL2DZ/6-311G (d, p) level. In addition, Hirshfeld surface analysis was also used to interpret intermolecular interactions in the NiL 2 complex by visual representations whereas molecular docking was studied to know the receptor-amino acid interactions, to predict the important functional groups or atoms in the complex.

Materials and Methods
2.1. General Procedure. All the chemicals were purchased from Aldrich, R&M, and HmbG and used without further purification. Elemental analysis was performed with a CHNS-O Flashea Siri 112 Analyzer. Magnetic measurements were carried out on a Johnson Matthey Mark I MSB magnetic susceptibility balance model MKIC using Gouy's method.
e molar conductance of freshly prepared 1.0 × 10 −3 M in DMSO solutions was measured for the NiL 2 complex using Jenway 4320 conductivity meter. Electronic spectra were recorded on Shimadzu UV-1800 UV spectrophotometer and the samples were prepared with 1.0 × 10 −5 M in DMSO solutions.

X-Ray Diffraction Studies.
A single-crystal X-ray diffraction (SCXRD) study of NiL 2 was performed on Bruker SMART Apex II Duo CCD area-detector diffractometers using MoKα radiation (λ � 0.71073Å). e data collection was performed by APEX2 software [12], whereas the cell refinement and data reduction were performed by SAINT software [12]. e crystallographic structure was solved by Direct Method using SHELXTL [13] and further refined by full-matrix least squares technique on F 2 using anisotropic displacement parameters by SHELXTL [13]. Absorption correction was applied to the final crystal data using the SADABS software [12]. All geometrical calculations were carried out using the program PLATON [14]. e molecular graphics were drawn using SHELXTL [13]. All the hydrogen atoms were positioned geometrically (C-H � 0.93Å) and refined using riding model U iso (H) � 1.2 U eq (C) which means the isotropic displacement parameters are set to 1.2(C) times the equivalent isotropic U values of the parent carbon atoms. Additionally, the N-bound H atoms were located in a difference Fourier map and freely refined (N-H � 0.86Å). Selected crystal structure parameters are listed in Table 1.

Computational Details.
is study reports computational studies on NiL 2 complex. All calculations were performed by Gaussian 16 using high performance computer (HPC) provided by CICT, UTM along with Gauss View 6.0 for visualizations. e geometries were fully optimized without any constraint on every bond length, bond angle, and dihedral angle. Geometry optimizations were conducted using the unrestricted DFT method at the level of B3LYP/ LANL2DZ/6-311G (d, p) (B3LYP/GENECP) with the keyword "OPT". e highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were also performed under the same basic set. e reactivity descriptors that include energy gap (ΔE gap ), hardness (η), softness (S), global electronegativity (χ), and electrophilicity (ω) have also been computed by the same approach as from our previous work [15].

Results and Discussion
Bis{2-(2-trifluoromethylbenzylidene)hydrazine-1-carbothioamido-κ 2 N 2 , S}nickel(II), NiL 2 complex, was synthesized according to our reported procedures in [10], however with different reactants. Selected experimental and theoretical geometric parameters optimized of NiL 2 complex structure are shown in Table 2. e molecular structure of the NiL 2 complex obtained empirically was compared with theoretical calculation via DFT ( Figure 1). Percentage of deviation between bond lengths and bond angles for NiL 2 complex was calculated using equation (1). From Table 2, the average deviation percentage for both bond length and bond angles is at a low value (1.94% and 1.14%) indicating that experimental and calculation work is in good agreement.
is is further proven by the statistical correlation graph that shows R 2 values of 0.99849 for bond length ( Figure S1) and 0.99384 for bond angle ( Figure S2). However, there is a slight difference in values from experimental crystallographic data which might be due to the theoretical results obtained for isolated complex in the gaseous phase, whereas the experimental results obtained for both intra-and interlinked complexes in the solid phase similar to the previous report [20]:  Table 2. Figure 2 shows the molecular structure and atom numbering of the NiL 2 complex, with thermal ellipsoids drawn at the 50% probability level. e NiL 2 complex is a bis-chelate complex of Ni(II) with two L � ligands acting as bidentate chelate units ( Figure 2). e distortion from square planar geometry is mainly due to the S1-Ni1-N1, S2-Ni1-N1, S2-Ni1-N4, and S1-Ni-N4 bond angles of 86.70(10), 96.57(10), 84.96 (9), and 94.56(10)°, respectively, which differs from the ideal 90°by a maximum value of 6.57°. Two ligand units, placed a bit curved to each other with twisted angles between the planes of the two coordinated ligands, are 25.03 (14)°with maximum r.m.s deviation of 0.159(3) A˚for N4 atom. e pattern of bond length within the previous 1-(2-trifluoromethylbenzylidene)thiosemicarbazide ligand reported in [21] clearly indicates that the molecule is present in the thioamide form with both C-N and C�S bonds length of 1.343 (6)Å and 1.699 (4)Å, respectively, consistently with the location of the H atom bonded to N2 atom. However, deprotonated for N2 atom in the present NiL 2 complex was observed. Data of Table 2 show that, in the Ni(II) complex, there is a shortening and lengthening of both C9-N2 and C9�S1 bonds with 1.303(6)Å and 1.717(4)Å, respectively. us, a tautomeric switch from thione to thiol form is postulate. e molecular packing of NiL 2 complex is mainly linked by three strong C8-H8A . . . S2, C8-H8A ... F2, and C17-H17A . . . F6 intramolecular hydrogen bonds listed in Table 3, forming one pseudo-five and two pseudo-six membered graph set motifs. In the crystal structure, the NiL 2 complex is interconnected through N3-H3B ... S2, N3-H3C . . . N5, N6-H6B ... S1, N6-H6C ... N2, C5-H5A ... F2, and C12-H12A ... F3 hydrogen bonds forming a three-dimensional architecture (Figure 3(a)). e molecules are further stabilized by weak Cg1 . . . Cg3 interactions (Cg1 and Cg3 are the centroids of Ni1/S1/C9/N2/N1 and C2/ C3/C4/C5/C6/C7, resp.) with the contact distance of 3.785(3)Å (symmetry code: 11 − x, 1 − y, z), forming one-dimensional dimeric wave-like parallel to b-axis (Figure 3(b)).

UV-Vis Spectroscopy.
e UV-Vis spectrum (Figure 4) of the NiL 2 complex, bis{2-(2-trifluoromethylbenzylidene) hydrazine-1-carbothioamido-κ 2 N 2 , S}nickel(II), exhibits two bands at λ max � 269 nm and 328 nm, which can be assigned to the π⟶π transition of the conjugated phenyl ring and n⟶π * intraligand charge transfer (ILCT) transition of the C�S and CN chromophore in ligand molecule [22]. In addition, a shoulder band which appeared at ∼450 nm in NiL 2 complex can be assigned to 1 A 1 g⟶ 1 A 2 g transition. is band is well correlated with the previous study of the square planar NiL 2 complex [22]. To further support, the magnetic moment of the NiL 2 complex was shown of value 0 B.M, which is one of the main criteria for square planar geometry. [21] whereas low molar conductance with 1.37 Ω −1 cm 2 mol −1 showed the absence of acetate ion and nonelectrolytes in DMSO solution [23].

Frontier Molecular Orbitals Studies.
e highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are frequently studied in order to impart key information regarding the electron-donor and electron-acceptor character of the complexes which shall lead to the interpretation of the charge transfer process. e lower energy of the HOMO indicates the lower ability as an electrondonor, resulting in higher energy of LUMO and higher resistance to accept electron. is allows elucidation of chemical stability by observing the difference in energy between HOMO and LUMO (E gap ). While large E gap is preferred for the high stability of complexes with respect to chemical reactions, low E gap is well sought by the researchers in relating to chemical reactivity in applications such as antibacterial studies due to the ability to encounter efficient charge transfer interactions. In addition, this study can also explain the chemical concept of chemical softness and hardness. With small E gap , the complexes are considered as "soft" base due to the high energy of HOMO and thus enhance the interaction with the LUMO of soft acids. Other than that, indices such as electron affinity and ionization potential are also commonly interconnected with the studies of HOMO and LUMO energies in pursuing a better grasp of how complexes theoretically behave, chemicalwise.
As can be seen in Figure 5, the electron density of the NiL 2 complex is mainly distributed over the nitrogen, sulphur, and Ni atoms for both HOMO and LUMO. e calculated values of reactivity descriptors parameters are summarized in Table 4. e given low energy gap (0.460 eV) thus indicates high reactivity of the complex due to ease of charge transfer process [24]. e high value of softness (2.174) or the low value of hardness (0.230) indicates lower energy is needed for electron transition from HOMO to LUMO which means that the complex is susceptible to deform and ready to interact with other nucleophilic active site such as amino acid.

Hirshfeld Analysis.
Hirshfeld surface analysis has been carried out to illustrate the interactions of the crystal structure and their 2D fingerprint plots were established using Crysta-lExplorer3.1 software [26]. e Hirshfeld surfaces for d norm were obtained and generated as a transparent surface to allow visualization of the molecular structure. e d norm (−0.337 to 1.450)Å mapping of the Hirshfeld surface ( Figure 6) exemplified several red spots in various sizes and intensities. e red spots remarked on the NiL 2 complex showed the dominant interactions involving the donor and acceptor. e C-H· · ·F, N-H· · ·N and N-H· · ·S contacts are present in the studied NiL 2 complex. As shown in Figure 6, the interactions at the NiL 2 complex backbone between the hydrogen of the amine and its adjacent sulphur atom (N3-H3B· · ·S2) and nitrogen atom (N6-H6C· · ·N2) form a dimeric arrangement in the crystal packing. Also, there is an additional red spot representing the intermolecular hydrogen bonding of the C12-H12A···F3 due to the side by side arrangement of the neighbouring complexes in the crystal packing. Besides, from the other side view of the NiL 2 complex, the intense red spots revealed the intermolecular hydrogen bonding of N3-H3A···N5 and N6-H6B· · ·S1 interactions of the NiL 2 complex ( Figure 6). ese two interactions between the adjacent NiL 2 complexes are raised due to their dimeric arrangement in the unit cell packing. e fingerprint plots indicate the percentage contributions of the various intermolecular contacts (Figure 7). In order to highlight all the interactions involved in the crystal packing, each fingerprint plot was divided into the specific pairs of atom-types contributions, such as H· · ·F, H· · ·H, H· · ·C, H· · ·S, H· · ·N, C· · ·C, and other. e blue coloured represents the assigned reciprocal contacts, while the grey shadow denotes the outline of the original fingerprint plots [27]. d e and d i are the distances from the Hirshfeld surface to the nearest atoms outside and inside the surface [28]. e F· · ·H/H· · ·F contacts appeared as the largest contribution to the Hirshfeld surface (28.5%). eir two symmetrical narrow spikes of d e + d i 2.20Å proved the presence of the intermolecular C-H· · ·F interactions of the NiL 2 complex. Furthermore, the characteristic spikes representing the shortest H· · ·H contacts contributed as the second-largest fingerprint plot to the Hirshfeld surface (22.2%) with a high concentration in the middle region as shown in light blue at d e + d i 2.25Å. e contribution of the C· · ·H/H· · ·C (12.5%) is indicated by a pair of peaks at d e + d i 2.80Å. In Addition, the spikes of S· · ·H/H· · ·S and N· · ·H/H· · ·N contacts showed 7.4% and 5.7% contribution, respectively, which correspond to the presence of N-H· · ·S interactions. e sharpest point in H· · ·S featured a closer contact of d e + d i 2.60Å, while d e + d i 2.20Å for N· · ·H contacts, respectively. Moreover, the F· · ·N/N· · ·F contacts showed a 20Å. e C· · ·C contacts usually refer to π-π staking interaction [29]. In this NiL 2 complex, C· · ·C contacts contributed 3.2% of the Hirshfeld surface with the sum of d e and d i being approximately 3.5Å. ere is also a negligible amount of other contacts contribution (C· · ·F, C· · ·N, F· · ·S, C· · ·S, and Ni· · ·F), with less than 2% in the compound. us, their contacts are almost insignificant to discuss.

Molecular
Docking. Docking analysis was conducted to investigate the possibility of molecular interaction of NiL 2 complex with biologically important proteins. Previous studies have shown the importance of docking analysis for a synthetic compound such as thiosemicarbazide and terphenyl derivatives [30,31]. Interaction of NiL 2 complex with plasma retinol-binding protein 4 (RBP4) (PDB id: 5NU7) was investigated to understand its potency. Physiologically, RBP4 acts as a transporter for retinol [32].
e NiL 2 complex docked inside the RBP4 active binding site which is at the same site as the retinol. A total of ten possible 3D docking orientations of NiL 2 complex inside RB4 active binding site are seen, the highest docking rank with the lowest energy (kcal/mol) as shown in Figure 8. Binding affinity is calculated as −3.3 Kcal mol −1 for NiL 2 complex and closer to retinol with −5.5 Kcal mol −1 (Table 5). According to these results, the most effective intermolecular hydrogen bonds are observed between NiL 2 complex through N-H atoms and Tyrosine 133 (2.05Å) or Aspartate 102 (2.18Å) in the active binding site (Figure 9). However, the N-H intramolecular hydrogen interaction is contrasted with Hirshfeld surface analysis, where F-H interaction is the most dominant (28.5%). It is due to the rotation around both Ni-N and Ni-S bonds in NiL 2 complex for insertion into the RBP4 active site. Similar formations of both antisymmetrical (anti) and symmetrical (syn) isomers of the Pd(II) and Pt(II) complexes have been previously reported [33,34]. erefore, the present NiL 2 complex has the potential to be a competitive substrate for retinol that is able to bind at the same active binding site of RBP4. Due to the high number of amino acids interacting with the NiL 2 complex (via hydrophobic interaction and          Bioinorganic Chemistry and Applications hydrogen bonds), the release of NiL 2 complex from the transporter protein would be slower than the retinol.

Conclusion
A new complex, bis{2-(2-trifluoromethylbenzylidene)hydrazine-1-carbothioamido-κ 2 N 2 , S}nickel(II), (NiL 2 ) was prepared and its structure was characterized by elemental analysis, molar conductance, magnetic susceptibility, and UV-Vis. e structure has been further confirmed by the single X-ray crystallographic which showed a distorted square planar geometry. In addition, the structure of the synthesized NiL 2 complex is stabilized by π-π, inter-and intramolecular interactions. e Hirshfeld surface analysis has confirmed the presence of several interactions with C-H· · ·F interactions being the most important features of crystal packing. e paramount findings by the HOMO-LUMO energy gap proven the efficiency of this complex to have charge transfer interactions within the molecule due to the small E gap . is suggested the facile electrons transfer from the NiL 2 donor orbital to the amino acid acceptor, Finally, molecular docking modelling is illustrated between NiL 2 complex and plasma retinol-binding protein 4 (RBP4) (PDB id: 5NU7) active site. NiL 2 has interacted with both Tyrosine 133 and Aspartate 102 amino acids through N-H hydrogen bonds.

Data Availability
Crystallographic data for the structure reported in this study is deposited at the Cambridge Crystallographic Data Centre under the CCDC no. 2023702. ese data can be obtained free of charge via the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; e-mail through deposit@ccdc.cam.ac.uk.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.

Supplementary Materials
Supplementary data include CIF file of the most important compounds described in this article. CCDC no. 2023702 contains supplementary crystallographic data for NiL 2. . (Supplementary Materials)  Bioinorganic Chemistry and Applications 9