Structural Characterization, DFT Geometry Optimization, Cyclic Voltammetry and Biological Assay of (Tellurite-pyridine) Mixed Ligandcomplexesof Cd(II)

This research work presents spectral characterizations (IR, 1 H NMR and 13 C NMR) of anionic tellurito Cd(II) complexes that prepared using cyanopyridine derivatives as a polydentate ligands. Also, X-ray based techniques involving (EDX and XRD) are applied for cadmium complexes to realize elemental composition and average crystallographic coherence. Moreover, the electrochemical studies represented on cyclic voltammetry are determined for Cd)II) in (absence/presence) of ligands to detect the role of complexation in solution measurements. All the previous experimental investigations are supported with molecular modeling of the geometric optimized structures based on density function theory (DFT) for all compounds accompanied by the calculations of different energetic parameters such as E HOMO and E LUMO . Finally, anti-microbial (antibacterial and antifungal), anti-oxidant and Bleomycin dependent DNA damage are screened for all samples to predict the inuence of metal complex formation on the biological activity of pyridyl ligands besides their priority. The biological studies were screened and emphasized Cd(II) complexes exhibit higher protection against DNA damage, lower antimicrobial and higher antioxidant features than the parent pyridyl ligands.


Introduction
Transitional metals can exhibit a wide range of coordination and reactivity features that can be employed with pyridyl ligands to prepare complexes.
Transition metal complexes display unique and impressive characteristics such as changing oxidation states and the ability to produce particular reactions with different biomolecules [1,2]. Therefore, the coordination between transition metals with pyridyl ligand swould prevent the resistance by microbes and enhance the antimicrobial activity of the pyridine derivative through new mechanisms of inhibition [3]. It was noticed that some metal−drug complexes are more effective than their pure drug [4,5].

Preparation of mixed ligand complexes
To a hot solution of ligands (HCPAand HCMPPA) in ethanol and sodium tellurite (Na 2 TeO 3 ) in distilled deionized water, a solution of cadmium chloride in distilled water was added slowly as shown in Scheme 3, 4. The mixture was heated in re ux for (3)(4) hr. The isolated solid complexes were ltered off, washed many times with hot distilled H 2 O and/or EtOH and nally dried in a vacuum desiccator over anhydrous CaCl 2 .

Analysis of complexes
Carbon, hydrogen and nitrogen percentage for ligands and their complexes were performed in Microanalytical Unit, Azhar University, Egypt. Complexometric analysis was utilized to predict the contents of Cd(II) in the prepared complexes. While, the gravimetric analysis was employed to calculate the content of Clwhich was determined as AgCl. electrolyte and connect with potentiostat of the type DY 2100 where the US convention is used to report CV data.

Molecular modeling
Density functional theory (DFT) modeling of the molecular structure and frontier molecular orbitals (HOMO/LUMO) is accomplished by using the Beck'sthree parameter exchange functional along with the Lee-Yang-Parr non local correlation functional (B3LYP) [27]. We used two different basis sets. We used 6-311+g (d, p) basis set for ligands and the Los Alamos National Laboratory basis set of double-zeta quality (LANL2DZ) for Cd complexes [28] in Gaussian 09 package in order to nd the structural and electronic parameters [29]. 2.7. Biological activities 2.7.1.Antifungal and antibacterial activities MIC (the minimum inhibitory concentration of the substance) was determined using the disc diffusion method as explained in Scheme (2S).

Antioxidant activity
The advantage of ABTS method is that possessing an extra free radical more than other techniques. Where, a stable color was produced over (1hr) in this reaction. The procedures of this method are explained in Scheme (3S).

Colorimetric assay of BMC-dependent DNA damage
The colorimetric assay for the prepared compounds and the ligands against DNA damage was illustrated in Scheme (4S) [30].

Molecular docking
Molecular docking calculations were carried out using docking server [31]. Gasteiger partial charges were added to the atoms of ligand. Non-polar hydrogen atoms were conjoined and rotatable bonds were identi ed. With the help of AutoDock tools [32], essential hydrogen atoms, Kollman united atom type charges and solvation parameters were added. A nity grid points and spacing of 0.375 Å were created using the Autogrid program [33]. Auto Dock parameter set-and distance-dependent dielectric functions were used to calculate the van der Waals and the electrostatic terms, respectively. Docking simulations were done by the use of the Lamarckian genetic algorithm (LGA) and the Solis & Wets local search method [34]. Orientation, initial position and torsions of the molecules of ligand were set randomly. All rotatable torsions were liberated during docking. Every docking experiment was derived from 10 different runs that were set to end after a maximum of 250000 energy evaluations. The population size was set to 150. During the search, a translational step of 0.2 Å and quaternion and torsion steps of 5 were applied.

Chemical composition and Physical properties
The practical elemental analysis results of the investigated compounds refer to great resemblances with the calculated chemical compositions as shown in Tables (1 & 2) in addition to some of characteristic physical properties.

Molecular chemical parameters
DFT (Density function theory) is adjusted to calculate quantum energies, the most important of which are E HOMO (Energy of the highest occupied molecular orbital) and E LUMO (Energy of the lowest unoccupied molecular orbital), because E gap (the difference between them) shows the stability of the compounds under study. The molecular structures with atom numbering of ligandsand their complexes are shown in (Figures 8 & 9). After the computational modeling simulation process, the following signi cant remarks can be recorded: (ω: global electrophilicity index), (η-: hardness), (μ: chemical potential), ( :electronegativity) and (σ: Softness) [46]as shown in (Tables 6 & 7). The redox behavior of CdCl 2 in 0.1M KCl as supporting electrolyte was examined by using cyclic voltammetry technique. Glassy carbon electrode (GCE) was used as working electrode within potential window (1V to -1.2V) and scan rate 0.1 V/s at 301.15K. Cd (II) solution was electroactive as it gave one cathodic peak and one anodic peak in cyclic voltammogram as shown in (Figure 14).
In the forward scan, (Cd 2+ /Cd) cathodic potential was at -0.9235V while in the reverse scan, the (Cd/Cd 2+ ) anodic potential was at -0.6507V. Thus, the Cd 2+ system was reversible and involved the transfer of two electrons. The redox mechanism can be represented by (Eqns. 9 and 10)

Cyclic Voltammetry theoretical approach
Applying the Randles-Sevcik equation (11), the analyte diffusion coe cient (D) in cm 2 .s -1 was given as follow [48,49]: Where" (I p ) is the current in Ampere, (n) is the number of electrons involved in the reaction (A) is surface area of the working electrode in cm 2 , (C) is metal cation concentration in mol.cm -3 and (ν) is scan rate in volts.sec -1 ". Also, (ΔE Peak ) the difference potential and (α) the charge transfer coe cient of electrons are calculated using equations (12) and (13) where, "E pc/2 is the half-wave potential of the cathodic peak, (R = 8.314 J.mol -1 .K -1 ) is the universal gas constant, (T) is the temperature in kelvin.The heterogeneous charge transfer rate constant (k s ) in cm/sec can be calculated by the following equation (14)  Where, "(F = 96485.33 coulombs) is Faraday constant". The cyclic voltammetric parameters for an anodic and cathodic peak are calculated and listed in Table (8). The surface coverage (Γ: the number of adsorbed species on a surface divided by the number of species in a lled monolayer on that surface) in mol.cm -2 as well as (Q) the quantity of charge that consumed during the reduction reaction or the quantity of charge that produced as a result of the oxidation can be evaluated from equations (15) and (16), respectively [53,54]. As CdCl 2 concentration increases, most of the cyclic voltammetric parameters (I p , ΔE P , Γ and Q) increase leading to more diffusion processes takes place between the bulk of solution and GCWE surface.
3.7.3. Cyclic voltammetry response of Cd(II) in presence of HCPA On adding HCPA to CdCl 2 solutionin 0.1 M KCl solution at GCE within potential range from1V to -1.2V and scan rate 0.1V/s as shown in (Figure 15), it was observed that there was shift in potential for both reduction and oxidation peaks. Cathodic current and anodic current also decreased with increasing concentration of HCPA The voltammogram demonstrates the effect of complexation between HCPA and Cd(II) ions. The diffusion of species (D), the redox reaction rates (αn) and the cyclic voltammetry parameters (Γand Q) decrease as aresult of complex formationin solution and weakness of GCWE role ( less αn), the change in the resultsshown in Table (9).

The stability constant and Gibbs free energies for the (Cd 2+ /HCPA) complex
The stability constants (β ML ) and Gibbs free energies (∆G) increase by further addition of HCPA to the Cd(II) ions indicating the sequential and progressive construction to form a stable complexin thesolution system as illustrated in Table (10). The following equations (17), (18) and (19) (19) Where, (E˚M) is the formal peak potential of metal ion at zero ligand addition, (E˚M l ) is the formal peak potential of complex at each ligand addition, (j = [L]/[M])is the molar ratio and (C L ) is molar ligand concentration. We can observe that as the ligand concentration increased as (β ML and ∆G) increased.

Antimicrobial studies
The activity index percent (%Activity Index) of ligands (HCPA and HCMPPA) and their chelates against "Staphylococcus aureus" as agram-positive bacteria, "Escherichia coli" asgram-negative bacteria and "Candida albicans" as a pathogenic fungus was calculated by equation (20)

BMC-dependent DNA damage
The bleomycin (BMC) is a member from glycopeptides antibiotics which is utilizes as antitumor agents. The bleomycin assay was certi ed as a speci c method to estimate the pro-oxidant activity of drugs and food antioxidants. BMC binds iron ions and DNA. If the compounds are able to reduce the bleomycin- 6gyw), Candida albicans (PDB code: 3ppc) and Covid 19 (PDB code: 7jpy).The docking studies showed an interaction between ligands and receptors as cleared in (Figures 22-25). The calculated bending energies of ligands as well as some parameters with the selected receptors were collected in Tables11-14.
The 2D plots of binding for ligands with the receptors were shown in (Figures 26-29), showing binding interaction sites of ligands with protein active sites of receptors. The HB plots that explained these interactions of ligands were shown in (Figures 30-33). Both estimated free energy of binding and interaction surface area revealed the most favored binding. The ligand which had more negative value of estimated free energy of binding represented more e cient binding. Based on data obtained from docking studies, it has been found that: 1. HCMPPA was the most e cient binding as it has the most negative value of estimated free energy of binding.
2. The order of best binding of ligands with antibacterial receptors (1xk6 and 6gyw) was found to be: HCMPPA > HCPA and this was congruent with experimental results.
4. There was great interaction between ligands and receptor of Covid 19 (PDB code: 7jpy) so it is possible to use ligands for Covid 19 treatment.

Conclusion
Tellurite-pyridine Cd(II) complexes were synthesized and characterized by several advanced spectroscopic techniques. The data showthe mononegative bidentate behavior of igandgiving anionic tellurito complex with octahedral con guration around Cd(II). Also, the molecular modeling of all compounds                The antioxidant activity assay ABTS method for HCPA and its Cd(II) complex Bleomycin-dependent DNA damage assay of HCPA and its Cd(II) complex

Figure 21
Bleomycin-dependent DNA damage assay of HCMPPA and its Cd(II) complex