Theoretical insights into the metal chelating and antimicrobial properties of the chalcone based Schiff bases

ABSTRACT The emergence of multi-drug resistant pathogens in infectious disease conditions accentuates the need for the design of new classes of antimicrobial agents that could defeat the multidrug resistance problems. As a new class of molecules, the Heterocyclic Schiff base is of considerable interest, owing to their preparative accessibility, structural flexibilities, versatile metal chelating properties, and inherent biological activities. In the present study, CAM-B3LYP/LANL2DZ and M062X/DEF2-TZVP level of density functional method is used to explore the complexation of chalcone based Schiff base derivatives by Co2+, Ni2+, Cu2+, and Zn2+ metal ions. The HL(1-3)-Co2+, HL(1-3)-Ni2+ and HL(1-3)-Zn2+ complexes formed the distorted tetrahedral geometry. Whereas, the HL(1-3)-Cu2+ complexes prefers distorted square-planar geometry. The BSSE corrected interaction energies of the studied complexes reveals that Cu2+ ion forms the most stable complexes with all three chalcone based Schiff bases. Of the three Schiff bases studied, the HL2 Schiff base acts as a potent chelating agent and forms the active metal complexes than the HL1 and HL3 Schiff bases. Further, the strength of the interaction follows the order as Cu2+ > Ni2+ > Co2+ > Zn2+. The QTAIM analysis reveals that the interaction between the metal ions and coordinating ligand atoms are electrostatic dominant. The metal interaction increases the π-delocalisation of electrons over the entire chelate. Hence, the antimicrobial activity of the metal complexes is more effective than the free Schiff bases. Moreover, the HL(1-3)-Cu2+ complexes shows higher antimicrobial activities than the other complexes studied.


Introduction
Infectious diseases have been a major haunt to the human civilisation resulting in a large number of deaths worldwide [1]. Although the development of anti-microbial has been the major advance in medicinal science, due to the emergence of drug-resistant pathogens, the struggle to control the microbial infections has persisted throughout human history. This clearly pointed out a need for the development of new classes of antimicrobials enriched by the innovatory and more effective mechanism of action [2]. Over the past several decades, tremendous research is going on in order to develop potent antimicrobial agents. Owing to the intensive search for effective antimicrobial agents, the Schiff base has attained a considerable attention by the researchers due to its preparative accessibility, structural flexibilities, versatile metal chelating properties, and inherent biological activities such as antitumor [3,4], anticonvulsant [5], antiviral [6,7], antibacterial [8], anti-tubercular [8], ROS scavenging activities [9]. Schiff base is a compound having azomethine -C=N-functional group which form a backbone for many organic compounds [10][11][12]. In particular, the hetero Schiff base in which the Schiff base tethered to the heterocyclic moieties is of prominent importance owing to their unique chelating property due to the presence of electronegative atoms such as N, O and S donor atoms [13].
The metal complexes of the Schiff bases exhibit a broad spectrum of antimicrobial activities; it has gained importance in medicinal and pharmaceutical fields. During the period of 1996 and until now, there is a rapid increase in the synthesis and characterisation of Schiff base metal complexes focussing on their biological activities. Of the numerous Schiff base metal complexes, the chalcone based Schiff base and its metal complexes are of great interest. The chalcone is an important class of phytochemical compound across the plant kingdom containing benzylideneacteophenone scaffold, where the two aromatic rings are connected by three carbon α, β unsaturated carbonyl bridge [14]. The structure of chalcone remains a fascination among the researchers due to a large number of replaceable hydrogen to yield a large number of derivatives, ease of synthesis, a variety of promising biological activity such as anti-oxidant, anti-viral, anti-fungal, anti-cancer, antifilarial and so forth [15]. Kalanithi et al. [16] have prepared the metal chelates of chalcone based Schiff bases of N-(3-aminopropyl) imidazole and reported that the metal complexes have better antibacterial and antifungal activities. Since the chalcone based Schiff base provides the potential binding sites for the metal ions, a deeper understanding of the coordination properties and the role of metal ions is essential. Even though the experimental results support the increased antibacterial and antifungal activity of the chalcone based Schiff base metal complexes, the knowledge on nature of metal-ligand binding, interaction energy, the effect of metal ion interaction on the frontier molecular orbitals, metal ion selectivity of Schiff bases is still lagging. Yet there is no theoretical work reported on the complexing properties of the chalcone based Schiff bases, we have investigated those properties using quantum chemical methods.
The quantum chemical studies can provide information at molecular level regarding their chelating properties and their detailed analysis will provide a deeper understanding of the metal complexes of chalcone base Schiff base. The quantum chemistry communities have accepted the DFT study as a cost-effective approach for the computation of molecular structure, vibrational frequencies, and energies of chemical reactions [17]. Hence, in the present study, the metal chelating properties of chalcone based Schiff base of N-(3-aminopropyl) imidazole have been analysed in detail through NBO, NPA, frontier molecular orbital, and QTAIM analysis using CAM-B3LYP level of DFT method. The present work may be helpful in developing potent multi-resistant anti-infectious drugs.

Computational details
The structures of the HL1, HL2, HL3, and their metal complexes were obtained using Marvin Sketch 16.3.14.0. The geometry optimizations and the electronic structure calculations of the isolated HL1, HL2, HL3 ligands, and their corresponding metal complexes were carried out using DFT methods such as CAM-B3LYP [18] combined with LANL2DZ basis set in which the LANL2 effective core potential is defined for the metal ions and D95 V basis set is defined for the elements H-He [19][20][21] and hybrid Minnesota functional called M062X [22] along with the Karlsruhe basis set def2-TZVP [23]. The harmonic vibrational frequencies calculated at the same level of theory in order to ensure that the optimised geometries are at energetic minima on potential energy surface (PES). The interaction energies were corrected with BSSE using counterpoise procedure of Boys and Bernardi [24] and calculated using the following equation where E ABC (ABC) is the energy of the complex, E ABC (A), E ABC (B), and E ABC (C) are the energies of the isolated monomers A, B, and C respectively. The topological parameters such as electron density ρ(r), Laplacian of electron density ∇ 2 r(r) and total electron density H BCP (r) at the BCP have been calculated using Bader's QTAIM analysis [25][26][27][28]. For this purpose, the wave-function files were generated using Gaussian 09 software and further AIM calculations also carried using MORPHY98 software package [29]. In order to obtain the net atomic charges and information about the orbitals involved in the charge transfer interactions between the metal ions and the donor ligands, the single point calculations such as NPA [30] and NBO analysis [31] were performed on the optimised geometries. All calculations were carried out using Gaussian 09 software [32]. The mass and volume of isolated Schiff bases and its complexes were calculated using YASARA Structure version 17.7.30 [33,34].

Results and discussion
The structure of the chalcone based Schiff bases {2- phenol (HL3)} were chosen based on the previous experimental report [16]. The chalcone based Schiff base is formed by supplanting the carbonyl oxygen of 2-hydroxychalcone by the N-(3-aminopropyl) imidazole. The difference between the three Schiff base derivatives is the substitutions at the para position of ring B of the chalcone. HL1 refers the unsubstituted ring, HL2 and HL3 refer to the CH 3 and NO 2 substituted ring respectively. The chalcone based Schiff bases acts as the tridentate ligand in which the azomethine nitrogen (N2), imidazole nitrogen (N10) and phenolic oxygen (O11) act as the donor ligands for the metal ions and can form active metal complexes by the interaction of Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ ions. The 1:1 chelating mode of metal complexes were constructed and fully optimised at both CAM-B3LYP/ LANL2DZ and M062X/def2-TZVP levels of theory. The harmonic vibrational frequency analysis calculated for the optimised geometries shows no imaginary frequency, which implies that all the optimised geometries are at energetic minima on the PES.

Effect of spin states on the electronic energies
The transition metal ions in which the d-orbital is not completely filled can exist in two possible spin states such as high and low spin respectively. Hence, in order to find the most stable spin state that corresponds to the lowest energy geometries i.e. most stable geometry, the complexes optimised at doublet and quartet, and singlet and triplet for the Co 2+ , and Ni 2+ chelates. In the case of Cu 2+ and Zn 2+ chelates, the spin effects have not been investigated, since Cu 2+ chelates possess only one unpaired electron in its outermost d-orbital, whereas for Zn 2+ chelates the d-orbital is completely filled. The calculated electronic energies of the aforesaid spin states presented in Table  1. From the obtained results, it is clear that the high spin metal chelates are the most stable rather than the low spin metal chelates. This is due to the increase in the amount of the exact exchange energy which strongly stabilises the high spin states with a large number of unpaired electrons with respect to the low spin states. In this regard, the quartet and triplet states of Co 2+ and Ni 2+ chelates will be considered for further studies.
Since the Zn 2+ chelates contain no unpaired electrons, the complexes were subjected to restricted DFT calculation. Whereas, for the systems containing unpaired electrons, the unrestricted DFT calculation is used in which there are two complete set of orbitals, one for alpha electrons and other for beta electrons. These two orbitals use the same set of basis functions but a different set of molecular orbital coefficients. Due to the different set of orbitals, the wavefunction is no longer an eigenfunction of the total spin <S 2 >. This will introduce some error called 'spin contamination' in the unrestricted DFT calculation. To check the presence of spin contamination the expectation value of the total spin <S 2 > taken from the Gaussian output files and are presented in Table 1. If there is no spin contamination the expectation value will exactly equal to S(S + 1) (where S = ½ times the number of unpaired electrons). If the deviation of the <S 2 > value is less than 10% means, then the spin contamination error is negligible. As seen from the Table 1, it is clear that the error percentage is 0.19%, 0.31%, and 0.53%-0.56% for Co 2+ , Ni 2+ , and Cu 2+ chelates respectively that lie below 10% and hence the obtained results are reliable [35]. Moreover, the calculated expectation values are 3.757, 2.006 and 0.754 for the Co 2+ , Ni 2+ , and Cu 2+ chelates respectively. It is noteworthy that the obtained values are close to the values of the quartet, triplet, and doublet wave function.

Geometrical parameters
The optimised geometries of the chalcone based Schiff bases (HL1, HL2, and HL3) are shown in Figure 1. These Schiff bases (HL1, HL2, and HL3) act as a tridentate ligand and can chelate the metal ions such as Co 2+ , Ni 2+ , Cu 2+ and Zn 2+ through the coordination of azomethine nitrogen (N2), imidazole nitrogen (N10) and phenolic oxygen (O11). Based on the previous experimental literature Cl − ion was also included in the metal coordination sphere in order to obtain a stable tetradentate coordination mode. Figure 2 shows the optimised geometries of the metal complexes along with their atomic numbering scheme and their corresponding geometrical parameters are presented in Tables  , HL2-M 2+ , and HL3-M 2+ (where M 2 + = Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+) complexes show similar values with the variation of about ± 0.01-0.08 Å and ± 0.01-0.23 Å calculated at CAM-B3LYP/LANL2DZ and M062X/def2-TZVP levels of theory respectively. Whereas, while comparing the coordination distances with respect to the metal ions, it is noteworthy that there is a significant change in the coordination distances and these changes are due to variation in their ionic radii and electronegativity of metal ions. Among the four coordination distances, the O11-M 2+ distance is found to be minimum and Cl27-M 2+ is found to be the maximum. This implies that the contribution of O11 in forming the metal complexes is larger rather than the N2, N10, and Cl27. This is due to the fact that, the donor ligand O11 with more negative charge (−0.81 and −0.75 e in isolated monomer) will transfer more charge to the metal centre than one with less negative charge (−0.56 and −0.48 e for N2 and −0.62 and −0.41 e for N10 in isolated monomer) [37]. Moreover, the ligand coordination number also influences the metalligand distances. The metal-ligand distance will be larger, for the donor ligand with maximum ligand coordination number (LCN) and less negative charge on it, as seen in the case of  N2 and N10. This is because the donor ligand with larger LCN shares more amounts of charges with its neighbour and thus transfers only less amount of charge to the metal centre [37]. However, in the case of Cl27-M 2+ coordination distance, although the Cl27 possess high negative charge (−1.00 e in isolated monomer) and zero LCN, their distance appear to be the maximum due to its larger ionic size (181 pm for Cl − ion) than the nitrogen and oxygen atoms. On comparing the geometrical   parameters of the isolated monomers and metal complexes, it is inferred that, after formation of the metal complexes, the bond lengths of N2-C3, N2-C5, C9-N10, N10-C18, and C14-O11 bonds are significantly affected due to the interaction of metal ions with N2, N10, and O11 donor ligands at both levels of theory. This is because, during the complex formation, the electron density from the bonding orbital (BD) of above-mentioned bonds is transferred to the anti-non-bonding orbital (LP*) of the metal centre. Moreover, in addition to this interaction, there is charge delocalisation from the LP of metal ion to the BD* of the above-mentioned bonds. The BD-LP* interactions decrease the occupancy of BD orbital and LP-BD* interactions increase the occupancy of BD* orbital corresponding to the N2-C3, N2-C5, C9-N10, N10-C18 and C14-O11 bonds. The increase in the occupancy of BD* and a decrease in the occupancy of BD orbitals will slightly decrease the bond stability resulting in the elongation of the corresponding bond lengths. Moreover, as seen from the Table 1, the HLn-Co 2 + , HLn-Ni 2+ , and HLn-Zn 2+ (where n = 1, 2, and 3) complexes possess distorted tetrahedral geometry whereas, the HLn-Cu 2+ complexes exhibits distorted square-planar geometry.

Stability of the HLn-M 2+ metal complexes
To gain more insight into the stability of the  Figure 3 shows that when the electronegativity of the metal ions increases, the stability of the metal complexes are found to be enhanced due to the high electron withdrawing ability of the metal ions. It is worthy to note that the predicted order of interaction energies is Cu 2+ > Ni 2 + > Co 2+ > Zn 2+ which correlates well with Irving-Williams order for the stability of metal complexes [38]. Moreover, the order of interaction energies for the three different substitutions is HL2-M 2+ > HL1-M 2+ > HL3-M 2+ .

Topological analysis
To get further insight into the metal-ligand bonding nature, the Bader's QTAIM analysis [25][26][27][28] was carried out for the studied HLn-M 2+ complexes. The electron density ρ(r), Laplacian of electron density ∇ 2 r(r) and total electron density (H BCP (r) = G BCP (r) + V BCP (r)) at BCP calculated using the Bader's theory formalism describes the stability of the metal-ligand bonding as well as the nature of that bonding. The sign of the ∇ 2 r(r) and H BCP (r) describes whether the electron density is locally concentrated (∇ 2 r(r) , 0 ; H BCP (r) < 0 indicates covalent interactions) or depleted (∇ 2 r(r) . respectively. In all the metal complexes the N10-M 2+ and O11-M 2+ bonds observed with high electron density and the N2-M 2+ and Cl27-M 2+ bonds observed with less electron density. It is expected that the stronger bonds are associated with the high electron density [41][42][43][44] as observed in the case of HLn-Cu 2+ resulting in high structural stability. Whereas, for Zn 2+ complexes, the coordination bonds observed with minimum ρ(r), ∇ 2 r(r) and H BCP (r) values at BCP implies that the Zn 2+ complexes are the least stable among the studied complexes. The obtained results of QTAIM analysis correlates well with the structural parameters and interaction energy values.

Natural charge analysis
The natural charge analysis is an intuitive tool for metal complexation studies since it provides valuable information about the charge transfer that takes place between metal ions and coordinating ligand atoms. The amount of net charge before and after complexation with the Co 2+ , Ni 2+ , Cu 2+ and Zn 2+ metal ions and the coordinating ligand atoms such as nitrogen, oxygen, and chlorine gives the deeper insight about the amount of charge gain or loss by the metal ions as well as the coordinating ligand atoms. Hence, in order to obtain the net atomic charges on the individual donor atoms and metal ions, the natural population analysis (NPA) has been carried out using CAM-B3LYP/LANL2DZ and M062X/def2-TZVP levels of theory and their corresponding results are presented in Table 8. From the obtained results, it is evident that, after the complex formation, there is a drastic change in the net atomic charges due to charge delocalisation. The amount of net charge on the donor ligand atoms and metal ions before complex formation is found to be −0.55 to −0.56 and −0.47 to −0.48 e, −0.50 to −0.62, and −0.41 to −0.50 e, −0.81, and −0.75 to −0.76 e, and −1.00 and 2.00e corresponding to N2, N10, O11, Cl27 and M 2+ atoms calculated at CAM-B3LYP/ LANL2DZ and M062X/def2-TZVP levels of theory respectively. After the complex formation, the positive charge on the metal ions is found to be decreased which implies that the metal ions gain a certain amount of electron from the coordinating ligand atoms. The amount of neutralised positive charge is found to be 1.03, 1.05, 1.10, and 0.73 e and 0.87, 0.86, 0.88, and 0.73 e and corresponding to the Co 2+ , Ni 2+ , Cu 2+ and Zn 2+ metal ions calculated at both levels of theory. The amount of charge gained by the metal ions follows the order Cu 2+ > Ni 2 + > Co 2+ > Zn 2+ which correlates well with the calculated interaction energy order in the present study and Irving -Williams order of stability of metal complexes [38]. Moreover, the variation in the charge gained by the metal ions is due to differences in their electronegativity values. Zhang [45] 428). Since the electronegativity defines the charge accepting ability of an element, the element with high electronegative value has a higher affinity for electrons. In the abovementioned order of electronegativity of metal ions, the Cu 2+ possess the higher electronegativity value followed by the Ni 2+ , Co 2+ and Zn 2+ metal ions. This phenomenon is well augmented with findings of the present study in which the Cu 2+ gains more amount of charges, whereas the Zn 2+ gains the least amount of charges due to its less electronegativity. From the studied metal complexes, it is inferred that the negative charge on O11 and Cl27 atoms is decreased, which implies that the donor ligands transfers its electron density to the metal cations. Whereas, in the case of N2 and N10 donor ligands, there is an increase in the net negative charges. From these observations, it is noteworthy that in addition to LMCT transitions, MLCT transitions can also occur, resulting in the rise of the negative charges on the donor ligand atoms. From the natural charge analysis, it is concluded that the electronegativity of the metal ions, plays a major role in the charge transfer interactions between Table 6. The electron density (ρ in a.u) and laplacian of electron density (∇ 2 r in a.u) of Coordinating ligand atoms of monomers and HL1-M 2+ , HL2-M 2+ , and HL3-M 2+ (where M 2+ = Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ ) complexes calculated at CAM-B3LYP/LANL2DZ and M062X/DEF2-TZVP levels of theory. coordinating ligands and the metal ions, which in turn enhances the stability of the metal complexes.

NBO analysis
In order to get a deeper insight into the intermolecular delocalisation effect due to the metal complexation, second-order perturbation theory analysis was carried out at CAM-B3LYP/ LANL2DZ level of theory using NBO 3.1 implemented in the Gaussian 09 software. This analysis gives detailed information about the occupancy of donor and acceptor NBO involved in the transitions and their corresponding stabilisation energy of the electron delocalisation effects. The stabilisation energy associated with the transition between the donor and acceptor NBO is estimated as where q i is the donor orbital occupancy, ε i and ε j are diagonal elements (orbital energies) and F ij is the off-diagonal NBO fock matrix element. The occupancy of the donor and acceptor NBOs and their corresponding stabilisation energy values are presented in the Supplementary Table S1. On comparing the occupancies of the donor and acceptor NBOs, before and after the complex formation it is noticed that there is a significant change in their occupancies due to the electron delocalisation during the complex formation. From the Tables S1-S3, it is noteworthy that the occupancies of the LP and LP* are found to be 1.00 and 0.00 for all metal ions except Zn 2+ ion in which the LP has the occupancy of about 2.00. After the complex formation, the occupancy of the metal ion LP* is found to be increased in the range of 0.040 to 0.163 for all the metal complexes. The reason for the rise in the LP* occupancy of the metal ion is due to the electron delocalisation from the LP of coordinating ligand atoms to the LP* of metal ions. Furthermore, the LP occupancy of metal ions is decreased due to the electron delocalisation from the LP of metal ions to the BD* of chalcone based Schiff bases. In all the metal complexes, the stabilisation energy of LP-LP*, BD-LP*, and LP-BD* types of orbital interaction were considered since these interactions are more important for metal coordination complexes. The stabilisation energy E(2) provides the strength of the delocalisation interaction between the donor and acceptor NBO. In the present study, the LP-LP* orbital interaction posses the higher E(2) values rather than the BD-LP* and LP-BD* interactions which imply that the degree of delocalisation between the donor and the acceptor NBO will be greater. In the case of metal coordination complexes, there is a general trend that during the complex formation, the lone pair of the coordinating ligand atoms will be transferred to the empty orbitals of the metal ions and this phenomenon is confirmed by the higher E(2) values for LP-LP* interactions. In the LP-LP* interactions the coordinating ligands act as the donor NBO (LP) and metal ions act as the acceptor NBO (LP*). From the second order perturbation analysis, it is noted that the degree of delocalisation is maximum for Cl27 (LP) -M 2+ (LP*) interactions implying that the contribution of Cl27 on complex formation is larger. Apart from Cl27, the metal ion also receives an electron density from the azomethine nitrogen (N2), imidazole nitrogen (N10) and phenolic oxygen (O11) of chalcone based Schiff bases which acts as a tridentate ligand. Although the individual contribution of the coordinating ligands N2, N10, and O11 seem to be minimal when compared to the Cl27, as a whole the overall contribution of the chalcone based Schiff base found to be larger than the Cl27. These results justify the MLCT and LMCT transitions discussed in the NPA analysis.
Several experimental reports suggest that the Schiff base metal complexes exhibit better antimicrobial activity than the free Schiff bases [13,17,[46][47][48][49][50]. The increased activity of metal complexes can be explained based on the overtone's concept of cell permeability [51] and chelation theory [52]. According to overtone's concept, the lipid membrane that surrounds the cell favours the passage of only lipid soluble materials due to which liposolubility is an important factor that controls antimicrobial activity [53]. From the NPA and NBO analysis, it is inferred that the positive charge on the metal ions is reduced to a greater extent due to the overlap of ligand orbital, partial sharing of the positive charges of metal ions with the ligand atoms and similarly partial sharing of the negative charge of ligand atoms with the metal ions. Due to these transitions, there is an increase in the π-delocalisation over the entire chelate which seems to increase the lipophilicity of these metal complexes. The increased lipophilic character enhances the penetration of the complexes into the lipid membrane and blocking the metal binding sites of cellular enzymes which play a major role in various metabolic pathways of the microorganisms results in the deactivation of the cellular enzymes [13,17,53].

Antimicrobial activity
The antimicrobial activity of the Schiff bases and its metal complexes is a function of the descriptor LUMO energy and density of the molecule. Since the LUMO is an electronic parameter that measures the electrophilicity of the molecules, the molecule can act as Lewis acid in which the incoming electrons are received in its LUMO. Molecules with low-lying LUMO orbitals are more capable of accepting electrons rather than the molecules with high-lying LUMO and thus they show higher activity. Density describes how close the atoms are packed in a molecule. The molecular density is defined as the molecular mass per unit molecular volume. The molecular density is negatively correlated with activity, which implies that if the molecule is compact, it will reduce the density which in turn increases the activity of the molecule [10]. The calculated values of LUMO energy and molecular density are presented in Table 9. It is evident from the Table 9 and Figure 4 that after the complexation, the energy of the LUMO corresponding to the HLn-Co 2+ , HLn-Ni 2+ , HLn-Cu 2+ and HLn-Zn 2+ is found to be decreased in the range of 2.78-3.98, 2.80-3.98, 2.95-5.16, and 2.79-3.94 eV, at CAM-B3LYP/LANL2DZ and 0.75-2.74, 0.74-3.26, 0.74-3.07 and 0.75-2.39 eV at M062X/DEF2-TZVP levels of theory with respect to the isolated ligands. Whereas, the density of the Schiff base metal complexes is found to be increased by 0.15-0.17 amu/A 3 respectively. The Cu 2+ interacted metal complexes show lower LUMO energy and density values, as compared to all other metal complexes. Whereas, the Zn 2+ interacted complexes show higher LUMO energy and density values. These results imply that the metal complexes are more active than the isolated Schiff bases. Moreover, the HL2 Schiff base possesses lower LUMO and lower density implying the HL2-M 2+ complexes are potent antimicrobial agents rather than the HL1-M 2+ and HL3-M 2+ Schiff base metal complexes. This finding correlates well with the interaction energy, NPA, and NBO analysis. The increased activity of the metal complexes is supported by the experimental findings.

Conclusions
In the present study, we have examined the metal chelating ability and the antimicrobial activity of the chalcone based Schiff base metal complexes at CAM-B3LYP/LANL2DZ, and M062X/def2-TZVP levels of theory and the following findings have emerged from the detailed investigation.
The metal chelation slightly induces an increase in the bond lengths of N2-C3, N2-C5, C9-N10, N10-C18, and C14-O11 bonds of the Schiff base, which leads to the increased antimicrobial activity. The HLn-Co 2+ , -Ni 2+ , and -Zn 2+ complexes prefer distorted tetrahedral geometry whereas, the HLn-Cu 2+ complexes prefer distorted square-planar geometry. The interaction energies decreases in the order Cu 2+ > Ni 2+ > Co 2+ > Zn 2 + and three different substitutions follow the order as HL2-M 2 + > HL1-M 2+ > HL3-M 2+ . The QTAIM analysis reveals that the nature of metal-ligand bonding is electrostatic dominant. The NPA analysis reveals that the charge gaining ability of the metal ion depends on the electronegativity value. The amount of charge gained by the metal ions from the donor ligands decreases in the order Cu 2+ > Ni 2+ > Co 2+ > Zn 2+ at both levels of theory. The NBO analysis reveals that the LP-LP*, BD-LP*, and LP-BD* orbital interactions are more important for studying the metal complexes. The obtained results justify the findings of NPA analysis such that the charge delocalisation from the donor LP to the metal ions LP* orbital leads to the decrease in the positive charge of metal ions. The increased delocalisation of π electrons and reduction in the positive charge of metal ions increases the lipophilicity of the metal complexes which in turn increases the antimicrobial activity of these complexes. The frontier molecular orbital analysis further justifies the increased antimicrobial activity of the metal complexes. CH 3 substituted chalcone based Schiff base (HL2) can act as a potent chelator of metal ions as well as the antimicrobial agent. Moreover, the Schiff base metal complexes show increased antimicrobial activity rather than the isolated Schiff bases. Our study reveals that the HLn-Cu 2+ complexes show higher antimicrobial activity among the complexes studied and these complexes can be used as metallodrugs in treating the infectious diseases.