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Article

Structural and Biological Comparative Studies on M(II)-Complexes (M = Co, Mn, Cu, Ni, Zn) of Hydrazone-s-Triazine Ligand Bearing Pyridyl Arm

by
Mezna Saleh Altowyan
1,
Ayman El-Faham
2,3,
MennaAllah Hassan
3,
Assem Barakat
4,
Matti Haukka
5,
Morsy A. M. Abu-Youssef
3,
Saied M. Soliman
3,* and
Amal Yousri
3,*
1
Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
2
Department of Clinical Sciences, College of Medicine, Dar Al Uloom University, P.O. Box 45142, Riyadh 11512, Saudi Arabia
3
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
4
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
5
Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland
*
Authors to whom correspondence should be addressed.
Inorganics 2024, 12(10), 268; https://doi.org/10.3390/inorganics12100268
Submission received: 14 September 2024 / Revised: 7 October 2024 / Accepted: 11 October 2024 / Published: 14 October 2024
(This article belongs to the Special Issue Metal-Based Compounds: Relevance for the Biomedical Field)
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Versions Notes

Abstract

:
The molecular and supramolecular structures of some M(II) complexes (M = Co, Mn, Cu, Ni, Zn) with a hydrazone-s-triazine ligand (BMPyTr) were discussed based on single crystal X-ray diffraction (SCXRD), Hirshfeld and DFT analyses. A new Co(II) complex of the same ligand was synthesized and its structure was confirmed to be [Co(BMPyTr)Cl2]·H2O based on FTIR and UV–Vis spectra, elemental analysis and SCXRD. The geometry around Co(II) was a distorted square pyramidal configuration (τ5 = 0.4), where Co(II) ion is coordinated to one NNN-tridentate ligand (BMPyTr) and two Cl- ions. A Hirshfeld analysis indicated all potential contacts within the crystal structure, where the percentages of O⋯H, N⋯H, C⋯H, and H⋯H contacts in one unit were 11.2, 9.3, 11.4, and 45.9%, respectively, while the respective values for the other complex unit were 10.3, 8.8, 10.6, and 48.0%. According to DFT calculations, the presence of strongly coordinating anions, such as Cl-, in addition to the large metal ion size, were found to be the main reasons for the small M-BMPyTr interaction energies in the cases of [Mn(BMPyTr)Cl2] (260.79 kcal/mol) and [Co(BMPyTr)Cl2]·H2O (307.46 kcal/mol) complexes. Interestingly, the Co(II) complex had potential activity against both Gram-positive (S. aureus and B. subtilis) and Gram-negative (E. coli and P. vulgaris) bacterial strains with inhibition zone diameters of 13, 15, 16, and 18 mm, respectively. Also, the new [Co(BMPyTr)Cl2]·H2O (IC50 = 131.2 ± 6.8 μM) complex had slightly better cytotoxic activity against HCT-116 cell line compared to BMPyTr (145.3 ± 7.1 μM).

1. Introduction

Heterocyclic rings play a crucial role as primary components in numerous compounds found in both natural and synthetic drugs [1,2]. Consequently, the scientific investigation of novel heterocyclic molecular systems has garnered significant attention from chemists due to their diverse applications [3,4,5]. Specifically, s-triazine heterocycles have shown interesting potential as energetic explosives and organic corrosion inhibitors [6]. Compounds containing both pyrazole and s-triazine rings have demonstrated minimal toxicity in terms of growth stimulation [7,8]. Furthermore, s-triazine derivatives displayed various anticancer activities, depending on the specific groups attached to the s-triazine core [8]. Additionally, s-triazines have a weak ligand field and can form stable high-spin metal complexes, leading to extended molecular and supramolecular architectures [9,10,11]. Moreover, s-triazine and its derivatives offer a diverse range of pharmacological benefits, including antibacterial, antiviral, anti-malarial, anti-inflammatory, anticancer, anti-leukemia, and anti-HIV activities, etc. [12,13,14,15,16]. Additionally, hydrazones with an azomethine -NHN=CH- group are a significant class of molecules that produce new compounds with a range of biological activities [17]. Also, they can be applied in dyes, nanoparticles, corrosion inhibition, the analysis of metal ions, and water treatment [18]. Furthermore, morpholine ring is already known as an active moiety in medicinal chemistry, either licensed or under investigation due to its beneficial features in biological and metabolic processes [19].
On the other hand, cobalt is a physiologically relevant metal. It plays a crucial role in numerous biological processes and exhibits significant biochemical activity as an essential trace metal [20]. Cobalt exists in two prevalent oxidation states, which are Co(II) and Co(III). The properties of the ligands are pivotal in determining the ultimate oxidation state of cobalt in its complexes. Recently, there has been a surge in the synthesis of cobalt complexes using multifunctional ligands [21,22,23,24]. Throughout the centuries, many cobalt complexes have been synthesized using multifunction ligands, and they have been employed to inhibit the growth of harmful microorganisms [21,22,23,24,25,26]. This has led to the exploration and development of many new cobalt complexes, holding promise in the design and production of antibacterial agents to combat antibiotic-resistant microorganisms [27,28,29]. Cobalt complexes find extensive applications across diverse fields of human interest, encompassing antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory, antischaemic, antiparasitic, antithrombolytic, and antitumor agents [27,28,29,30,31,32,33,34,35,36,37,38]. This broad range of applications is attributed to the biological significance of cobalt and its synergistic activity with other drugs. Moreover, s-triazine ligands, in combination with cobalt, have been investigated for their potential as catalysts in chemical synthesis transformations and medical applications [2,39,40,41,42,43,44,45,46,47].
As a continuation of the interesting structural and the promising biological properties of s-triazine derivatives and their metal complexes, we presented here the synthesis and characterization of a new heteroleptic cobalt(II) complex with 2,4-bis(morpholin-4-yl)-6-[(E)-2-[1-(pyridin-2-yl)ethylidene]hydrazin-1-yl]-1,3,5-triazine as the ligand (BMPyTr; Figure 1). Several characterization tools were utilized to study and confirm its structure, such as FTIR and UV–Vis spectroscopic techniques, as well as elemental analysis and single crystal X-ray diffraction (SCXRD). A comparative study for the molecular and supramolecular structure aspects, as well as the biological activity (antibacterial and anticancer) of the new complex with the structurally related complexes [48,49,50], is also presented. Theoretical DFT studies on the M-BMPyTr affinity were performed to show the different factors which affect the interaction energy between the ligand BMPyTr and different metal ions.

2. Results and Discussion

2.1. Synthesis and Characterization

The reaction of BMPyTr and CoCl2·6H2O in ethanol afforded a new heteroleptic complex [Co(BMPyTr)Cl2]·H2O (Scheme 1). The structure of the complex was confirmed using elemental analysis, FTIR spectroscopy, and single crystal X-ray diffraction (SCXRD). The FTIR spectrum of the Co(II) complex showed distinct spectral bands at 1600 and 1569 cm−1 due to the ν(C=N) vibrations (Figure S1). The ν(C=N) mode is observed in the free ligand at 1584 cm−1 (Figure S2). The significant shifts in the ν(C=N) mode is a consequence of the complexation between Co(II) and BMPyTr via the triazine, azomethine, and pyridine nitrogen atoms. The ν(C=C) vibration was detected at 1500 and 1492 cm−1 in the FTIR spectrum of [Co(BMPyTr)Cl2]·H2O and BMPyTr, respectively, showing little variation compared to the ν(C=N) mode.
The UV–Vis spectra of the Co(II) complex and its free ligand BMPyTr (2.5 × 10−4 M) were measured in DMSO and ethanol as solvents (Figure 2). The spectral band observed in ethanol at 305 nm for BMPyTr could be assigned to the n → π* transition. This band undergoes a bathochromic shift to 325 nm in the case of the Co(II) complex. The corresponding bands in DMSO are detected at 305 and 312 nm, respectively. In addition, the spectral bands observed at 230 and 235 nm for BMPyTr and [Co(BMPyTr)Cl2]·H2O in ethanol could be assigned to the π → π* transition. A new broad band appeared in the Co(II) complex at 415 and 405 nm in DMSO and ethanol, respectively. This band could be assigned to the d-d transition of the high-spin Co(II) complex [51].

2.2. X-ray Structure Description

The structure of the studied complex was confirmed using X-ray crystallography to be [Co(BMPyTr)Cl2]·H2O (1; Figure 3). It crystallized in the triclinic crystal system and P-1 space group. The unit cell parameters were a = 8.50463(10), b = 11.85531(14), c = 22.1524(2) Å, α = 84.2782(9)°, β = 87.3524(9)°, and γ = 89.2680(10)°. The number of molecules in the unit cell was four, while the unit cell volume and crystal density were 2219.94(4) Å3 and 1.593 mg/m3, respectively (Table 1).
The structure of this complex showed two [Co(BMPyTr)Cl2]·H2O molecules as an asymmetric formula, which were slightly different in their geometric parameters (Table 2). In this neutral complex, the Co(II) was penta-coordinated with two chloride ions and three nitrogen atoms from the BMPyTr ligand. There were three different Co-N interactions where the Co-N(hydrazone) bonds were the shortest. The respective Co1-N2 and Co1B-N2B distances were determined to be 2.0360(13) and 2.0301(12) Å, respectively. The longest Co-N interactions were related to the Co-N(s-triazine) where the corresponding Co1-N4 and Co1B-N4B distances were 2.1762(13) and 2.1919(12) Å, respectively. Hence, the order of the Co-N distances was Co-N(hydrazone) < Co-N(pyridine) < Co-N(s-triazine). In the structurally related [Mn(BMPyTr)Cl2] (2) and [Cu(BMPyTr)Cl2]·H2O (3) complexes, the order of the metal to nitrogen distances was the same [51]. For example, the Mn-N(hydrazone), Mn-N(pyridine), and Mn-N(s-triazine) distances were 2.183(1), 2.264(2), and 2.428(1) Å, respectively. The bite angles of BMPyTr in 1 were 75.55(5)° (N2-Co1-N1) and 77.91(5)° (N2-Co1-N4) for one unit, and 75.82(5)° (N2B-Co1B-N1B) and 77.71(5)° (N2B-Co1B-N4B) for the other unit. In addition, there were two Co-Cl coordination interactions. In one unit, the Co1-Cl2 and Co1-Cl1 distances were 2.2909(4) and 2.3414(4) Å, respectively, while for the other unit, the Co1B-Cl2B and Co1B-Cl1B distances were 2.2840(4) and 2.3221(4) Å, respectively. The Cl-Co-Cl angles were 120.068(17) (Cl2-Co1-Cl1) and 122.675(17)° (Cl2B-Co1B-Cl1B). Therefore, the structure of the CoN3Cl2 coordination sphere could be described as a highly distorted penta-coordinated system. The Addison τ5 parameter was calculated to be 0.35 for one unit and 0.37 for the other unit, with letter B in atom numbering. As a result, the structure could be described as a highly distorted penta-coordinated system which is close to square pyramidal [52]. These results for [Co(BMPyTr)Cl2]·H2O (1) are found to be in good agreement with those for the [Mn(BMPyTr)Cl2] (2) and [Cu(BMPyTr)Cl2]·H2O (3) complexes, where the τ5 values were calculated to be 0.33 and 0.24, respectively [48]. Hence, the square pyramidal configuration showed the lowest distortion in case of 3. It is worth noting that the X-ray structure of 1 indicated the presence of one hydration water molecule in the outer sphere, which did not participate in the coordination with Co(II) but significantly contributed in the supramolecular structure of complex 1.
The supramolecular structure of 1 is controlled by two types of non-covalent interactions, which are the N-H⋯O and O-H⋯Cl hydrogen bonds (Table 3). The presentation of these hydrogen bond contacts is shown in Figure 4A. There are two significant N-H⋯O hydrogen bonds, which occurred between the N-H of the hydrazone linkage as a hydrogen-bond donor and the freely un-coordinated O-atom from the crystal water molecule as hydrogen-bond acceptor. The hydrogen to acceptor distances were 1.92(2) and 2.00(2) Å for N3-H3⋯O3 and N3B-H3B⋯O4, respectively, while the donor to acceptor distances were 2.7737(19) and 2.8074(18) Å, respectively. Furthermore, there were four O-H⋯Cl interactions, which occurred between the crystal water hydrogen atoms as hydrogen-bond donor and the coordinated chloride anion as hydrogen-bond acceptor. In this case, the hydrogen to acceptor (Cl) distances ranged from 2.29(3) Å (O3-H3C⋯Cl2) to 2.45(3) Å (O4-H4C⋯Cl1B), while the donor (O) to acceptor (Cl) distances ranged from 3.1605(15) to 3.2639(14) Å, respectively. The resulting hydrogen packing scheme is shown in Figure 4B. Hence, the supramolecular structure of complex 1 could be described as a hydrogen bonding network extended along the a-direction.
Interestingly, the X-ray structure analysis indicated the presence of some anion-π interactions occurred between the coordinated chloride anion and the pyridine π-system. There were three Cl⋯C(pyridine) interactions which were different in their distances (Table 4). In one unit, the Cl2⋯C1(pyridine) distance was 3.420(2) Å, while for the other unit, the Cl2B⋯C1B(pyridine) and Cl2B⋯C2B(pyridine) distances were 3.444(2) and 3.437(2) Å, respectively (Figure 5). In complex 3, there was one short Cl⋯C contact (3.427(2) Å) which was detected, while no anion-π interactions were observed in case of 2.

2.3. Hirshfeld Analysis

The stability of the crystal structure results from various forces that maintain the molecules in a specific arrangement. Hirshfeld calculations could provide a complete picture about the forces which are responsible for the supramolecular structure of organic and inorganic compounds [53,54,55,56,57,58,59,60,61]. The dnorm maps for complex 1 are shown in Figure 6. The curvedness and shape index surfaces are shown in Figure S3.
With the aid of Hirshfeld calculations, all potential contacts within the crystal structure are collected in Table S1. The results of the quantitative analysis for the different intermolecular interactions in complex 1 are shown in Figure 7. For one unit, the percentages of Cl⋯H, O⋯H, N⋯H, C⋯H, and H⋯H are 16.7, 11.2, 9.3, 11.4, and 45.9%, respectively. The respective values for the unit with letter B in the atom numbering are 16.8, 10.3, 8.8, 10.6, and 48.0%, respectively. In case of complex 2, their percentages are 20.9, 8.9, 8.1, 7.1, and 45.8%, respectively [48].
The fingerprint plots shown in Figure 8 and Figure S4 revealed many strong intermolecular contacts. The dnorm map provides a summary of all short contacts, represented by red and white areas, signifying interaction distances shorter or equal to the van der Waals radii sum of the interacting atoms, respectively. Conversely, contacts longer than the van der Waals radii sum of the interacting atoms appear as blue-colored regions. The dnorm map indicated the importance of Cl⋯H, O⋯H, N⋯H, C⋯C, C⋯H, and H⋯H interactions in the molecular packing of 1. The shortest Cl⋯H, O⋯H, N⋯H, and C⋯H contacts are Cl2⋯H3C (2.180 Å), O3⋯H3 (1.768 Å), N7⋯H16C (2.534 Å), and C9⋯H16C (2.608 Å), respectively. For C⋯C interactions, the C1⋯C2 (3.329 Å) and C1B⋯C2B (3.319 Å) are the shortest (Table S1). In addition, there are short H⋯H interactions which are the H3A⋯H13C (2.147 Å) and H14A⋯H18C (2.154 Å). In 2, the shortest Cl⋯H (2.532 Å) and O⋯H (2.477 Å) contacts are generally longer than those detected in 1 [48].

2.4. Enrichment Ratio

The possibility of each atom pair in the crystal to make intermolecular interaction was investigated by calculating the enrichment ratio (EXY) [62]. The results of the enrichment ratio are depicted in Table 5. Since the enrichment ratios for the Cl⋯H, O⋯H, N⋯C, and H⋯C are greater than the unity, each of these atom pairs have a high probability for carrying out intermolecular interactions in the crystal structure. The rest of the other contacts with an enrichment ratio less than the unity have a low possibility of occurring.

2.5. Energy Framework Analysis

The energy framework is crucial for comprehending the various energy types that play a role in the supramolecular assembly of molecules within crystals [63,64,65,66,67,68,69,70,71,72,73,74]. Table S2 provides an energy breakdown, including the contributions of different components (Eele, Epol, Edis, Erep, and Etot). The results provide the total interaction energy (Etot) of −594.4 kJ/mol involving the electrostatic (−233.351 kJ/mol), polarization (−152.334 kJ/mol), dispersion (−427.525 kJ/mol), and repulsion (218.646 kJ/mol). It is obvious that, the Cl⋯H interaction between the central molecule and the −x, −y, −z symmetry water molecules (turquoise and magenta) are the strongest among near neighbors, with a total energy of −125.2 kJ/mol for each (Figure S5). The total energy diagram showed a strong resemblance to the dispersion energy frameworks (Figure 9), suggesting their significant contribution to the total forces in crystal packing.

2.6. Comparative DFT Study

Density functional theory (DFT) calculations were conducted utilizing the X-ray structure coordinates for energy computations of the [M-BMPyTr]2+ systems. A comparative analysis of the ligand’s affinity towards various divalent metal ions was performed for complexes 1–3, [Zn(BMPyTr)(NO3)2]; 4, [Zn(BMPyTr)(NCS)2]; 5 [Cu(BMPyTr)(NO3)2]; 6, [Ni(BMPyTr)(H2O)3](NO3)2·3H2O; 7, and [Ni(BMPyTr)(H2O)3](NO3)2·H2O; 8 [48,49,50]. Then, the computed energies were used to calculate the M-BMPyTr interaction energies as described in Table 6. The Co(II)-BMPyTr interaction energy (Eint) was computed to be 307.46 kcal/mol (average value). On the other hand, the M-BMPyTr interaction energies were calculated to be 260.79, 366.09, −322.23, −314.89, 364.27, −356.37, and 361.57 kcal/mol for complexes 2–8, respectively. Since, all the studied systems comprised a divalent metal ion, there are two main factors affecting the M-BMPyTr interaction energies, which are the metal ion size and the nature of other coordinating ligand. The small-size metal ion has higher positive charge density, leading to higher interaction energy with BMPyTr. In contrast, strongly coordinating anions such as Cl¯ significantly reduce the positive charge density of the metal ion compared to either the weakly coordinating anion such as NO3¯ and SCN- or a neutral ligand such as H2O. In this regard, the least M-BMPyTr interaction energy was detected in case of complexes 1 and 2. The order of the M-BMPyTr interaction energy is predicted to be 2 < 1 < 5 < 4 < 7 < 8 < 6 < 3.

2.7. Biological Studies

2.7.1. Antimicrobial Assay

The efficiency of [Co(BMPyTr)Cl2]·H2O as an antimicrobial agent against selected harmful microbes was tested and the results are compared with other reported metal complexes [48,50] (Table 7). Complex 1 showed no activity against the studied fungal species as no zones for inhibitions were detected in the cases of A. fumigatus and C. albicans. In contrast, this complex showed good activity against both Gram-positive and Gram-negative bacterial strains. Regarding the Gram-positive bacteria, S. aureus and B. subtilis, the inhibition zones were 13 and 15 mm, respectively, while for the Gram-negative bacteria, E. coli and P. vulgaris, the inhibition zones were 16 and 18 mm, respectively. The initial assessment of the antimicrobial activity indicated the better action of the [Co(BMPyTr)Cl2]·H2O complex against the Gram-negative bacteria compared to the Gram-positive bacteria.
On the other hand, the minimum inhibitory concentrations (MICs) for the [Co(BMPyTr)Cl2]·H2O complex against the studied bacteria are given in Table 7. The MIC values for this complex against S. aureus and B. subtilis were 1250 and 625 μg/mL, respectively. For E. coli and P. vulgaris, the MIC values were 156 and 78 μg/mL, respectively. Accordingly, the [Co(BMPyTr)Cl2]·H2O complex showed better activity against P. vulgaris, while it showed moderate activity compared with gentamicin as a positive control. It is worth noting that the free ligand showed no antibacterial activity under the same experimental conditions. Also, the results of the antimicrobial activities of the studied complex were compared with the structurally related [Mn(BMPyTr)Cl2]; 2, [Cu(BMPyTr)Cl2]·H2O; 3, [Zn(BMPyTr)(NO3)2]; 4, and [Zn(BMPyTr)(NCS)2]; 5 complexes. In this regard, the new Co(II) complex showed better activity against S. aureus, E. coli, and P. vulgaris compared to the [Mn(BMPyTr)Cl2] complex. The latter has inhibition zones of 11, 10, and, 12 mm, respectively, while the MIC values were 2500, 2500, and 1250 μg/mL, respectively. Also, 1 showed better activity against the Gram-negative bacteria (E. coli) compared to the [Cu(BMPyTr)Cl2]·H2O, [Zn(BMPyTr)(NO3)2], and [Zn(BMPyTr)(NCS)2] analogs (Table 7). Furthermore, 1 had better activity towards the Gram-negative bacteria (P. vulgaris) in comparison to the [Cu(BMPyTr)Cl2]·H2O complex.

2.7.2. Cytotoxicity Assessments

The in vitro cytotoxic activities of the free ligand and the [Co(BMPyTr)Cl2]·H2O complex against human colon HCT-116 and lung A-549 cancer cell lines using MTT assay were determined and compared with the structurally related [Mn(BMPyTr)Cl2], [Cu(BMPyTr)Cl2]·H2O, [Zn(BMPyTr)(NO3)2], and [Zn(BMPyTr)(NCS)2] complexes [48,50]. The %viability is drawn against the concentration in μM in order to determine the IC50 of the synthesized complexes (Figure 10). The results clearly revealed the good cytotoxicity of the ligand (BMPyTr) and their metal complexes 1–5 against both cell lines.
In addition, the IC50 values of the free ligand and its metal(II) complexes are compared with the standard drug cis-platin as a reference drug (Table 8 and Figure 11). The free ligand has the highest IC50 value of 145.3 ± 7.1 μM against the colon carcinoma HCT-116 cell line, while for the complexes 1–5, the IC50 values are 131.2 ± 6.8, 118.8 ± 6.0, 40.3 ± 2.3, 51.46 ± 2.16, and 62.81 ± 2.82 μM. On the other hand, the IC50 values for these complexes against lung carcinoma A-549 cell line are 224.0 ± 10.3, 61.0 ± 2.5, 27.7 ± 1.1, 71.88 ± 5.07, and 97.26 ± 5.07 μM, respectively, while the free ligand has an IC50 value of 155.7 ± 7.6 μM. For cis-platin, the IC50 values are 17.8 ± 1.6 and 24.9 ± 1.7 µM, respectively. Hence, the Cu(II) complex showed the highest potency against both cell lines [48,50] compared to the Co(II), Zn(II) and Mn(II) complexes, while the [Co(BMPyTr)Cl2]·H2O complex had the lowest efficiency as an anticancer agent against both cell lines. It is worth noting that the cytotoxicity activity of all complexes was improved (except complex 1 against the HCT-116 cell line) compared to the free ligand for both cell lines. Examining the cytotoxic effect of CoCl2 against the A-549 cancer cell line indicated no activity for the metal salt [75] (Table S15). As a result, the enhanced cytotoxic effect of 1 could be attributed to the complex rather than the free BMPyTr or CoCl2. Interestingly, complexes 1–3, which had the same coordination sphere but differed in the metal ion, were found to have different activities, as shown in Table 8. In this regard, the variation in the metal ion had a significant impact on the cytotoxic effects of the studied complexes.

3. Materials and Methods

3.1. Materials and Physical Characterizations

A description of the materials and instrumentation used in this work are summarized in the Supplementary Data.

3.2. Synthesis of BMPyTr

The ligand (BMPyTr) was prepared according to the method mentioned by our research group [48,49] (Method S1).

3.3. Synthesis of [Co(BMPyTr)Cl2]·H2O

The metal complex was synthesized by mixing 10 mL ethanolic solution of CoCl2·6H2O (47.6 mg, 0.2 mmol) with a 10 mL ethanolic solution of BMPyTr (77.0 mg, 0.2 mmol). This mixture was filtered and allowed to evaporate slowly at RT. After approximately three days, dark purple crystals formed, which were then collected by filtration.
[Co(BMPyTr)Cl2]·H2O; m.p > 350°C; Yield 89%: Anal. Calc. for C18H26Cl2CoN8O3: C, 40.62; H, 4.92; N, 21.05; Co, 11.07%. Found: C, 40.39; H, 4.84; N, 20.91; Co, 10.98 %. IR (KBr, cm−1): 3403 ν(O–H)water, 3222 ν(N–H), 2964, 2919, 2858 ν(C–H), 1600, 1569 ν(C=N), 1501ν(C=C), 1258 ν(C–N), 1391 ν(N–O). The FTIR spectra of the complex and the free ligand are shown in Figures S1 and S2, respectively.

3.4. Crystal Structure Determination

The crystal structure of [Co(BMPyTr)Cl2]·H2O was measured following the procedures described in Method S2 [76,77,78,79].

3.5. Hirshfeld Analysis

The Crystal Explorer Ver. 17 program was used to perform Hirshfeld analysis [80,81]. Details for the protocol used to perform the energy framework analysis are found in Method S3 [63,64,65,66,67,68,69,70,71,72,73,74].

3.6. Computational Details

The calculations were conducted using the X-ray structure coordinates, employing the ωB97XD method [82] with the aid of Gaussian 09 program [83,84]. The TZVP basis sets were employed for all atoms. The calculations were performed for the free M(II) and BMPyTr as well as their complex species [M-BMPyTr]2+.

3.7. Biological Studies

The anticancer [85] and antimicrobial [86] activities were assessed using the protocols outlined in Methods S4 and S5.

4. Conclusions

The heteroleptic [Co(BMPyTr)Cl2]·H2O complex was synthesized and its structure was confirmed with the aid of elemental analysis, FTIR, UV–Vis spectra, and X-ray crystallography. The Co(II) had a penta-coordination environment with a highly distorted square pyramidal configuration. Using Hirshfeld surface analysis, the most dominant interaction was that of the hydrogenic H⋯H contacts (45.9–48%). Additionally, the presence of short Cl⋯C contacts indicated the existence of anion–π stacking interactions. DFT calculations explored the effect of metal ion size and the nature of coordinating ligands on the M(II)-BMPyTr interaction energies, where the Mn(II)-BMPyTr and Co(II)-BMPyTr interaction energies were the lowest. The free ligand (BMPyTr) and its [Co(BMPyTr)Cl2]·H2O complex were tested for their cytotoxicity against the HCT-116 and A-549 cancer cell lines using the MTT assay, and the results were compared with the structurally related complexes. All complexes showed improved activity (except 1 versus HCT-116 cells) compared to BMPyTr. The improvement of the activity confirmed the important role of metal ions on the biological activity of the studied metal-BMPyTr complexes. Despite the free ligand (BMPyTr) having no antimicrobial activity, its metal(II) complexes showed diverse activities against the studied microbes. The [Co(BMPyTr)Cl2]·H2O complex demonstrated good activity against both Gram-positive (S. aureus and B. subtilis) and Gram-negative bacteria (E. coli and P. vulgaris).

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics12100268/s1, Figure S1: The FTIR spectra of the [Co(BMPyTr)Cl2]·H2O; Figure S2: The FTIR spectra of the free ligand (BMPyTr); Figure S3: The curvedness and shape index surfaces for the [Co(BMPyTr)Cl2]·H2O complex; Figure S4: The fingerprint plots for the unit with letter B in the atom numbering for [Co(BMPyTr)Cl2]·H2O complex; Figure S5: Visualization of molecular interactions within a cluster with a radius of 3.8 Å between the central molecule under investigation and its neighboring molecules, viewed along the a-axis; Figure S6: 1H NMR of the ligand in CDCl3; Figure S7: 13C NMR of the ligand in CDCl3; Table S1: The short intermolecular interactions in the [Co(BMPyTr)Cl2]·H2O; Table S2: Different interaction energies of the molecular pairs in kJ/mol; Table S3: Evaluation of anticancer activity against HCT-116 cell line for BMPyTr; Table S4: Evaluation of anticancer activity against HCT-116 cell line for 1; Table S5: Evaluation of anticancer activity against HCT-116 cell line for 2; Table S6: Evaluation of anticancer activity against HCT-116 cell line for 3; Table S7: Evaluation of anticancer activity against HCT-116 cell line for 4; Table S8: Evaluation of anticancer activity against HCT-116 cell line for 5; Table S9: Evaluation of anticancer activity against A-549 cell line for BMPyTr; Table S10: Evaluation of anticancer activity against A-549 cell line for 1; Table S11: Evaluation of anticancer activity against A-549 cell line for 2; Table S12: Evaluation of anticancer activity against A-549 cell line for 3; Table S13: Evaluation of anticancer activity against A-549 cell line for 4; Table S14: Evaluation of anticancer activity against A-549 cell line for 5; Table S15: Evaluation of anticancer activity against A-549 cell line for CoCl2; Method S1: Synthesis of ligand (BMPyTr); Method S2: Crystal structure determination; Method S3: Energy framework analysis protocol; Method S4: Evaluation of anticancer activity; Method S5: Evaluation of antimicrobial activity.

Author Contributions

Conceptualization, M.A.M.A.-Y., A.Y., A.E.-F. and S.M.S.; methodology, M.H. (MennaAllah Hassan), M.S.A. and A.Y.; software, M.H. (Matti Haukka), A.Y. and S.M.S.; validation, A.E.-F., A.Y. and A.B.; formal analysis, M.H. (MennaAllah Hassan), M.H. (Matti Haukka) and A.Y.; investigation, All authors; resources, A.E.-F., A.B., M.S.A. and S.M.S.; data curation, M.H. (MennaAllah Hassan) and A.Y.; writing—original draft preparation, All authors; writing—review and editing, All authors; supervision, M.A.M.A.-Y., A.Y., A.E.-F. and S.M.S.; funding acquisition, M.S.A. All authors have read and agreed to the published version of the manuscript.

Funding

Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2024R86), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.

Acknowledgments

Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2024R86), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Conflicts of Interest

The authors declare no conflicts of interest.

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Inorganics 12 00268 g001
Figure 1. Structure of BMPyTr.
Figure 1. Structure of BMPyTr.
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Inorganics 12 00268 sch001
Scheme 1. Synthesis of [Co(BMPyTr)Cl2]·H2O.
Scheme 1. Synthesis of [Co(BMPyTr)Cl2]·H2O.
Inorganics 12 00268 sch001
Inorganics 12 00268 g002
Figure 2. The UV–Vis spectra of [Co(BMPyTr)Cl2]·H2O and BMPyTr in DMSO (A) and ethanol (B).
Figure 2. The UV–Vis spectra of [Co(BMPyTr)Cl2]·H2O and BMPyTr in DMSO (A) and ethanol (B).
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Inorganics 12 00268 g003
Figure 3. X-ray structure showing the numbering of the atom (A) and the distorted coordination geometry around Co1 (B) for [Co(BMPyTr)Cl2]·H2O.
Figure 3. X-ray structure showing the numbering of the atom (A) and the distorted coordination geometry around Co1 (B) for [Co(BMPyTr)Cl2]·H2O.
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Inorganics 12 00268 g004
Figure 4. The important H-bond contacts (A) and the corresponding packing scheme (B) for [Co(BMPyTr)Cl2]·H2O.
Figure 4. The important H-bond contacts (A) and the corresponding packing scheme (B) for [Co(BMPyTr)Cl2]·H2O.
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Inorganics 12 00268 g005
Figure 5. The anion-π stacking interactions that occurred in 1.
Figure 5. The anion-π stacking interactions that occurred in 1.
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Inorganics 12 00268 g006
Figure 6. Full dnorm map for [Co(BMPyTr)Cl2]·H2O. The most important interactions are (A) O⋯H, (B) N⋯H, (C) Cl⋯H, (D) C⋯C, (E) C⋯H, and (F) H⋯H.
Figure 6. Full dnorm map for [Co(BMPyTr)Cl2]·H2O. The most important interactions are (A) O⋯H, (B) N⋯H, (C) Cl⋯H, (D) C⋯C, (E) C⋯H, and (F) H⋯H.
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Inorganics 12 00268 g007
Figure 7. The percentages of close contacts in the two units of 1.
Figure 7. The percentages of close contacts in the two units of 1.
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Figure 8. The decomposed dnorm maps and fingerprint plots for significant contacts in 1.
Figure 8. The decomposed dnorm maps and fingerprint plots for significant contacts in 1.
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Inorganics 12 00268 g009
Figure 9. Energy framework diagram for separate electrostatic (a), dispersion (b), and total interaction energy (c). The cylinder thicknesses indicated the relative strengths of interactions between molecules.
Figure 9. Energy framework diagram for separate electrostatic (a), dispersion (b), and total interaction energy (c). The cylinder thicknesses indicated the relative strengths of interactions between molecules.
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Inorganics 12 00268 g010
Figure 10. The viability assay for the free ligand (BMPyTr), [Co(BMPyTr)Cl2]·H2O (1), [Mn(BMPyTr)Cl2] (2), [Cu(BMPyTr)Cl2]·H2O (3), [Zn(BMPyTr)(NO3)2] (4), and [Zn(BMPyTr)(NCS)2] (5). All experiments were carried out in triplicate and the detailed results of the cell viability are given in Tables S4–S15.
Figure 10. The viability assay for the free ligand (BMPyTr), [Co(BMPyTr)Cl2]·H2O (1), [Mn(BMPyTr)Cl2] (2), [Cu(BMPyTr)Cl2]·H2O (3), [Zn(BMPyTr)(NO3)2] (4), and [Zn(BMPyTr)(NCS)2] (5). All experiments were carried out in triplicate and the detailed results of the cell viability are given in Tables S4–S15.
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Inorganics 12 00268 g011
Figure 11. The IC50 (μM) for BMPyTr and complexes 1–5 against HCT-116 and A-549 cell lines.
Figure 11. The IC50 (μM) for BMPyTr and complexes 1–5 against HCT-116 and A-549 cell lines.
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Table 1. Crystal data for [Co(BMPyTr)Cl2]·H2O.
Table 1. Crystal data for [Co(BMPyTr)Cl2]·H2O.
[Co(BMPyTr)Cl2]·H2O
CCDC2,340,998
empirical formulaC18H26Cl2CoN8O3
fw532.30
temp (K)120(2)
λ (Å)1.54184
cryst systTriclinic
space groupP  1 ¯
a (Å)8.50463(10)
b (Å)11.85531(14)
c (Å)22.1524(2)
α (deg)84.2782(9)
β (deg)87.3524(9)
γ (deg)89.2680(10)
V (Å3)2219.94(4)
Z4
ρcalc (Mg/m3)1.593
μ (Mo Kα) (mm−1)8.615
No. reflns.89,427
Unique reflns.9559
Completeness to θ = 67.684°100%
GOOF (F2)1.093
Rint0.0304
R1 a (I ≥ 2σ)0.0270
wR2 b (I ≥ 2σ)0.0724
a R1 = Σ||Fo| − |Fc||/Σ|Fo|. b wR2 = {Σ[w(Fo2 − Fc2)2]/Σ[w(Fo2)2]}1/2.
Table 2. Selected bond lengths (Å) and angles (°) for [Co(BMPyTr)Cl2]·H2O.
Table 2. Selected bond lengths (Å) and angles (°) for [Co(BMPyTr)Cl2]·H2O.
Bond Distances
Co(1)-N(2)2.0360(13)Co(1B)-N(2B)2.0301(12)
Co(1)-N(1)2.1375(13)Co(1B)-N(1B)2.1459(13)
Co(1)-N(4)2.1762(13)Co(1B)-N(4B)2.1919(12)
Co(1)-Cl(2)2.2909(4)Co(1B)-Cl(2B)2.2840(4)
Co(1)-Cl(1)2.3414(4)Co(1B)-Cl(1B)2.3221(4)
Bond angles
N(2)-Co(1)-N(1)75.55(5)N(2B)-Co(1B)-N(1B)75.82(5)
N(2)-Co(1)-N(4)77.91(5)N(2B)-Co(1B)-N(4B)77.71(5)
N(1)-Co(1)-N(4)153.21(5)N(1B)-Co(1B)-N(4B)152.95(5)
N(2)-Co(1)-Cl(2)131.14(4)N(2B)-Co(1B)-Cl(2B)131.95(4)
N(1)-Co(1)-Cl(2)90.03(4)N(1B)-Co(1B)-Cl(2B)90.80(4)
N(4)-Co(1)-Cl(2)104.93(4)N(4B)-Co(1B)-Cl(2B)102.87(3)
N(2)-Co(1)-Cl(1)107.06(4)N(2B)-Co(1B)-Cl(1B)104.10(4)
N(1)-Co(1)-Cl(1)91.95(4)N(1B)-Co(1B)-Cl(1B)92.45(4)
N(4)-Co(1)-Cl(1)99.20(3)N(4B)-Co(1B)-Cl(1B)99.31(4)
Cl(2)-Co(1)-Cl(1)120.07(2)Cl(2B)-Co(1B)-Cl(1B)122.68(2)
Table 3. Hydrogen bonds for [Co(BMPyTr)Cl2]·H2O (Å and °).
Table 3. Hydrogen bonds for [Co(BMPyTr)Cl2]·H2O (Å and °).
D-H⋯Ad(D-H)d(H⋯A)d(D⋯A)<(DHA)Symmetry Codes
N(3)-H(3)⋯O(3)0.85(2)1.92(2)2.7737(19)175(2)
N(3B)-H(3B)⋯O(4)0.81(2)2.00(2)2.8074(18)173(2)
O(3)-H(3D)⋯Cl(1)0.83(3)2.43(3)3.2414(15)167(3)−x − 1, −y + 1, −z + 2
O(3)-H(3C)⋯Cl(2)0.88(3)2.29(3)3.1605(15)176(3)−x, −y + 1, −z + 2
O(4)-H(4C)⋯Cl(1B)0.83(3)2.45(3)3.2639(14)169(3)−x, −y + 1, −z + 1
O(4)-H(4A)⋯Cl(2B)0.87(3)2.31(3)3.1865(14)177(3)−x + 1, −y + 1, −z + 1
Table 4. Anion-π stacking contacts for 1.
Table 4. Anion-π stacking contacts for 1.
ContactLength (Å)Symm. Code
Cl(2)⋯C(1)3.420(2)−x, −y, 2 − z
Cl(2B)⋯C(1B)3.444(2)1 − x, 2 − y, 1 − z
Cl(2B)⋯C(2B)3.437(2)1 − x, 2 − y, 1 − z
Table 5. Enrichment ratio calculations for 1.
Table 5. Enrichment ratio calculations for 1.
Contact%C a%R bEXYAtom%S c
Cl⋯H16.711.91.4H70.2
O⋯C0.81.00.8O6.05
O⋯H11.28.51.3N7.1
N⋯C1.81.11.6C8
N⋯H9.310.00.9Cl8.45
H⋯C11.411.21.0
H⋯H45.949.30.9
Cl⋯N0.21.20.2
a %contact b ratio of random contact c %contribution for a chemical species X.
Table 6. The calculated M(II)− BMPyTr interaction energies using ωB97XD method.
Table 6. The calculated M(II)− BMPyTr interaction energies using ωB97XD method.
No.ComplexM(II)BMPyTrM(II)+ BMPyTr[M(II)− BMPyTr]2+Eint a (kcal/mol)
1A[Co(BMPyTr)Cl2]·H2O−1381.84−1288.52−2670.36−2670.85−311.54
1B[Co(BMPyTr)Cl2]·H2O b−1381.84−1288.54−2670.38−2670.86−303.38
2[Mn(BMPyTr)Cl2]−1150.15−1288.57−2438.72−2439.13−260.79
3[Cu(BMPyTr)Cl2]·H2O−1639.50−1288.56−2928.06−2928.64−366.09
4[Zn(BMPyTr)(NO3)2]−1778.45−1288.49−3066.95−3067.47−322.23
5[Zn(BMPyTr)(NCS)2]−1778.45−1288.48−3066.94−3067.44−314.89
6[Cu(BMPyTr)(NO3)2]−1639.50−1364.96−3004.46−3005.04−364.27
7[Ni(BMPyTr)(H2O)3](NO3)2·3H2O−1507.30−1288.55−2795.85−2796.42−356.37
8[Ni(BMPyTr)(H2O)3](NO3)2·H2O−1507.30−1288.55−2795.85−2796.42−361.57
a Eint = Ecomplex − (Emetal+ Eligand) and b unit with letter B in atom numbering.
Table 7. Antimicrobial activities of BMPyTr and its complexes a.
Table 7. Antimicrobial activities of BMPyTr and its complexes a.
MicroorganismBMPyTr12 f3 f4 g5 gControl
S. aureusNA b (ND) c13(1250)11(2500)18(625)14(625)15(625)24(78) d
B. subtilisNA b (ND) c15(625)19(312)20(312)15(625)16(312)26(39) d
E.coliNA b (ND) c16(156)10(2500)NA(ND)NA b (ND) cNA b (ND) c30(10) d
P.vulgarisNA b (ND) c18(78)12(1250)14(1250)18(156)20(78)25(5) d
A. fumigatusNA b (ND) c-NA b (ND) cNA b (ND) c10(625)NA b (ND) c17(5) e
C. albicansNA b (ND) c-8(5000)NA b (ND) c9(625)10(312)20(5) e
a Inhibition zone diameter; mm (MIC; μg/mL) b NA: No activity; c ND: Not determined; d Gentamicin; e Ketoconazole; f [48]; and g [50].
Table 8. The IC50 (μM) for BMPyTr and complexes 1–5 against HCT-116 and A-549 cell lines.
Table 8. The IC50 (μM) for BMPyTr and complexes 1–5 against HCT-116 and A-549 cell lines.
Cell LineHCT-116A-549
BMPyTr155.7 ± 7.6145.3 ± 7.1
1224.0 ± 10.3131.2 ± 6.8
261.0 ± 2.5118.8 ± 6.0
327.7 ± 1.140.3 ± 2.3
451.46 ± 2.1671.88 ± 5.07
562.81 ± 2.8297.26 ± 5.07
cis-platin17.8 ± 1.624.9 ± 1.7
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Altowyan, M.S.; El-Faham, A.; Hassan, M.; Barakat, A.; Haukka, M.; Abu-Youssef, M.A.M.; Soliman, S.M.; Yousri, A. Structural and Biological Comparative Studies on M(II)-Complexes (M = Co, Mn, Cu, Ni, Zn) of Hydrazone-s-Triazine Ligand Bearing Pyridyl Arm. Inorganics 2024, 12, 268. https://doi.org/10.3390/inorganics12100268

AMA Style

Altowyan MS, El-Faham A, Hassan M, Barakat A, Haukka M, Abu-Youssef MAM, Soliman SM, Yousri A. Structural and Biological Comparative Studies on M(II)-Complexes (M = Co, Mn, Cu, Ni, Zn) of Hydrazone-s-Triazine Ligand Bearing Pyridyl Arm. Inorganics. 2024; 12(10):268. https://doi.org/10.3390/inorganics12100268

Chicago/Turabian Style

Altowyan, Mezna Saleh, Ayman El-Faham, MennaAllah Hassan, Assem Barakat, Matti Haukka, Morsy A. M. Abu-Youssef, Saied M. Soliman, and Amal Yousri. 2024. "Structural and Biological Comparative Studies on M(II)-Complexes (M = Co, Mn, Cu, Ni, Zn) of Hydrazone-s-Triazine Ligand Bearing Pyridyl Arm" Inorganics 12, no. 10: 268. https://doi.org/10.3390/inorganics12100268

APA Style

Altowyan, M. S., El-Faham, A., Hassan, M., Barakat, A., Haukka, M., Abu-Youssef, M. A. M., Soliman, S. M., & Yousri, A. (2024). Structural and Biological Comparative Studies on M(II)-Complexes (M = Co, Mn, Cu, Ni, Zn) of Hydrazone-s-Triazine Ligand Bearing Pyridyl Arm. Inorganics, 12(10), 268. https://doi.org/10.3390/inorganics12100268

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