Abstract
It is absolutely essential to combat some classes of tumours since they are thought to pose major health risks, necessitating the discovery and development of efficient anticancer medicines. Ruthenium coordination compounds have demonstrated a promising anticancer and antibacterial activity. Novel tetradentate macrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes were synthesised by condensation of 4-bromobenzene-1,2-diamine with dicarboxylic acid. Analytical techniques and diverse spectroscopy equipment, including infrared, magnetic, thermal, 1H NMR, 13C NMR, electronic, PXRD, and mass spectra, were used to characterise the compounds. It was discovered that the complexes' geometrical structure was distorted octahedral. Density functional theory (DFT) at the B3LYP level was used to optimise the molecular geometries of the ligands and the metal complexes. The LUMOs' energy was connected to their biological activities. The antibacterial efficacy of the ligands (TAMacL1–TAMacL3) and their Ru(III) complexes against various bacterial Gram+ve (S. mutans and S. aureus), Gram−ve bacterial strains (K. pneumoniae and E. coli) and fungi (F. oxysporum and C. albicans) species has been investigated. The antioxidant capacity was assessed using the DPPH free radical test, with an IC50 range of 0.414–0.205 L and a range of 26.21–66.86%. The significant bioactivity of all synthesised compounds was observed to increase with chelation due to the process of charge transfer from metal to ligand. Our synthesised compounds' anticancer effects might be related to a mechanism that interferes with DNA replication rather than DNA cleavage, comparable to that of 5 fluorouracil. The interaction of the macrocyclic compounds with the target proteins' receptor active sites was also determined using molecular docking (PDB IDs 3T88, 6WII, 3TY7, 3L8R, 3DRA, and 8EBB). The molecular docking and several biological research were connected with one another. The research presented here proposes using these ligands and complexes in the creation of novel anticancer medications.
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Introduction
Metallopharmaceuticals have traditionally employed coordination chemicals. It is possible to create novel chemistries with these metals in ligand systems, as evidenced by the many roles that transition metals complexes of amide-based macrocyclic ligands play in biological systems. [1, 2]. N-donor metal complexes have drawn a lot of interest because of their fascinating chemical properties and possible biological uses. Due to their industrial, carcinostatic, anticancer, antiviral, and antimalarial activity, complexes of ligands containing N4 donor sequences are of great interest. [3]. Among the various approaches invented for combating this issue, the discovery of novel medicines with higher activity and different ways of exposure is more beneficial for researchers [4].
It is vital to structurally optimise or modify current antibiotics to increase their range of activity and binding affinity while preserving their safety profiles and bioavailability in order to combat the fast emergence of drug resistance in microorganisms [5]. Pharmacologically significant compounds have been developed using heterocyclic ring structures. It has been established that heterocyclic molecules with oxygen and nitrogen are physiologically active [6]. The past 10 years have seen an increase in the synthesis of heterocyclic compounds with high nitrogen contents due to their potential uses in a variety of domains, particularly medical chemistry [7]. The kind of coordinating ligands, the oxidation state of the central metal ion, and the coordination geometry of the metal complexes all affect the reactivity of transition metal chelates [8]. One of the main drivers behind the search for new effective medicines to stop bacterial development is the existence of antibiotic resistance [9]. Because both the ligands and the metal ions have the capacity to affect different phases of pathogenic life cycles, the metal ions complexed with bioactive substances are more effective [10]. Because research into the theoretical modelling of drug creation has taken front stage in recent years, computational chemistry has attracted a lot of interest. In theoretical molecular modelling, density functional theory (DFT) has taken off like a meteor. Many molecular characteristics may be calculated using the DFT approach with more accuracy than with the conventionally coupled ab initio methods, and at a more affordable computing cost [11]. A review of the literature revealed that DFT has significant accuracy in replicating the values for the geometrical structure that are indicated experimentally [12].
Transition metal ions are regarded as crucial ions in bodily biological processes [13]. For instance, people have high levels of zinc (II), nickel (II), and copper (II). They can be located in the active sites of many enzymes [14] or as structural elements of such enzymes. On the other hand, polyamines in general, including diamines and triamines, are good complexing agents and may coordinate to a variety of transition metal ions [15]. Therefore, by coordinating certain metal ions to them, the physiological relevance of organic molecules with nitrogen donors and their active function was growing [16]. As a result, transition metal complexes are crucial to many biological processes [17,18,19]. Metal ions have been found to have a significant impact on the antibacterial and antifungal properties of antibiotics [20]. Ruthenium (III) and (II) tetraamines (d5 and d.6) represent an interesting area of research in medicinal chemistry due to their solubility, stability in aqueous media, and biological activity [21, 22].
Consequently, in light of the foregoing details and as a continuation of our earlier work on the synthesis of macrocyclic complexes [23], Herein, we define the synthesis, characterisation and molecular modelling of tetraamide macrocyclic-ligands (TAMacL1–TAMacL3) and associated [Ru(III)(TAMacL1)Cl2]-[Ru(III)(TAMacL3)Cl2] complexes. The freshly synthesised complexes are characterised using a variety of physico-chemical and spectroscopic approaches However, calculations using the density functional theory (DFT) have been done to support the optimised geometrical shapes of compounds. Additionally, against several cancer cell lines and harmful microbe strains, the anticancer and antimicrobial properties of the ligands (TAMacL1–TAMacL3) and their corresponding Ru(III) complexes are assessed. Moreover, DPPH tests are used to evaluate their antioxidant capabilities. We also found that molecular docking results are in the good agreement with the experimental findings.
Experimental section
Material and methods
Methanol, 4-bromobenzene-1,2-diamine, dicarboxylic acids (malonic acid, succinic acid, glutaric acid), and ruthenium chloride were the compounds and solvents employed in this study. All chemicals were procured from Merck. Using KBr discs and a Unicam Mattson 1000 FTIR spectrometer, infrared measurements were taken (4000–200 cm−1. A Perkin-Elmer UV–visible Spectrophotometer Lambda 25 in DMSO was used to record UV–visible spectra, and an elemental analysis was performed using a Vario EL III CHNS analyzer. A model-306 Systronics conductivity bridge was used to evaluate the molar conductance of metal complexes in dry DMF with a concentration of 1 × 10–3 M. The experiment was done at room temperature [24]. At room temperature, EPR spectra of powdered materials were recorded using a JEOL-FA200 ESR spectrophotometer at X-band frequencies, and DPPH was utilised as a field maker (g 2.0036). Shimadzu TGA-50H thermal analyzer with 10 Celsius/min. was used to perform thermogravimetric analysis in inert environment N2with flow of 20 cm3 min1. The current substances' mass spectra (in m/z) were found using a waters Q-tof Micro YA263 mass spectrometer. The API 2000 mass spectrometer, which has a Shimadzu Prominence LC and an electrospray source, was used to record the mass spectra. 1H-NMR and 13C NMR spectra were recorded in DMSO solvent on JEOL ECZS NMR instrument.
Synthetic process
Macrocyclic Ligands (TAMacL1–TAMacL3)
For the synthesis of ligand TAMacL1, the ethanolic solutions of 4-bromobenzene-1,2-diamine (20 mmol, 3.740 g) and adipic acid (2.081 g, 20 mmol) were reflexed in 100-ml RB (round bottom) flask in 2:2 molar ratios for 8–9 h in the presence of conc. HCl at 75–80 °C. After the contents were cooled, a light brown crystalline substance that had been present overnight at 0 °C separated. The reaction was monitored by TLC using petroleum ether, ethyl acetate, toluene, and methanol solvents and recrystallised by using the solvent ethanol and benzene. It underwent filtering, several cold MeOH washes, and vacuum drying over P4O10. For the synthesis of macrocyclic ligands TAMmacL2 and TAMacL3, the same method was followed using succinic (2.361 g, 20 mmol) and glutaric acid (2.642 g, 20 mmol), respectively, instead of adipic acid (Scheme 1) [25].
TAMacL1 (2,12-dibromo-5,9,14,18-tetrahydrodibenzo[b,i]1,4,8,11]tetraazacyclotetradecine-tetraone)
TAMacL2 (2,13-dibromo,octahydrodibenzo[b,j][1,4,9,12]tetraazacyclotetradecine-6,9,16,19-tetraone)
TAMacL3 (2,14-dibromo,octahydrodibenzo[b,k][1,4,10,13]tetraazacyclotetradecine-6,10,17,21-tetraone)
Synthetic process of macrocyclic ligands and their Ru(III) complexes
Macrocyclic Complexes [Ru(III)(TAMacL1)Cl2]-[Ru(III)(TAMacL3)Cl2]
For the synthesis of macrocyclic complex [Ru(III)(TAMacL1)Cl2]Cl, the hot ethanolic solutions of RuCl3 (1 mmol, 0.2254 g) and macrocyclic ligand TAMacL1 (0.5079 g, 1 mmol) were refluxed in 100-ml RB (round bottom) flask at 80 °C for 9–10 h in 1:1 metal-to-ligand ratio. A coloured complex was formed after cooling, and these were undergoing filtering, several cold MeOH washes, and vacuum drying over P4O10. TLC was used to monitor the reaction, which was carried out with petroleum ether, ethyl acetate, toluene, and methanol as solvents and recrystallised with ethanol and benzene as solvents. For the synthesis of macrocyclic complexes [Ru(TAMacL2)Cl2] and [Ru(TAMacL3)Cl2], the same method was followed using TAMacL2 (0.66 g, 1 mmol) and TAMacL3 (0.69 g, 1 mmol) macrocyclic ligands, respectively, instead of TAMacL1 [26].
[Ru(III)(TAMacL1)Cl2]Cl (2,12-dibromo,tetrahydrodibenzo[b,i]1,4,8,11]tetraazacyclotetradecine-tetraone,dichloro-ruthenium(III)chloride).
[Ru(III)(TAMacL2)Cl2]Cl (2,13-dibromo,octahydrodibenzo[b,j][1,4,9,12]tetraazacyclotetradecine-6,9,16,19-tetraone,dichloro-ruthenium(III)chloride).
[Ru(III)(TAMacL3)Cl2]Cl (2,14-dibromo,octahydrodibenzo[b,k][1,4,10,13]tetraazacyclotetradecine-6,10,17,21-tetraone,dichloro-ruthenium(III)chloride).
IR spectra: a tetraamide macrocyclic ligand TAMacL1, b complex [Ru(TAMacL1)Cl2]Cl
Quantum chemical calculations
Using the DFT method, the macrocyclic ligands (TAMacL1–TAMacL3) and Ru(III) complexes were optimised in three dimensions. An octahedral geometry was optimised for the Ru(III) complex. All DFT calculations were carried out using a hybrid functional B3LYP (Becke's three-parameter hybrid function utilising the correlation functional LYP), based on the basis sets def2-SVP for C, H, N, and O atoms as well as def2-SVPZZ for Ru atoms carried out by Avogadro 4.0 and Orca software. The terms HOMO and LUMO, respectively, stand for the electropositive and electronegative densities also used to calculate quantum chemical parameters [27, 28].
1H-NMR spectrum of tetraamide macrocyclic ligand TAMacL1
Antimicrobial activity
Antibacterial activity
The antibacterial study of synthetic compounds against (S. aureus and S. mutans) and (E. coli and K. pneumoniae) Gram+ve and Gram−ve strain, respectively [29], was performed using the agar well diffusion technique. The nutritional agar was uniformly distributed [22]. The Muller Hinton Agar medium was transferred to petri plates, and plates were swabbed with 100-µl of test microorganism inoculated and kept for 15 min for adsorption. Wells were then bored into the seeded agar plates and loaded with 100 µl of volume having concentration 15 mg/ml of each compound reconstituted in DMSO. For 24 h, all plates were incubated at 35 °C. By measuring the expansion of the inhibition zone against the test organisms using a zone reader (HI antibiotic zone scale), the antimicrobial activity of each drug was assessed. The outcomes of the compounds following zone development were contrasted with those of the common antibiotic ampicillin and gentamycin.
Antifungal activity
The agar plate technique was used to test the ligands (TAMacL1–TAMacL3) and Ru(III) complexes antifungal activity against the fungus F. oxysporum and C. albicans [30]. The concentrations 15 mg/ml of the chemicals were added directly to the medium. The inoculum needle was used to apply the fungus to the medium. The petri dishes were placed in an incubator at 25 °C for 96 h while being covered in polythene sheets with a limited amount of alcohol. By noting the diameter of the fungal colony, the growth of fungi was quantified. Fungal growth inhibition% = (Ac − Bt) × 100/Ac, where Ac is the diameter of the fungus colony in the control plate and Bt is the diameter of the fungus colony on the test plates after 96 h. Nystatin was used as standard to compare the antifungal activity results of the synthesised (TAMacL1–TAMacL3) and Ru(III) complexes.
Antioxidant activity
The described complexes' in vitro antioxidant properties were assessed by scavenging the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical [31]. The radical scavenging test is based on how the radical's absorbance changes when antioxidants deactivate it. The standard substance was ascorbic acid. The described complexes' stock solutions were dissolved in methanol/DMSO (5:1) before being diluted to various quantities. The solution [3.9 ml, 0.004% (w/v)] of DPPH in methanol was administered to each experiment at different concentrations (100, 200 and 300 µg ml−1) of high-performance liquid chromatography (HPLC) methanol. The tubes were kept at room temperature for 30 min, and the absorbance at 517 nm was recorded. Both tests were performed in triplicate and were averaged. SCA% = [(Acontrol − Atest)/Acontrol)] × 100 where Acontrol is the control absorbance (DPPH without sample) and Atest is the sample absorbance (DPPH plus scavenger) to describe the percentage of scavenging activity on DPPH.
Cytotoxicity
The MTT assay was used to evaluate the cytotoxic effects of the macrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes to grown cancer cells. The NCCS Pune, India, provided three different human cancer cell lines: hepatocellular carcinoma (HePG2), colorectal carcinoma (HCT116) and mammary gland breast carcinoma (MCF7). These cell lines were used to screen the investigated compounds' in vitro anticancer activity in accordance by using the MTT assay. [32] Foetal bovine serum, MTT, DMSO, and 5 fluorouracil are the reagents that were employed. Fluorouracil was employed as a benchmark anticancer medication in this study. This test is based on the fact that, in living cells, mitochondrial succinate dehydrogenase converts the yellow tetrazolium bromide (MTT) into a purple formazan derivative. 10% foetal bovine serum was used to grow the cells in RPMI 1640 medium. Antibiotics of 100 units per ml penicillin and 100 g/ml streptomycin were introduced at 37 °C in an incubator with 5% CO2. The cells were seeded at a density of 1.0 × 104 cells/well on a 96-well plate for 48 h at 37 °C and 5% CO2 [33]. The cells were then exposed to various chemical concentrations and incubated for one day. Following a one-day drug incubation period, 20 L of MTT solution containing 5 mg/mL was added and incubated once more for 5 h. To dissolve the produced purple formazan, 100 L of dimethyl sulfoxide (DMSO) was applied to each well. The IC50 values were used to reflect the cytotoxicity of the drugs.
Molecular docking
Utilising the AutoDock and PyRx technologies, molecular docking experiments were developed. Predicting the potential binding modes of the most active drugs with the receptors of (PDB ID 3T88, 6WII, 3TY7, 3L8R, 3DRA, and 8EBB) is greatly aided by these investigations. Antibacterial targets included E. coli (3T88), K. pneumonia (6WII), S. aureus (3T47), and S. mutans (3L8R), whereas antifungal targets included C. albicans (3DRA) and F. oxysporum (8EBB). For molecular docking investigations, we chose receptors (3T88, 6WII, 3TY7, 3L8R, 3DRA, and 8EBB). The reason for choosing these five proteins is that the resolution of picking proteins is low, ensuring higher protein structure quality. These proteins are chemically similar to ligands (TAMacL1–TAMacL3) and their ruthenium complexes [Ru(TAMacL1)Cl2]–[Ru(TAMacL3)Cl2]. These proteins with the greatest enrichment value were chosen for docking because of their structure. The docking modes of synthesised substances and receptors may be calculated and displayed using the docking interactive molecular graphics programme [34]. The ligand and receptor must be entered in PDB format. The amino acid chain was preserved, but the water molecules, co-crystallised ligands, and other unsupported elements (Na, K, Hg, etc.) were eliminated. The ligand's structure was produced using the Avogadro 4.O programme as a PDB file. The protein data bank (http://www.rcsb.org/pdb) provided the crystal structures of (PDB ID 3T88, 6WII, 3TY7, 3L8R, 3DRA and 8EBB) E. coli (3T88), K. pneumonia (6WII), S. aureus (3T47), S. mutans (3L8R) were specified as antibacterial target, C. albicans (3DRA) and F. oxysporum (8EBB).
Results and discussion
Molar conductance
The synthesised complexes [Ru(TAMacL1)Cl2]Cl, [Ru(TAMacL2)Cl2]Cl, and [Ru(TAMacL3)Cl2]Cl are defined as electrolytes as the conductivity values in dimethylformamide solution at the conc. of 10–3 M are 105, 103, and 108 Ω−1 cm2 mol−1, respectively, at 25 °C [35]. The conductivity of macrocyclic compounds was also measured in acetone at the conc. of 10–3 M and found 101–107 Ω−1 cm2 mol−1, which confirms the molar conductivity measurements. Accordingly, one chloride ion is found outside the coordination sphere, indicating that this complex 1:1 electrolyte has an ionic nature and supports the IR characterisation component.
IR spectra
In order to describe the structures of the macrocyclic ligands (TAMacL1–TAMacL3) and their octahedral complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2] in detail, their IR spectra have been examined (Figures S1–S3). The IR spectra of compounds showed a single wide band at 3245–3275 cm−1 owing to v(NH) stretching vibration, indicating the condensation of the carboxylic group of adipic acid with the amino group of 4-bromo-1,2-diaminobenzen [36]. Bands in the ligand's IR spectra that may be attributed to the amide [I ν(C=O), amide II ν(C–N) δ(N–H)], amide III δ(N–H) and amide IV wagging [(C=O)], vibration, respectively, are mostly seen in the areas of 1660–1710, 1505–1555, 1235–1260 and 630–660 cm−1 [37] (Fig. 1). The existence of the sec. ν(NH) group is shown by a sharp band at 3288–3302 cm−1. These bands are moved to lower energy areas in comparison with the unbound macrocyclic ligands, demonstrating that the ligands coordinate to metal ions via the nitrogen atom of the (-NH) group [38]. Bands in the 454–478 cm−1 range were assigned as ν(M–N) presented more solid evidence for macrocyclic ligands association with the ruthenium metal. The bands in the 324–342 cm−1 range may have a ν(M–Cl) vibration associated with them [39] (Table 1).
1H-NMR and 13C-NMR spectral study
In DMSO-d6 solvent, the 1H-NMR and 13C-NMR spectra of amide-based macrocyclic ligands (TAMacL1–TAMacL3) were obtained (Fig. 2 and Figures S4–S7). A fairly wide signal for the amine protons, peaks for aromatic protons at δ 6.2–6.9 ppm, and the signal for the methyl proton show at 2.3 ppm in the 1H-NMR spectrum of 4-bromobenzene-1,2-diamine. No peak could be ascribed for an –OH or an –NH2 group in the 1H NMR spectra of the macrocyclic ligands (TAMacL1–TAMacL3), supporting the development of the postulated macrocyclic ligands after condensation. The tetraamide macrocyclic ligands' 1H-NMR spectra revealed a wide signal at δ 10.03–10.25 ppm that was potentially attributed to the –NH protons [40]. In macrocyclic compounds, signals may be seen around δ 6.87–8.05 ppm and δ 2.2–2.3 ppm, respectively, which correspond to aromatic protons and methyl protons in Table 2. The resonance signal at 166.05 ppm in the 13C NMR spectra of macrocyclic ligand [TAMacL1] belonged to the carbons connected to the nitrogen atoms and was suggestive of their proposed coordination in the ligands. However, the absence of a signal at 184 and 159 ppm, which would have shown the full condensation, confirmed the creation of the macrocyclic moiety. The signals in the ppm range of δ 115.12–135.22 ppm further demonstrated the presence of aromatic carbons in macrocyclic moiety. The signals for aliphatic carbons presented in the macrocyclic ligands in Fig. 3 [41] are seen in the range of δ 47.47–48.57 ppm (Table 3).
13C-NMR spectrum of tetraamide macrocyclic ligand TAMacL1
Electrospray ionisation mass spectra
The electrospray ionisation mass spectra of macrocyclic complex [Ru(TAMacL1)Cl2] are represented in Fig. 4. The (M.F) of [Ru(TAMacL1)Cl2] is (C18H14Br2RuCl3N4O4) (Mol. Wt. 717.56) in Fig. 4. The ESI-mass spectrum of complex [Ru(TAMacL1)Cl2] displays the M/Z peak consistent to [M]+ and [M + 2]+ ions. The [M]+ peak is consistent to [C18H14Br2Cl3N4O4]+ at m/z = 716.42.31 (due to 35Cl) and the peak [M + 2]+ corresponding to [C18H14Br2Cl2N4O4]+ at m/z = 718.4231 (due to 37Cl). The results from the elemental analysis were confirmed by the molecular ion peak. Some fragmentations of macrocyclic complex [C18H14Br2RuCl2N4O4] at 682.1 [C18H14Br2N4O4]+, 612.1 [C15H12Br2RuCl2N4O2]+, 612.05 [C3H4N2O2]+, 100.08 [C6H8N4O4]+, 200.05 [C18H14Br2N4O4]+, 513.3671 [C6H5BrN2]+, 185.02 [C12H10Br2N4]+, 348.3103 [C4RuCl2N4]+, 276.2746 were also observed. The EI-MS spectra of (TAMacL1–TAMacL3) and their Ru(III) are represented in Figures S8-S11.
a EI-MS spectra of ligand (TAMacL1), b complex [Ru(TAMacL1)Cl2]Cl
Electronic spectra
The UV–Vis spectra of ligands (TAMacL1–TAMacL3) reveal an absorption band in the 272–395 nm range, which may be connected to n → π* transition that originates largely in the amide (> C–NH) chromophore and changes to a lower frequency during complexation. From these results, it is concluded that the nitrogen atom of amide group coordinated to the metal ion. The absorption at 388 cm−1 and 276 cm−1, which correspond to the 2T2g → 4T1g and 2T2g → 4T2g transitions, respectively, can be seen in the complex's electronic spectrum. The bands seen in the area at 531 cm−1 and 432 cm−1 are those of π−π* and n–π* transitions, respectively. These band locations line up with the octahedral complex prediction given in Table 4.[42].
EPR spectra of Ru(III) complexes
The low spin t2g5 configuration for the Ru(III) complexes was suggested by magnetic moment values for complexes. The magnetic moment values for the complexes [Ru(TAMacL1)Cl2]Cl, [Ru(TAMacL2)Cl2]Cl, and [Ru(TAMacL3)Cl2]Cl at (RT) room temp. have been measured, and the values obtained were 1.83 B.M., 1.85 B.M., and 1.88 B.M., respectively. These values correspond to one unpaired electron. At room temperature, the EPR spectra of Ru(III) macrocyclic complexes were obtained in the X-band. Because the measured 'g' values are particularly sensitive to tiny changes in structure and metal–ligand covalency, the low spin d5 configuration is a great way to study molecule structure and bonding. The complexes' EPR spectra show the characteristics of distorted geometry with \(g_{ \bot }\) about 2.12–2.26 and g|| around 1.81–1.96. These data show tetragonal distortion in the complexes for an octahedral field with tetragonal distortion gx = gy ≠ gz given in Table 5. The position of lines and the type of macrocyclic ruthenium complexes' EPR spectra explained the distorted octahedral geometry of low spin ruthenium(III) complexes [43].
TGA
The thermogram curves of macrocyclic ligands (TAMacL1–TAMacL3) and Ru(III) complexes were carried out in the temperature range 40–800 °C under N2 gas flow at 10 °C/min. In the temperature range of 90 to 200 °C, there is no weight loss, which excludes the presence of coordinated or uncoordinated water molecules. Due to the elimination of chloride anions, all of the complexes tested experience first step disintegration with weight losses of 10.12–19.35% (about 10.12–19.35%) at 230–250 °C. Due to the loss of the entire ligand, the complexes exhibit experimentally 56.23–64.86% (about 56.18–63.88%) second step breakdown in the temperature range 280–560 °C shown in Fig. 5. The final residue's metal oxide content was determined by IR spectra and matches the calculated amount.
Thermo-gravimetric analysis of macrocyclic ligands and Ru(III) complexes
Using Coats-Redfern and FWO (Figures S12–S17), the heat of activation (Ea) was computed for the number of breakdown stages from the TG and DTG in order to analyse the nature of metal ions on thermal conduct and the influence of the structural properties of the chelating agents. The composition approach was considered as a first-order reaction, and the activation order parameters were calculated using the Eyring equation. Tables S2 and S3 illustrate the results. [44]
Kinetic parameters
The activation energy obtained by the Kissinger methodology is equivalent to the activation energy discovered by the (O.F.W. method and C. R integral method. The equation was used to determine the thermodynamic parameters, including the Arrhenius factors (∆H), (A), (∆S) and (∆G), after the kinetic study.
where h represents the Planck constant (6.626 × 10–34 Js−1) and kB represents the Boltzmann factor (1.38 10–23 Js−1). At various heating rates, the Arrhenius factor was calculated using a variety of kinetic approaches. The results of (∆S), (∆H) and (∆G) were furthered using a heating rate of 10 °C/min using a novel kinetic technique. The positive values of (∆H) and (∆G) show that the thermal breakdown of ligands (TAMacL1–TAMacL3) and related Ru (III) macrocyclic complexes is endergonic, unfavourable, and non-spontaneous [45].
PXRD analysis
The structural characterisation and lattice size determination were done using the powder X-ray diffractogram of the ligands (TAMacL1–TAMacL3) and Ru(III) complexes (Fig. 6). The observed data for the complexes under research were compared to other data from the literature that had comparable cells, and then, they were indexed to the same geometry. Macrocyclic ligands (TAMacL1–TAMacL3) and Ru(III) complexes X-ray diffractograms were scanned in the 2θ = 10°–90° range at 1.540A wavelength. The diffractogram and related data show the interplanar spacing (d-values), relative intensity, and 2 values for each peak. A computer programme has been used to index the X-ray diffraction pattern of these compounds in relation to significant peaks with relative intensities larger than 10% [45]. The parameters of unit cell of the complex [Ru(TAMacL1)Cl2]Cl were a = 14.6495, b = 17.7782, c = 8.5463 with α = β = γ = 90°. The condition a ≠ b ≠ c and α = β = γ = 90° of macrocyclic complex was in well accordance with orthorhombic crystal systems and octahedral geometry were confirmed. According to the PXRD results, the ligands, behave as tetradentate chelating agents. Furthermore, as the Cl− anions are coordinated to the ruthenium atom, a hexacoordinated environment for ruthenium has been postulated.
a PXRD data of TAMacL1, b PXRD data of [Ru(TAMacL1)Cl2]Cl
Molecular modelling
The bond lengths in ligand TAMacL1C=O and C–N (1.24842 and 1.60058 Å) become longer in Ru(III) complex (1.24842 and 1.60058 Å); this confirms that ruthenium atom coordinates to (C–N–H) group of the ligand. These values of bond lengths of ligands (TAMacL1–TAMacL3) and their complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2]Cl calculated using density functional theory (DFT) given in Table 6. The bond angle (º) readings for the examined complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2] given in Table 7 have confirmed the hexacoordinated environment around the central meatal atom, i.e. octahedral geometry of the complexes and the results were also supported the postulated structure (Fig. 7)[46].
Optimised structure of macrocyclic ligand TAMacL1 and complex [Ru(TAMacL1)Cl2]Cl
Quantum chemical calculations
Numerous quantum chemical reactivity descriptors that are used to assess chemical reactivity in addition to the uniqueness of the reactive site in chemical systems are effectively quantified using the density functional theory (DFT). The optical characteristics, stability, chemical reactivity, and electrical properties are investigated and described using frontier molecular orbitals. Electron excitation moves from HOMO to LUMO with the help of the roles of donor and acceptor, HOMO and LUMO. In this work, B3LYP/def2svp was used to quantify the FMOs energies, i.e. EHOMO, ELUMO, and their energy gaps (Figs. 8 and 9) EHOMO–ELUMO of the macrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2], represented in Fig. 10 [47, 48].
EHOMO–ELUMO energy gap of the ligands (TAMacL1–TAMacL3)
EHOMO–ELUMO energy gap of Ru(III) complexes
Benesi–Hildebrand plots for determination of binding constant (10 µM) with Ru3+ concentration
A reactive, soft, and unstable chemical system was one with a low ∆E (The HOMO–LUMO energy gap) value. Because the computed global softness (S) values for the examined compounds were lower than the calculated global hardness (η), the synthesised amide macrocyclic ligands (TAMacL1–TAMacL3) were comparatively stable and unreactive [49]. The examined metal complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2]Cl, may have better electron-donating capability than ligands and certain conventional compounds, as evidenced by the lower electron-contributing ability of the compounds with the lowest values of EHOMO. The macrocyclic complex [Ru(TAMacL3)Cl2]Cl is highly reactive as compare to other macrocyclic compounds with ΔE = 5.570 given in Table 8 [50]. These findings led to the conclusion that metal complexes would be superior candidates for biological activity and antioxidants.
Determination of binding constant by Benesi–Hildebrand method
The Benesi–Hildebrand equation [51] was used to get the binding constant, and the equation below was used to calculate Kα.
Here, Kα represents the binding constant, A represents the absorbance when the added guest is presented, Ao represents the absorbance when the added guest is absent, and Amax represents the absorbance when the added [Mx+]max present, where [MX+] is [Ru3+]. The slope of the straight line plotting 1/(A − Ao) versus 1/[Ru3+] might be used to calculate the binding constant (Kα) and is found to be 5.86 × 105 M−1. The higher value of binding constant 5.86 × 105 M−1 indicates the strong interaction with Ru3+ ion (Fig. 10).
Biological activities
Antimicrobial activity
The antimicrobial efficacy of all the novel series of macrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2] metal chelates was assessed in contrast to Gram+ve bacteria (Streptococcus mutans and Staphylococcus aureus), Gram−ve bacteria (Klebsiella pneumoniae and Escherichia coli) and fungal strains (Fusarium oxysporum and Candida albicans) for their in vitro antimicrobial potential, while Gentamicin, Ampicillin, and Nystatin were used as standard drugs for bacterial and fungal strain, respectively. The outcomes (Table 9) and some of the tested plates are displayed. seen in Figure S25., At 15 mg/ml (Fig. 11a, b), preliminary screening was conducted. It was discovered that macrocyclic complex [Ru(TAMacL3)Cl2]Cl showed higher antibacterial activity with the zones of inhibition of 25.8 mm against S. mutans, 21.5 mm against S. aureus and complex [Ru(TAMacL2)Cl2]Cl showed higher activity with zone of inhibition of 23.8 mm against E. coli and 22.4 mm against K. pneumonia. The impermeability of the microbes' cells or variations in the ribosome of microbial cells cause the variance in [Ru(TAMacL2)Cl2]Cl antibacterial efficacy against the two pathogens. The size of the inhibitory zone in the complexes under study showed that the kind of divalent cation has an impact on the antibacterial activity of [Ru(TAMacL2)Cl2]Cl. Similarly, the macrocyclic complex [Ru(TAMacL3)Cl2]Cl showed higher antifungal activity with 25.8 mm inhibition of zone against C. albicans and 23.5 mm against F. oxysporum at 15 mg/ml. (Fig. 11c). In contrast to the non-electrolytic behaviour of ligands, it is important to confirm that the maximum activity of [Ru(TAMacL1-3)Cl2]Cl complexes [52] may be linked to its ionic character. A survey of the macrocyclic compounds reported so far by earlier investigators indicates that the macrocyclic ligands and their transition metal complexes possesses potent antimicrobial property. The antimicrobial action of the complexes of Zn(II), Ni(II), and Co(II) had the highest average activity than their respective ligands reported by Sumrra et al. [52, 53] The findings of the current study showed superiority over the reported compounds.
Antibacterial (a, b) and antifungal (c) activity of the ligands and their Ru(III) complexes [diameter of inhibition zone in mm]
Metal chelates often exhibit such antibacterial action because the metal ions they contain are lipophilic [53]. Additionally, the chelates may prevent microbial cells from respirating. As a result, the microbial cells will not be able to make the proteins necessary to stop the organism from growing further. This subsequently supported the idea that chelation improves antibacterial action. On the other hand, ground-state features can be related to the biological activity of the produced complexes. Table 6 shows that the largest value of dipole moment is found in Ru (III) complexes. This discovery could be a contributing factor to the strong action of Ru (III) complexes [54]. The presence of a greater number of chloride ions in Ru(III) complexes, where Ru(III) includes 3Cl−, may also play a significant role in their increased activity [55]. This chloride ion may facilitate the synthesis of hypochlorous acid, which then breaks down into HCl and O2. The oxygen destroys the microorganisms by oxidising the biological components. Additionally, the interaction of the chloride ion with membrane proteins and enzymes may help to explain why there is a greater activity when Cl− is present.
Antioxidant activity
The capacity of the synthesised macrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes to scavenge the stable DPPH (2,2-diphenyl-1-picryl hydrazyl) radical is used to assess their antioxidant activity. Spectrophotometric analysis was used to measure the DPPH scavenging capability. Free radicals are often created by a variety of bio-redox pathways and have been connected to the ageing process in various chronic, life-limiting disorders including cancer, myocardial infarction, cataracts, etc. As a result, efforts to lessen the harm these species do are being embraced as the basis for cutting-edge treatment approaches. Table 10 lists the ligand's and its metal complexes' % antioxidant activity. The ability of synthetic compounds to scavenge the stable radical DPPH or donate hydrogen was used to measure their antioxidant activity. The UV–Vis spectrophotometer can measure the DPPH's transformation from purple to yellow following reduction by measuring the decline in absorbance at 517 nm. The ability of the macrocyclic compounds to scavenge free radicals was compared to that of the well-known natural antioxidant ascorbic acid shown in Fig. 12. In comparison with macrocyclic ligands (TAMacL1–TAMacL3), the macrocyclic Ru(III) complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2] showed superior antioxidant activity due to the coordination of ligand with metal ion [56]. The antioxidant potency (IC50) follows the order ascorbic acid > [Ru(TAMacL3)Cl2] > [Ru(TAMacL2)Cl2] > [Ru(TAMacL3)Cl1] > TAMacL3 > TAMacL2 > TAMacL3.
The scavenging activity at various concentrations of the tetraamide macrocyclic ligands and Ru(III) Complexes with DPPH radical
Cytotoxicity
Employing a colorimetric MTT assay, cytotoxic activity was accessed for macrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes against three distinct human cancer cell lines, HePG2, HCT116, and MCF7. The mitochondrial dehydrogenase activity is measured using this technique to assess the viability of cells. The growth inhibitory concentration value (IC50) was used to explain the cytotoxicity results. This shows the amount of the chemicals needed to result in a 50% reduction in cell growth compared to untreated controls after 72 h of incubation. IC50 values have been calculated using the cancer cell line's survival curve. For each test compound, concentrations of 1.56, 3.125, 6.25, 12.5, 25, 50, and 100 g/ml were recognised shown in Fig. 13. 5-fluorouracil is used as reference, and the findings of IC50 conc. of ligands (TAMacL1–TAMacL3) and their Ru(III) complexes were compared with this, shown in Table 11. The values ± SD were given by calculating the average of three separate experiments. According to the findings, ruthenium-based macrocyclic complexes are more effective against the cancer cell lines as compared to the ligands. The metal complexes Ru(III) showed potential cytotoxic activity greater than the ligands TAMacL3. In comparison with the ligands TAMacL1–TAMacL3, the Ru(III) complexes demonstrated superior cytotoxic action against the HePG2 and HCF-7 cell lines (IC50 values of 9.06 and 7.42 g/ml, respectively) given in Table 11. Therefore, it may be inferred that this molecule might be employed in the development of novel anticancer medications. This outcome is consistent with Wang et al.'s study [57], in which they assessed the cytotoxicity of pyrazolone-based compounds against four cancer cell lines. The IC50 of the macrocyclic ligands and their Ru(III) complexes ranged from 9.06 to 29.69 g/ml, covering a wide range of cytotoxicity against the various cancer cell lines. This behaviour suggests that all complexes showed high to moderate anticancer activity against the cell lines.
Survival curve of the tumour call line for 5-fluorouracil, (TAMacL1) and Ru(III) complex [Ru(TAMacL1)Cl2]
In silico molecular docking study
When utilising the AutoDock Vina programme, docking experiments are used to determine the biocidal implication of the synthesised ligands [58]. The recovered PDB file (3T88, 6WII, 3TY7, 3L8R, 3DRA, and 8EBB) E. coli (3T88), K. pneumonia (6WII), S. aureus (3T47), and S. mutans (3L8R) were specified as antibacterial target, C. albicans (3DRA) and F. oxysporum (8EBB) were specified as antifungal target was entered into Auto Dock Vina as an input and designated as a macromolecule that prepares the protein by adding charges and hydrogen bonds to the atoms. In the process of preparing the ligand, numerous tautomers were produced, bond ordering was assigned, ring conformations were created, and stereo chemistry of the ligand was carried out. All of the produced conformations were then employed for a docking investigation.
Selecting the active residues and the Run auto grid option created a receptor grid around the protein active region. Run Vina was used to do the docking calculations, and the result was utilised to find the optimal docked structure using the binding affinity. In kcal/mol, the anticipated binding affinity is shown. The binding score for the best docked complex, which indicates a good inhibition, is − 11.2 for the TAMacL3 ligand against 3T88. For analysis, the one with the greatest binding affinity is taken into account. The binding affinities of various ligands with various receptors are displayed in Table 12 [59, 60].
The macrocyclic ligand TAMacL3 showed upright interaction by the Escherichia coli protein.
Figure 14 depicts the analysis of protein–ligand interactions, including hydrogen bonding and hydrophobic interactions. The typical H-bonding interactions (green colour) are shown in residues with Asp755 residue within 3.03 Å and with Asp474 residue within 2.69 Å, respectively. Several nonpolar hydrophobic connections were exposed between the aromatic carbons of the ligand (TAMacL3) and Gly476, Met475, Met194 shown in Fig. 14. The best-docked ligand, TAMacL3, has a binding energy of − 11.2 kcal mol−1 with the E. coli (3T88) protein binding site.
a 2D plot of macrocyclic ligand TAMacL3 with the protein receptor E. Coli (3T88), b 3D plot of ligand TAMacL3
Similarly, the macrocyclic ligand TAMacL3 showed good interactions with the S. aurous protein (3TY7). Typical H-bonding interactions (green colour) are shown in residues with Phe238 and Asp237 residue within 3.00 Å. Several nonpolar hydrophobic interactions were discovered between the aromatic carbons of the macrocyclic ligands and Lys857 shown in Fig. 15. The ligand, TAMacL3 showed highest binding energy of − 11.00 kcal/mol with the S. aurous (3TY7) protein binding site.
a 2D plot of macrocyclic ligand TAMacL3 with the protein receptor S. aurous (3TY7) and b 3D plot of ligand TAMacL3
Conclusion
In the present study, novel N4-tetraazamacrocyclic ligands (TAMacL1–TAMacL3) and their Ru(III) complexes [Ru(TAMacL1)Cl2–Ru(TAMacL3)Cl2] were synthesised. To characterise, several analytical and spectroscopic approaches were utilised and clarify the distorted octahedral geometry of the metal complexes. Also, DFT method was consistent with the experimental finding. The biological activity of the synthesised ligand and their complexes was studied against microbes for their in vitro antimicrobial potential. The results reviled that the macrocyclic complex [Ru(TAMacL3)Cl2]Cl showed higher antibacterial activity with the zones of inhibition of 25.8 mm against S. mutans, 21.5 mm against S. aureus and complex [Ru(TAMacL2)Cl2]Cl showed higher activity with 23.8 mm inhibition of zone against E. coli and 22.4 mm against K. pneumonia at 15 mg/ml. Similarly, Furthermore, the macrocyclic complex Ru(TAMacL3)Cl2] have higher ability to scavenge free DPPH radical. The antioxidant potency (IC50) of the macrocyclic complex Ru(TAMacL3)Cl2] was 0.22 mg/mL, relative to ascorbic acid (IC50 = 0.12 mg/mL). By screening some of the compounds against three distinct human cancer cell lines, HePG2, HCT116, and MCF7, results showed that Ru(III) complexes demonstrated superior cytotoxic action against the HePG2 and HCF-7 cell lines (IC50 values of 9.06 and 7.42 g/ml, respectively). Molecular docking studies of the macrocyclic ligands and their Ru(III) complex with receptors of (PDB ID 3T88, 6WII, 3TY7, 3L8R, 3DRA, and 8EBB) detected that the ligand (TAMacL3) showed lowest binding ability with binding energy of − 11.2 kcal mol−1 with the receptor of E. coli (PDB ID: 3T88). As a consequence, molecular docking investigations backed with the experimental findings of antimicrobial properties. As a result, they may be regarded as promising prospective medications for therapeutic intervention in a variety of disorders.
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Acknowledgements
The author (Subhash) is highly thankful to the University Grants Commission, New Delhi, India, for financial assistance in the form of a Junior Research Fellowship (NTA Ref. No. 92, CSIR-UGC NET DECEMBER, 2018). The authors gratefully acknowledge DST-FIST programme 2017 (final proposal no. SR/FST/CS-I/2017/12(C) dated 10.5.2018, Department of Chemistry, Kurukshetra University, Kurukshetra) for providing financial support in form of NMR spectral studies. I am also thankful to Dr. Senthilkumar Muthaiah, NIT, Kurukshetra, for his goodwill and expert guidance.
Funding
The author (Subhash) is highly thankful to the University Grants Commission, New Delhi, India, for financial assistance in the form of a Junior Research Fellowship (NTA Ref. No. 92, CSIR-UGC NET DECEMBER, 2018).
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The idea was suggested by Subhash and Ashu Chaudhary. The experimental section was performed by Jyoti, Monika Gupta, and Anita Phor. Interpretation of data, preparing of the manuscript, and its editing were performed by Subhash. All authors reviewed the manuscript.
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Subhash, Jyoti, Gupta, M. et al. Synthesis, spectral characterisation, in vitro cytotoxicity, antimicrobial, antioxidant, DFT and molecular docking studies of Ru(III) complexes derived from amide-based macrocyclic ligands. Res Chem Intermed 50, 1081–1111 (2024). https://doi.org/10.1007/s11164-023-05124-1
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DOI: https://doi.org/10.1007/s11164-023-05124-1