Experimental and theoretical corroboration of antimicrobial and anticancer activities of two pseudohalides induced structurally diverse Cd (II)-Salen complexes
Introduction
Though cadmium is traditionally plotted as a hazard for the environment and different organisms yet it is broadly utilized in electric batteries, pigments in plastics, and electroplated steel [1]. The combinational impact of Cd (II) ions and organic host along with anions like SeCN−, N3−, SCN−, I−, Br−, Cl−, etc. can substantially decrease the toxicity of the core metal ion and influence the potential biological applications. In the interim, Cd (II)-Salen buildings announced for expanded acknowledgment within the sight of an appropriate pseudo-halide linker because of its rich structural feature and working as the prime role for antimicrobial and anticancer activities [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The high-level cadmium exposure also has a detrimental effect on the liver and kidney (cancer mortality) [12]. Moreover, Cd (II) linked CPs infinite frameworks (1D to 3D) have been the subject of great interest in recent years as they are superior to monomer/dimer analogues attributable to their expected applications in catalysis, optical properties, supramolecular chemistry, clathrate, and materials science [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]. In the expansion, the d10 configuration, zero CFSE, and softness of Cd (II) ion allow a wide assortment of geometrical arrangements and coordination numbers [23]. In this fashion, a genuine interest is growing in the structure and unions of minimal effort Cd (II)-interceded supramolecular design in recent years, which possibly progressed pharmacological properties. Nowadays, the multifaceted advantage of different Salen-based ligands along with pseudo-halides has been preferred for better chelation with Cd (II) metal ion. Besides, metal-based bio-medicinal drugs syntheses by exploiting N/O-donor ligands platform along with azomethine (CH=N-) linkage have picked up extraordinarily significant throughout the most recent couple of years not only structural chemistry but these are also having potential as drug carriers, antimicrobial and imaging agents [24], [25], [26], [27]. Meanwhile, the medicinal inorganic chemistry branch received a continuing research interest in the diverse field of biomedical applications such as DNA binding [28], antimicrobial [29], anticancer [30], antiviral [31], antifungal, antimalarial, antitumor agents [32], [33], [34], [35], anti-inflammatory and antiamoebic activities [36,37]. In the 21st century, for globally developing country's cancer is the foremost lethal infection where Pancreatic disease is the fourth driving reason for disease-related demise [38], [39], [40], [41], [42]. Now a day's novel M (II)-Salen complexes have been prescribed for cancer treatment and other diseases [43,[44], [45], [46], [47]] and it is the other substitute to platinum drugs e.g. cisplatin or carboplatin [48,49]. However, these metal drugs are still enduring from several side effects, including nephrotoxicity, gametogenesis, and neurotoxicity [50], thus require some targeted syntheses.
The coordination behaviours of Zn2+/Cd2+/Hg2+ ions with N2O4-proligand platform is continuously well-studied research area because of its flexible coordination numbers, nuclearities, and interesting molecular crystalline architectures. Pseudo-halides like N3−/SCN− are flexible spacers which potentially bridged with M(II) ions to fortify polynuclear complex formations (Scheme S2A-S2B) [51,52] where stereochemistry and coordination number accomplishment the idea of pseudo-halides as well as to the steric necessities of the ligands [53,54]. To date, we have only explored the cytotoxic effect of dicyanamide modulated Zn (II)-Salen complexes [55,56] but at this minute Cd (II)-Salen complexes cytotoxic impacts are detailed. Our choice over cadmium metal isn't just for its growing biological interest but also to the novel applications such as solid-state emitting materials [57], light-harvesting photo catalysis, and fluorescent sensors for organic or inorganic analyses [58].
Taking after all these foundations, the present communication focuses on the syntheses, characterization, crystal structures, self-assembled molecular architectures, antimicrobial profile, and cytotoxic effects of two polymeric Cd (II) complexes viz., [Cd4(L1)2(ƞ1-NCS)2(µ2-ƞ2:ƞ1-OAc)2] (C1) and [Cd4(L2)2(µ1,1-N3)4]n (C2) respectively (H2L1= N, N’-ethylene bis(3-methoxysalicylaldimine, H2L2= N, N’-ethylene bis(3-ethoxysalicylaldimine). Finally, the molecular docking experiment was depicted to explain the binding capability between the Cd (II) complexes and bacteria/cancer-targeted macromolecular protein chain. Consequently, we are the first time developing the experimental and theoretical corroboration of polymeric Cd (II)-supramolecular architecture towards antimicrobial and anticancer properties.
Section snippets
Starting materials and instrumentation
The research chemicals and solvents used in the current research work were of commercially available and reagent grade. Purchased reagents used without any further purification. Ortho vanillin and ethylenediamine was bought from the Sigma Aldrich Company. Cd (OAc)2.2H2O, KSCN, and NaN3 were bought from E. Merck, SDFCL, India. Elemental (CHN) assessments were assigned on a Perkin-Elmer 2400 basic analysers. FT-IR and Raman spectra were recorded as KBr pellets (4000–400 cm-1) utilizing the
Synthetic rationalization
Salen-type ligands were synthesized by the condensation of ethylenediamine with ortho vanillin in MeOH at 1:2 molar ratio (Scheme 1) [67]. Cd(II)-mediated complexes derived from ortho vanillin condensed Schiff bases were prepared in moderate good yield by taking the following more familiar in situ procedure where (1:1:1M) of cadmium acetate dehydrate, respective ligands, and KSCN/NaN3 in minimum volume aqueous methanol solution under stirred and refluxed after addition of a few drops DMF (
Structural descriptions of [Cd4(L1)2(ƞ1-NCS)2(µ2-ƞ2:ƞ1-OAc)2] (C1)
Single-crystal X-ray diffraction study of C1 reveals that it is a neutral tetranuclear complex formulated as [Cd4(L1)2(ƞ1-NCS)2(µ2-ƞ2:ƞ1-OAc)2] and crystallized in the orthorhombic system with space group Pbcn (Z=4). The ORTEP crystallographic asymmetric unit is presented below (Fig. 1) and the selected important bond lengths and bond angles are given in Table S1. The formation of tetranuclear assembly involves the cumulative coordination action of the two doubly deprotonated ligands [L1]2−.
The
Hirshfeld surface
Short intermolecular contacts of the tetranuclear cadmium complexes can be evaluated using the Hirshfeld surface (HS) and 2D unique mark plot. The atomic HS [75,76] is framed dependent on the electron dispersion of a particle and has been resolved as the aggregate of spherical atom electron densities [77]. HS is extraordinary for each set of crystal structures. Condition (1), which depends on both de and di, and the van der Walls radii of the atom give the standardized contact separation (dnorm
FT-IR and Raman characterization
Salen ligands and complexes were characterized by FT-IR and Raman spectroscopic methods. The characteristic imines (C=N) stretching vibration of ligands were found to be 1632 cm−1 (Fig. S1) [80]. The absence of the N-H stretching band in complexes (at 3150 cm−1) indicated the condensation of all the primary amine groups [80]. Band near at 3431-3437 cm−1 of two ligands is due to O-H stretching, which is completely disappeared in the synthesized tetranuclear Cd (II) complexes. Herein, FT-IR and
Antibacterial/fungal assay
The antimicrobial activity of the ligands and associated complexes was tested against two Gram-positive and two Gram-negative bacteria and a fungal strain (Fig. S18). The mean zone diameter and MIC values of selected compounds are tabulated (Table 3, Table 4). H2L1 shows activity against all selected microorganisms (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans) except Bacillus subtilis, among them good activity against Staphylococcus aureus whereas H2L2
Time-kill kinetics
Time-kill kinetic study exhibits basic pharmacodynamic information on the relationship between the synthesized compound and the growth of microorganisms. Along these lines, this test, adds to a superior comprehension of ebb and flow and future use of the compound against the diseases brought about by the individual bacteria or fungi. Time kill kinetics study for C2 against one Gram-positive, one Gram-negative bacteria and one fungus is shown in Fig. S19-21. The untreated controls represented
Anticancer activity
The MTT test of the newly synthesized compounds showed a huge anticancer movement on A549 and Panc-1 disease cells (Fig.6A-6B). Increasing concentration (5-40 µM), there was an increment in cancer cells death. The microscopic images demonstrate the anticancer potential of these compounds about the paclitaxel (Fig. S22-S23). C2 outshined in both cancerous cell lines, killing capability on both A549 (80.99%) and Panc-1 (74.13%) cell, while L1, L2 and C1 also showed significant anticancer
Mitochondrial membrane potential loss
Mitochondrial dysfunction or loss of mitochondrial transmembrane potential (ΔΨM) has been shown to induce programmed cell death and thus play a central role in the apoptotic pathway [91]. The mitochondrial depolarization was determined in A549 cancer cells and a significant decrease in Rh123 fluorescence was found when cells were treated with the synthesized compounds (Fig. 7). Moreover, C2 (20 µM) displayed the highest mitochondrial depolarization 2fold) in A549 cancer cells over the other
Structure-activity relationship (SAR)
The synthesized Cd (II)-Salen complexes structure-activity relationship (SAR) can be clarified in (Fig. S24). The biological data revealed there is an enhancement of antibacterial/fungal movement because of the formation of azomethine linkage (-C=NH-) in the synthesized Cd (II) complexes when contrasted with bio-active and sensitive starting material ortho vanillin [90]. In this context, the normal cell processes can be affected through the formation of hydrogen bonding with azomethine nitrogen
Molecular docking
Auto Dock is considered as the modern unique methods used to illustrate and demonstrate the benefits of biological features of ligands and C1-C2 and to have reliable results on experimental data. To understand the compatibility of Cd (II) complexes towards both co-crystallized proteins, docking studies have been performed with all possible combinations and the results are shown in Table 6. Interestingly, the outcomes from this method are in acceptable understanding and match well with their
Concluding remarks
Utilizing two different Salen-based ligands and pseudo-halide spacers we serendipitous isolated two tetranuclear Cd (II) complexes, [Cd4(L1)2(ƞ1-NCS)2(µ2-ƞ2:ƞ1-OAc)2] (C1) and [Cd4(L2)2(µ1,1-N3)4]n (C2). Two complexes are the typical example of pseudo-halide dependent structural diversity where C1 is discrete, while C2 1D polymers. SCXRD revealed that in C1 and C2, common Cd4-structural motifs are present with two non-identical geometrical environments around the central Cd (II) ion. C1 and C2
CRediT authorship contribution statement
Dhrubajyoti Majumdar: Data curation, Conceptualization, Methodology, Investigation, Software, Visualization, Writing - original draft, Writing - review & editing. Jessica Elizabeth Philip: Software, Visualization. Sourav Das: Software, Visualization. Bidyut Kumar Kundu: Software, Visualization. Reena V. Saini: Software, Visualization. Gourav Chandan: Software, Visualization. Kalipada Bankura: Software, Visualization. Dipankar Mishra: Supervision, Writing - review & editing, Funding acquisition,
Declaration of Competing Interest
All authors declare no competing interest regarding the article publication.
Acknowledgments
This research work did not receive any specific grant from funding agencies in the public, commercial or not-profit sectors. Dr. Dipankar Mishra gratefully acknowledges the financial grant sanctioned by UGC, New Delhi, in his favour refer to Minor Research Project (F.PSW-232/15-16(ERO).
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N) and ν(C
O) peaks in IR spectra of the ligand L appeared at 1615 cm−1 and 1255 cm−1, respectively. The peaks shifted to lower and higher frequency by Δν of 4–12 cm−1 in the complexes. The new peaks assignable to ν(M