Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
Physicochemical, in-vitro therapeutic activity and biomolecular interaction studies of Mn(II), Ni(II) and Cu(II) complexes tethered with O2N2 ligand backbone
Graphical abstract
Introduction
Among the leading causes of death globally, diabetes and infections caused by pathogens are among the front-runners [1]. As per the recent statistics by the International Diabetes Federation [2], diabetes [3,4] accounted for the suffering of 425 million people in 2017 and by the end of 2045, it is estimated that this number will rise upto 629 million people. Categorized mainly into type I and type II diabetes, the latter is prevalent in about 90% of the cases [5]. Many classes of oral drugs are available for diabetes treatment, the important ones being Metformin and Sitagliptin [6]. These drugs are very effective for glycemic control but at the cost of undesirable side effects and toxicity such as weight loss, hypoglycemia, abdominal and gastrointestinal distress [6,7]. Another serious concern to ponder over are the deadly diseases arising through microbial infections caused by drug resistant pathogens leading to increasing menace of drug tolerance [[8], [9], [10], [11]]. As per the statistical report by the UN Interagency Coordinating Group on antimicrobial drug resistance, an estimate of 10 million people would die in each of the approaching years and by the year 2030, would push 24 million people towards endangering poverty and economic crisis [12]. Research, innovation and development of novel antimicrobials is the only key for sustainability against this threat. The lookout for new and improved drug candidates can be satiated with the aid of medicinal inorganic chemistry [13]. This field has to its credits, the most notable anticancer drug cisplatin [14] and many such unconventional metal-based drugs with highly stringent biological activities against emerging health hazards. Transition metal complexes (TMCs), in particular, offer a huge scope with varied coordination spheres, ligand designs and oxidation states bestowing the ability to methodically amend various properties of the complexes towards biological ligands and receptors [15,16]. Middle and late 3d trace metals, viz. manganese, nickel and copper were chosen for the present study citing the pivotal roles played by these metals in biological systems, especially in humans [17,18]. Recently, nature mimicking manganese metalloporphyrines were found to behave as antioxidants with excellent superoxidase dismutase (SOD) mimicking activity higher than native Mn-SOD mitochondrial enzymes [19]. Few Mn(II) complexes derived from ONS and ON donor Schiff base ligands have demonstrated remarkable antifungal and antibacterial activities better than standard antibiotics [[20], [21], [22]]. With very rare reports on the antidiabetic activity of manganese complexes, one salen derived Mn(II) complex has displayed glucose lowering effect in diabetic mice models through DPP-4 inhibition pathway with activity comparable to metformin drug [23]. There are ample reports on the antibacterial activities of nickel complexes [24]. One of them being the nickel(II) complex tethered with substituted benzaldehyde and substituted thiosemicarbazide ligand system which triggered growth inhibition of drug resistant Staphylococcus aureus bacteria [25]. Recently, a series of salen derived nickel complexes exhibited exemplary activity against MRSA bacteria and HeLa cancer cells through cell membrane inhibition mechanism [26]. There are fewer reports of nickel compounds studied for their antidiabetic activity and not many have shown significant insulin-mimicking or antidiabetic actions. One such report is of Ni(II) complexes of 6-methyl-3-formylchromone derived hydrazones which were explored for their inhibitory activity towards α-amylase and α-glucosidase enzymes [27]. Therefore, nickel complexes have a great scope for their pharmacological exploration to treat drug resistant pathogens and diabetes. Copper compounds could also act as prototypical medicinal agents citing the imperative biological role of copper. Vast classes of copper complexes have been studied for their excellent anticancer and antimicrobial potential [28]. Thiosemicarbazide and sodiumsalicylaldehyde sufonate Schiff base derived Cu(II) complex displayed excellent activity against gram positive bacteria [29]. Aminothiophenol and formylbenzonitrile Schiff base appended copper(II) complex demonstrated great inhibitory potential against Salmonella typhi bacteria, the activity comparable to standard antibacterial drug, Chloramphenicol [30]. Another copper(II) compound of a Schiff base ligand derived from 2-hydroxy napthaldehyde and aminothiophenol exhibited good antibacterial activity against Bacillus subtilis whose activity was comparable to that of a standard drug, ampicillin [31]. These metals, manganese, nickel and copper with a combination of O2N2 donor Schiff base motifs consisting of the most common salen and salan (reduced form of salen which is more flexible and stable) compounds will evidently prove to be bioactive agents as these type of ligands are known to exhibit exemplary antimicrobial, antidiabetic and anticancer activities [32,33].
Citing the need for new and improved drug candidates for the treatment of drug resistance and type II diabetes, we have herein reported three compounds of manganese(II), nickel(II) and copper(II) as plausible bioactive agents. The developed compounds which are all appended with a flexible ‘salan’ kind of O2N2 donor ligand were evaluated for their antimicrobial activity against few drug resistant and prominent bacteria and fungi species and for their capability to induce glucose uptake in a typical diabetic environment. The manganese and nickel species which were found to show antidiabetic and antimicrobial activities respectively were also studied for their reactivity and stability in biological media conditions through pH variation and BSA interaction studies using multi-spectroscopic techniques.
Section snippets
Materials and methods
The chemicals and solvents used for the experiments were procured from verified vendors and were used without any further purification. Double distilled water was used for all the experiments. Metal precursors, manganese sulphate tetrahydrate and copper acetate monohydrate were purchased from S D Fine Chem Ltd. and nickel acetate tetrahydrate was purchased from Spectrochem Pvt. Ltd., all with an assay purity >98%. For the biological media studies, bovine serum albumin with an assay purity >99%
Synthesis and characterization
Reactions between equimolar solutions of the ligand, {H2(hpdbal)2-an} (L) and the metal precursors of manganese, nickel and copper resulted in the formation of the compounds 1, 2 and 3 respectively. Eqs. (2), (3), (4) represent the stoichiometric synthetic routes employed for obtaining the complexes. All the obtained complexes are soluble and stable in DMSO and DMF solvents but are insoluble in water, ethanol and methanol. The structures of these complexes were confirmed on the basis of
Conclusions
Our attempt in this work was to develop biocompatible metal based drug alike candidates against emerging pathogens and for glucose uptake inducing activities. Pertinently, three transition metal complexes, viz. [MnII(H2O)2{(hpdbal)2-an}] (1), [NiII{(hpdbal)2-an}] (2) and [CuII{(hpdbal)2-an}] (3) were synthesized, characterized and assessed for these activities. The nickel(II) salan complex (2) interestingly displayed a significant 87% growth inhibition against Candida albicans species. Our
CrediT authorship contribution statement
Manasa Kongot:Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing - original draft, Visualization, Writing - review & editing.Dinesh S. Reddy:Validation, Resources, Writing - original draft, Writing - review & editing.Vishal Singh:Validation, Formal analysis, Investigation.Rajan Patel:Resources, Writing - original draft, Visualization, Funding acquisition.Nitin Kumar Singhal:Resources, Writing - original draft, Visualization, Funding acquisition.Amit
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
We are indebted to ‘The Community for Antimicrobial Drug Discovery’, Australia. The antimicrobial screening performed by CO-ADD (The Community for Antimicrobial Drug Discovery) was funded by the Wellcome Trust (UK) and The University of Queensland (Australia). The authors are thankful to Science and Engineering Research Board, DST, India (SB/FT/CS-100/2013) and Department of Biotechnology, DST, India (BT/PR10353/PFN/20/889/2013) for granting financial aid for this work. We also thank the
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