Design, Synthesis and Evaluation of a Series of Zinc(II) Complexes of Anthracene-Affixed Multifunctional Organic Assembly as Potential Antibacterial and Antibiofilm Agents against Methicillin-Resistant Staphylococcus aureus.

A novel class of zinc(II)-based metal complexes, i.e., [Zn2(acdp)(μ-Cl)]·2H2O (1), [Zn2(acdp)(μ-NO3)]·2H2O (2), and [Zn2(acdp)(μ-O2CCF3)]·2H2O (3) (Cl- = chloride; NO3- = nitrate; CF3CO2- = trifluoroacetate) of anthracene-affixed multifunctional organic assembly, H3acdp (H3acdp = N,N'-bis[anthracene-2-ylmethyl]-N,N'-bis[carboxymethyl]-1,3-diaminopropan-2-ol), have emerged as promising antibacterial and antibiofilm agents in the domain of medicinal chemistry. Accordingly, complexes 1-3 were synthesized by utilizing H3acdp in combination with ZnCl2, Zn(NO3)2·6H2O, and Zn(CF3CO2)2·H2O respectively, in the presence of NaOH at ambient temperature. The complexation between H3acdp and Zn2+ was delineated by a combined approach of spectrophotometric and spectrofluorometric titration studies. The stoichiometry of acdp3-/Zn2+ in all three complexes is observed to be 1:2, as confirmed by spectrophotometric/spectrofluorometric titration data. Elemental analysis (C, H, N, Zn), molar conductance, FTIR, UV-vis, and thermoanalytical (TGA/DTA) data were effectively used to characterize these complexes. Besides, the structures of 1-3 were established by density functional theory (DFT) calculation using B3LYP/6-311G, specifying a self-assembled compact geometry with average Zn···Zn separation of 3.4629 Å. All three zinc complexes exhibited significantly high antibacterial and antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA BAA1717). However, complex 1 showed a more recognizable activity than 2 and 3, with minimum inhibitory concentration (MIC) values of 200, 350, and 450 μg/mL, respectively. The antimicrobial activity was tested by employing the minimum inhibitory concentration (MIC) and time-kill assay. The crystal violet (CV) assay and microscopic study were performed to examine the antibiofilm activity. As observed, complexes 1-3 had an effect on the production of extracellular polymeric substance (EPS), biofilm cell-viability, and other virulence factors such as staphyloxanthin and hemolysin production, autoaggregation ability, and microbial cell-surface hydrophobicity. Reactive oxygen species (ROS) generated due to inhibition of staphyloxanthin production in response to 1-3 were also analyzed. Moreover, complexes 1-3 showed an ability to damage the bacterial cell membrane due to accumulation of ROS resulting in DNA leakage. In addition, complexes 1-3 displayed a synergistic/additive activity with a commercially available antibiotic drug, vancomycin, with enhanced antibacterial activity. On the whole, our investigation disclosed that complex 1 could be a promising drug lead and attract much attention to medicinal chemists compared to 2 and 3 from therapeutic aspects.

[1]  A. Crispini,et al.  Zinc(II) Complex with Pyrazolone-Based Hydrazones is Strongly Effective against Trypanosoma brucei Which Causes African Sleeping Sickness , 2022, Inorganic chemistry.

[2]  A. Majumder,et al.  Cu(II), Mn(II) and Zn(II) Complexes of Anthracene‐Affixed Carboxylate‐Rich Tridentate Ligand: Synthesis, Structure, Spectroscopic Investigation and Their DNA Binding Profile , 2022, ChemistrySelect.

[3]  R. Eswaramoorthy,et al.  Synthesis, Characterization, and Biological Activities of Novel Vanadium(IV) and Cobalt(II) Complexes , 2022, ACS omega.

[4]  A. Majumder,et al.  A Family of [Zn6] Complexes from the Carboxylate-Bridge-Supported Assembly of [Zn2] Building Units: Synthetic, Structural, Spectroscopic, and Systematic Biological Studies. , 2021, Inorganic chemistry.

[5]  S. Subramaniyan,et al.  Jacalin Hydrocolloid Nanoconjugates Mitigate Methicillin Resistant Staphylococcus aureus (MRSA) Biofilms on Meat Products , 2021, ACS Food Science & Technology.

[6]  Bin Yang,et al.  Discovery of a Dimeric Zinc Complex and Five Cyclopentenone Derivatives from the Sponge-Associated Fungus Aspergillus ochraceopetaliformis , 2021, ACS Omega.

[7]  Shenyuan He,et al.  Synthesis, Structure Characterization, and Antioxidant and Antibacterial Activity Study of Iso-orientin-Zinc Complex. , 2021, Journal of Agricultural and Food Chemistry.

[8]  Xuedong Zhou,et al.  Reactive Oxygen Species in Pathogen Clearance: The Killing Mechanisms, the Adaption Response, and the Side Effects , 2021, Frontiers in Microbiology.

[9]  A. Pugazhendhi,et al.  In vitro analysis of green fabricated silver nanoparticles (AgNPs) against Pseudomonas aeruginosa PA14 biofilm formation, their application on urinary catheter , 2021 .

[10]  N. El‐Metwaly,et al.  Synthesis and characterization for pharmaceutical models from Co(II), Ni(II) and Cu(II)-thiophene complexes; apoptosis, various theoretical studies and pharmacophore modeling , 2021 .

[11]  K. Acharya,et al.  Executing a Series of Zinc(II) Complexes of Homologous Schiff Base Ligands for a Comparative Analysis on Hydrolytic, Antioxidant, and Antibacterial Activities. , 2020, ACS applied bio materials.

[12]  V. De Feo,et al.  Effect of Adiantum philippense Extract on Biofilm Formation, Adhesion With Its Antibacterial Activities Against Foodborne Pathogens, and Characterization of Bioactive Metabolites: An in vitro-in silico Approach , 2020, Frontiers in Microbiology.

[13]  Youngmee Kim,et al.  A novel metal-organic frameworks based photo-crosslinked hydrogel system for efficient antibacterial applications. , 2020, ACS applied materials & interfaces.

[14]  M. Castilho,et al.  Structure-activity relationships and mechanism of action of Tetragomycin derivatives as inhibitors of Staphylococcus aureus staphyloxanthin biosynthesis. , 2020, Microbial pathogenesis.

[15]  G. Vinoth,et al.  Synthesis, spectral, electrochemical, in-vitro antimicrobial and antioxidant activities of bisphenolic mannich base and 8-hydroxyquinoline based mixed ligands and their transition metal complexes , 2019, Journal of Molecular Structure.

[16]  D. Mishra,et al.  Evidence of biomimetic and non-antibiotic characteristics of zinc-carboxymethyl chitosan-genipin organometallic complex and its biocompatibility aspects. , 2019, Biomacromolecules.

[17]  A. Oliver,et al.  Synthesis, structure and properties of new heterometallic octanuclear Li2Na2Cu4 and decanuclear Li2Zn8 complexes , 2019, Polyhedron.

[18]  R. Chávez,et al.  Osmotic Imbalance, Cytoplasm Acidification and Oxidative Stress Induction Support the High Toxicity of Chloride in Acidophilic Bacteria , 2019, Front. Microbiol..

[19]  Arumugam Priya,et al.  5-Dodecanolide interferes with biofilm formation and reduces the virulence of Methicillin-resistant Staphylococcus aureus (MRSA) through up regulation of agr system , 2019, Scientific Reports.

[20]  S. K. Pandian,et al.  Myrtenol Attenuates MRSA Biofilm and Virulence by Suppressing sarA Expression Dynamism , 2019, Front. Microbiol..

[21]  Shangshang Qin,et al.  Synthesis and Bioactivities of New Membrane-active Agents with Aromatic Linker: High Selectivity and Broad-Spectrum Antibacterial Activity. , 2019, ACS infectious diseases.

[22]  A. Annamalai,et al.  Exploring Morin as an anti-quorum sensing agent (anti-QSA) against resistant strains of Staphylococcus aureus. , 2019, Microbial pathogenesis.

[23]  A. Chattopadhyay,et al.  Phosphatase-like Activity of Tetranuclear Iron(III) and Zinc(II) Complexes. , 2018, Inorganic chemistry.

[24]  J. Grivel,et al.  Synthesis and thermal decomposition study of dysprosium trifluoroacetate , 2018, Journal of Analytical and Applied Pyrolysis.

[25]  Jeong Hyun Kang,et al.  Inhibition of malodorous gas formation by oral bacteria with cetylpyridinium and zinc chloride. , 2017, Archives of oral biology.

[26]  A. Nascimento,et al.  Thermal behavior in oxidative and pyrolysis conditions and characterization of some metal p-aminobenzoate compounds using TG–DTA, EGA and DSC-photovisual system , 2017 .

[27]  Luca M. Carrella,et al.  Dinuclear and tetranuclear complexes of copper coordinated by an anthracene-based new μ-bis(tridentate) ligand: Synthesis, structure, spectroscopy and magnetic properties , 2016 .

[28]  P. Portius,et al.  Homoleptic Poly(nitrato) Complexes of Group 14 Stable at Ambient Conditions. , 2016, Inorganic chemistry.

[29]  Y. Ueno,et al.  An autopsy case of zinc chloride poisoning. , 2016, Legal medicine.

[30]  E. Chiancone,et al.  Salmonella enterica serovar Typhimurium growth is inhibited by the concomitant binding of Zn(II) and a pyrrolyl-hydroxamate to ZnuA, the soluble component of the ZnuABC transporter. , 2016, Biochimica et biophysica acta.

[31]  Jintae Lee,et al.  Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and the hemolytic activity of Staphylococcus aureus , 2016, Scientific Reports.

[32]  N. Katoh,et al.  Clinical usefulness of Mohs' chemosurgery for palliative purposes in patients with cutaneous squamous cell carcinoma with risk factors or without indication for surgery: Three case reports , 2015, The Journal of dermatology.

[33]  G. Wang,et al.  Synthesis, characterization, antimicrobial activity and mechanism of a novel hydroxyapatite whisker/nano zinc oxide biomaterial , 2014, Biomedical materials.

[34]  G. Das,et al.  Biocompatible nanocarrier fortified with a dipyridinium-based amphiphile for eradication of biofilm. , 2014, ACS applied materials & interfaces.

[35]  E. Aizenman,et al.  The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease , 2014, Front. Aging Neurosci..

[36]  B. Shivalinga,et al.  An in vitro study to evaluate the effects of addition of zinc oxide to an orthodontic bonding agent , 2014, European journal of dentistry.

[37]  Richard D. Smith,et al.  Activated ClpP kills persisters and eradicates a chronic biofilm infection , 2013, Nature.

[38]  S. Nair,et al.  Efficacy of tetracycline encapsulated O-carboxymethyl chitosan nanoparticles against intracellular infections of Staphylococcus aureus. , 2012, International journal of biological macromolecules.

[39]  Pengxuan Li,et al.  A highly selective fluorescent sensor for distinguishing cadmium from zinc ions based on a quinoline platform. , 2012, Inorganic chemistry.

[40]  L. Juillerat-Jeanneret,et al.  Anthracene-tethered ruthenium(II) arene complexes as tools to visualize the cellular localization of putative organometallic anticancer compounds. , 2012, Inorganic chemistry.

[41]  Christopher S. Murphy,et al.  2-Anthryltriazolyl-containing multidentate ligands: zinc-coordination mediated photophysical processes and potential in live-cell imaging applications. , 2010, Inorganic chemistry.

[42]  N. Perkas,et al.  Coating of glass with ZnO via ultrasonic irradiation and a study of its antibacterial properties , 2009 .

[43]  N. Huby,et al.  Molecular engineering to improve the charge carrier balance in single-layer silole-based OLEDs , 2009 .

[44]  S. Lippard,et al.  Solution and fluorescence properties of symmetric dipicolylamine-containing dichlorofluorescein-based Zn2+ sensors. , 2009, Journal of the American Chemical Society.

[45]  N. Farrell,et al.  Zinc metalloproteins as medicinal targets. , 2008, Chemical Society reviews.

[46]  V. Zeleňák,et al.  Correlation of infrared spectra of zinc(II) carboxylates with their structures. , 2007, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[47]  C. Lodeiro,et al.  Synthesis, Complexation and Spectrofluorometric Studies of a New NS3 Anthracene-Containing Macrocyclic Ligand , 2006 .

[48]  Carla Renata Arciola,et al.  The significance of infection related to orthopedic devices and issues of antibiotic resistance. , 2006, Biomaterials.

[49]  Michael Sullivan,et al.  Metalloproteomics: high-throughput structural and functional annotation of proteins in structural genomics. , 2005, Structure.

[50]  W. Wong,et al.  Μ-η1:η1-N,N'-imidazolidine-bridged dicopper(II/III) complexes of a new dinucleating μ-bis(tetradentate) schiff base ligand : Synthesis, structural characterization, 1H NMR spectroscopy, and magnetic coupling , 2005 .

[51]  J. D. Baldeck,et al.  Physiologic actions of zinc related to inhibition of acid and alkali production by oral streptococci in suspensions and biofilms. , 2004, Oral microbiology and immunology.

[52]  Gerard Parkin,et al.  Synthetic analogues relevant to the structure and function of zinc enzymes. , 2004, Chemical reviews.

[53]  A. Turner.  Exploring the structure and function of zinc metallopeptidases: old enzymes and new discoveries. , 2003, Biochemical Society transactions.

[54]  H. Adams,et al.  A new carbonate bridged tetranuclear zinc(II) complex of an asymmetric tetrapodal compartmental ligand , 2001 .

[55]  J. Berg,et al.  The Galvanization of Biology: A Growing Appreciation for the Roles of Zinc , 1996, Science.

[56]  A. Becke.  Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[57]  J. Henrichsen.  Bacterial surface translocation: a survey and a classification , 1972 .

[58]  J. Pople,et al.  Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules , 1972 .

[59]  N. J. Rose,et al.  Molecular Addition Compounds of Iodine. I. An Absolute Method for the Spectroscopic Determination of Equilibrium Constants , 1959 .

[60]  A. Ananda,et al.  Assessment of antibacterial efficacy of a biocompatible nanoparticle PC@AgNPs against Staphylococcus aureus. , 2019, Microbial pathogenesis.