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 <i>Staphylococcus aureus</i>

Abstract

A novel class of zinc(II)-based metal complexes, i.e., [Zn 2 (acdp)(μ-Cl)]·2H 2 O ( 1 ), [Zn 2 (acdp)(μ-NO 3 )]·2H 2 O ( 2 ), and [Zn 2 (acdp)(μ-O 2 CCF 3 )]·2H 2 O ( 3 ) (Cl – = chloride; NO 3 – = nitrate; CF 3 CO 2 – = trifluoroacetate) of anthracene-affixed multifunctional organic assembly, H 3 acdp (H 3 acdp = 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 H 3 acdp in combination with ZnCl 2, Zn(NO 3 ) 2 ·6H 2 O, and Zn(CF 3 CO 2 ) 2 ·H 2 O respectively, in the presence of NaOH at ambient temperature. The complexation between H 3 acdp and Zn 2+ was delineated by a combined approach of spectrophotometric and spectrofluorometric titration studies. The stoichiometry of acdp 3– /Zn 2+ 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.