Synthesis, DFT calculation, molecular docking studies and biological evaluation of a novel series of Schiff base tetradentate macrocyclic ligands and their Zn(II) complexes as antimicrobial, anti-inflammatory and anticancer agents

Zinc-based coordination compounds, which are inexpensive, non-toxic, and abundant on earth, are attracting scientific interest as potential candidates for use as antimicrobial, anticancer, and anti-inflammatory agents. In the present work, novel Schiff base macrocyclic Zn(II) complexes [Zn(N8O4L1)Cl-2-Zn(N8O4L3)Cl-2] were synthesized by the reaction of ZnCl2 and macrocyclic ligands (N8O4L1-N8O4L3) derived from the condensation of ligand (N4L) and dicarboxylic acids [HOOC-(CH2)(n)-COOH]. The structural confirmation of the newly synthesized compounds was accomplished through various analytical techniques including elemental analysis, infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), UV-visible spectroscopy, and powder X-ray diffraction (XRD) studies. The spectral data provided evidence that the macrocyclic ligands acted as tetradentate ligands, forming coordination bonds with Zn(II) ions through the nitrogen atom of the imine (>C=N) group. The coordination complexes exhibited an octahedral geometry around the zinc ion, with two chloro groups covalently attached. Density functional theory (DFT) studies of the synthesized Schiff base macrocyclic compounds were carried out to determine their structural and electronic properties. All of the synthesized compounds were evaluated for their biochemical properties, including antimicrobial, anti-inflammatory, and anticancer activities. The antimicrobial potential of the macrocyclic compounds was examined against a panel of pathogenic microbes, including Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and fungal strains (Aspergillus niger and Candida albicans). The result showed that the macrocyclic complexes have remarkable antimicrobial potential as compared to their corresponding macrocyclic ligands at the same concentration. Then, the newly synthesized Schiff based macrocyclic compounds were evaluated for their anti-inflammatory activity using an egg albumin method in which the macrocyclic complex [Zn(N8O4L2)Cl-2] with an IC50 value of 8.36 mu g/mL was found to be the most potent anti-inflammatory compound, relative to sodium diclofenac (IC50 = 4.59 mu g/mL). The synthesized compounds were subjected to further evaluation to assess their potential as anticancer agents against MDA-MB-231 (human breast cancer cell line), HCT-116 (human colon cancer cell line), and A549 (human lung cancer cell line). Among them, the macrocyclic complex [Zn(N8O4L3)Cl-2] showed superior and more specific cytotoxicity against the tested cancer cell line, as demonstrated by its low IC50 value. In addition, molecular docking studies were conducted to explore the potential interactions between the newly synthesized compounds and the target proteins VEGFR2 (PDB ID 1YWN), EGFR (PDB ID 1M17), and DNA gyrase B (PDB ID 4URO). It was found that there was a high correlation between the experimental results and the docking calculations. Hence, these newly synthesized compounds can serve as inspiration for developing new anti-inflammatory and anticancer drugs. [GRAPHICS] .