Synthesis and characterization of mixed ligand transition metal complexes and their antibacterial properties against drug-resistant bacteria

Abstract

Transition metal complexes are widely studied in medicinal chemistry, this is because of their interesting biological activity against various human diseases. This project is aimed at the synthesis of mixed ligand complexes of copper, cobalt and nickel using solvent reaction and mechanochemical methods. The four ligands being 4-chloromethyl pyridine 4PY, and four synthesized ligands pyridin-4-ylmethyl 4-nitrobenzoate L1, 4-(pyridine-4-ylmethoxy)aniline L2, pyridin-4-ylmethyl 4-aminobenzoate L3, and 4-((4-nitrophenoxy) methyl)pyridine L4 were successfully synthesized using a solvent reaction method which all followed the SN2 mechanism. Their characterization was done using proton NMR, mass spectrometry, elemental analysis and Single crystal X-Ray diffraction (SC-XRD). The cobalt, nickel and copper pyridyl complexes were synthesized in considerable yields while characterization techniques confirmed their successful synthesis. The complexes were codenamed as metal and the ligand (ML), compounds of 4PY were synthesized using the conventional solvent assisted methods but produced lower and less purer products than the green mechanochemical synthesis. The electronic spectra together with the magnetic susceptibility studies showed that the cobalt metal complexes were d 7 tetrahedral complexes, while the nickel were d 8 tetrahedral, with NiL1 showing a partial d 8 octahedral geometry, and the copper complexes were d 9 tetrahedral complexes. The cobalt complexes showed better bioactivity towards the Gram-negative bacteria, especially towards K. pneumoniae. Most active compounds against Multidrug Resistant-K. pneumoniae were bacteriostatic while all the compounds except CoL3 and CoL4 were bacteriostatic against K. pneumoniae. The Alkaline phosphatase (AKP) release assay of Co4PY-H, Co4PY, CoL2, CoL3 showed that they disrupted the cell membrane integrity of K. pneumoniae, additionally, CoL3 disrupted the cell membrane of MRSA. Although more active towards the Gram-positive bacteria, the nickel complexes were less effective than the control silver sulfadiazine (AgSD). The active nickel complexes should have been more active than the control drug AgSD, according to molecular docking scores against the S. aureus protein PBP2a, the K. pneumoniae OmpK36, and the DHPS protein, but their activity was quenched by their solubility problems. The copper complexes were more effective against Gram-positive bacteria, with CuL4 performing best, vi notably against MRSA and S. aureus, and 4PY complexes being the least effective. Additionally, it was shown that the CuL4 and Cu4PY-H disrupted the S. aureus cell membrane more effectively than the AgSD control.