Novel hydrazone-oxime schiff base: Synthesis, spectroscopic and elemental characterization, coordination behavior with first-row and post-transition metals, and assessment of enhanced antimicrobial activity upon metallation

Abstract

A novel bidentate hydrazone-based Schiff base ligand, systematically designated as (E)-N'-(4-fluoro-2-hydroxybenzylidene)-4-methoxybenzohydrazide, was efficiently synthesized through an acid-catalyzed condensation reaction between equimolar quantities of 4-methoxybenzohydrazide and 4-fluoro-2-hydroxybenzaldehyde in an appropriate protic solvent. This ligand served as the chelating scaffold for the preparation of a homologous series of six transition metal(II) coordination complexes incorporating Ni(II), Co(II), Cu(II), Pd(II), Mn(II), and Fe(II) centers. Structural elucidation and verification of the ligand's integrity, as well as the coordination mode and geometry of the derived complexes, were accomplished via an integrated suite of analytical and physicochemical techniques: elemental microanalysis (CHN), Fourier-transform infrared (FT-IR) spectroscopy, electronic absorption (UV-Vis) spectroscopy, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, molar conductivity measurements in suitable non-aqueous solvents, and magnetic susceptibility studies (using Gouy or Faraday methods). The collective data confirmed that the ligand functions as a bidentate chelator, coordinating to the metal ions predominantly through the azomethine nitrogen (-CH=N-) and the deprotonated phenolic oxygen (from the ortho-hydroxy substituent on the benzylidene ring), yielding neutral or charged complexes with proposed octahedral (for d6-d8 first-row metals with potential axial ligation or solvent coordination) or square-planar (particularly for Pd(II) and potentially Cu(II)/Ni(II) under strong-field conditions) geometries around the central metal ion. The free ligand and its metallated derivatives were subjected to in vitro antimicrobial susceptibility screening against representative Gram-positive and Gram-negative bacterial strains, as well as clinically relevant fungal pathogens, employing standardized microbiological protocols (e.g., agar well diffusion, broth microdilution, or disc diffusion assays). The results revealed that the metal complexes exhibited markedly superior broad-spectrum antimicrobial potency relative to the uncoordinated ligand, consistent with the established chelation-enhanced bioactivity paradigm in coordination chemistry: metallation reduces the overall polarity of the complex, partially delocalizes the metal charge across the donor atoms, augments lipophilicity, and thereby facilitates enhanced permeation across microbial lipid bilayers, culminating in improved intracellular target engagement and disruption of essential cellular processes. Particularly noteworthy were the Cu(II) and Pd(II) complexes, which demonstrated the most robust and broad-spectrum inhibitory effects across the tested microbial panel, often outperforming reference standards and positioning them as compelling lead candidates for the rational development of novel metal-based antimicrobial therapeutics to combat emerging resistance mechanisms. Further mechanistic investigations, including cytotoxicity profiling, target identification (e.g., DNA/protein interactions, ROS generation), and preliminary in vivo evaluations, are warranted to fully elucidate their therapeutic potential.