Integrated experimental and theoretical investigation of Cu(II), Mn(II), and Sr(II) chelates of an indole-based hydrazide derivative: synthesis, structural characterization, molecular docking, DFT studies, and biological evaluation.

Schiff base ligands and their coordination complexes are of significant interest due to their structural versatility and therapeutic potential. In this study, a novel Schiff base ligand, (Z)-N'-((1H-indol-3-yl)methylene)isonicotinohydrazide (HL), was synthesized with a 93% yield via the condensation of 4-pyridinecarboxylic acid hydrazide and indole-3-carboxaldehyde. Stable metal complexes of copper(II), manganese(II), and strontium(II) were subsequently prepared in a 2:1 ligand-to-metal ratio, achieving yields of 86%, 90%, and 84%, respectively. Structural elucidation was rigorously performed using elemental analysis, Fourier transform infrared (FT-IR), ultraviolet-visible spectroscopy (UV-Vis), and nuclear magnetic resonance (1H NMR) spectroscopy, confirming neutral bidentate coordination via the azomethine nitrogen and carbonyl oxygen. In addition to these methods of characterization, molecular modeling techniques, particularly density functional theory (DFT), were performed to assess the electronic structure of the novel Schiff base ligand and the metal-complexes formed with the Schiff base could be used to determine the interactions between molecular orbitals. DFT calculations (B3LYP/LANL2DZ/6-31G(d,p) with PCM solvation) revealed a reduction in the HOMO-LUMO energy gap (ΔE) from 4.16 eV in HL to 2.77 eV in HL-Sr, indicating increased chemical reactivity upon complexation and high electrophilicity, indicating good kinetic stability. In vitro antibacterial and antifungal evaluations demonstrated concentration-dependent activity; notably, metal coordination enhanced antimicrobial efficacy, with HL-Sr displaying strong antibacterial inhibition against P. aeruginosa (9.47 mm at μg/mL) comparable to the standard drug Streptomycin (10.63 mm). In vitro assays showed enhanced antibacterial and antifungal activity upon metal coordination. Although lower than reference drugs, these compounds serve as promising lead structures for future optimization rather than immediate clinical candidates. Molecular docking supported strong binding of the synthesized Schiff base metal complexes to biological targets. Molecular docking against S. aureus DNA Gyrase B and A. niger endoglucanase showed that the uncoordinated ligand HL achieved higher binding affinities (-12.11 kcal/mol and -12.60 kcal/mol, respectively) than the commercial control drugs Streptomycin (-10.90 kcal/mol) and Ketoconazole (-8.60 kcal/mol), while the metal complexes exhibited favorable interactions with key active site residues. These results highlight the synthesized compounds as promising candidates for pharmaceutical and biomedical applications.