Synthesis, Crystal Structures and Urease Inhibition of Ni(II) complexes Constructed from Schiff bases with 2,2’-bipyridine as co-ligands

Abstract

In this study,three new Ni(II) complexes, namely, [Ni(C₁₆H₁₃Cl₂NO₃) (C₁₀H₈N₂)]·H₂O·2CH₃OH (C1), [Ni(C₁₆H₁₃Cl₂NO₃)]·3H₂O·CH₃OH (C2), and [Ni(C₁₆H₁₃Cl₂NO₃)(C₁₀H₈N₂)]·1.5H₂O (C3), were synthesized using chlorinated Schiff base ligands derived from the condensation of 3,5-dichlorosalicylaldehyde with L/D-phenylalanine, combined with Ni²⁺ ions and 2,2'-bipyridine as a co-ligand (for C1 and C3). All complexes C1-C3 were characterized by single-crystal X-ray diffraction and elemental analysis. This study systematically investigates the influence of co-ligands (2,2'-bipyridine vs. solvent molecules) and amino acid configurations (L-vs.D-phenylalanine) on the structural stability and urease inhibitory activity of the complexes. In vitro urease inhibitory assays showed that C1 exhibited the most potent activity (IC₅₀ = 10.68±0.09 μM), which significantly surpassed the positive control AHA ( IC₅₀ = 27.73±0.33μM), followed by C3 (IC₅₀ = 15.49±0.29μM) and C2 (IC₅₀ = 36.49±0.13μM). Molecular docking indicated that C1 binds to the urease active pocket stably via hydrogen bonding with HIS593 and hydrophobic interactions with ARG439/ALA440. DFT calculations revealed that the carboxyl oxygen atoms of C1 are potential electrophilic attack sites, while pyridine ring regions are prone to nucleophilic attacks. Structure-activity relationship (SAR) analysis suggested that the L-phenylalanine fragment and 2,2'-bipyridine co-ligand are crucial for enhancing urease inhibitory activity. These findings provide valuable insights for the development of novel Schiff base metal complexes as potent urease inhibitors.