From Antibacterial to Antifungal: Structure, Safety, and Serum Albumin Binding of Zn(II)-Nalidixate Complexes with Phenanthroline and Bipyridine

Nalidixic acid (Nal) is a quinolone antibiotic with activity against Gram-negative bacteria and is used to treat urinary tract infections caused by microorganisms belonging to the genera Escherichia, Proteus, Shigella, Enterobacter, and Klebsiella. The complexation of this molecule with zinc and auxiliary ligands such as phenanthroline (Phen) and 2,2’-bipyridine (Bipy) could modify its pharmacological and pharmacokinetic properties. This work presents the synthesis and characterization of the ZnNal complex ([Zn(Nal)₂(H₂O)₂]·2MeOH). Its molecular structure in the solid state was determined by X-ray diffraction. The complex crystallizes in the monoclinic space group P2₁/n with Z = 2 molecules per unit cell. In the solid state, the nalidixic acid (Nal) molecule appears as its anionic form (Nal⁻), deprotonated in the carboxyl group. The complex is centrosymmetric, with the Zn(II) ion at the center of a slightly elongated octahedral geometry, equatorially coordinated to a bidentate nalidixate anion and axially to a water molecule. The study includes the evaluation of antimicrobial activity of the binary complex and its derivatives with phenanthroline (ZnNalPhen) and bipyridine (ZnNalBipy) against both ATCC strains and clinical isolates. Additionally, compound safety was assessed using the Artemia salina model. ZnNal preserves the antimicrobial potency of the free ligand while exhibiting attenuated toxicity in this model, suggesting a more favorable biocompatibility profile for potential therapeutic applications. Notably, ZnNalPhen was the only complex active against Candida strains, highlighting that coordination with 1,10-phenanthroline expanded the antimicrobial spectrum of the parent ligand Nal to include antifungal activity. Furthermore, both ternary complexes showed an improved safety profile compared to Nal alone. Besides, zinc(II) complexes can be efficiently transported by albumin, which is a key factor in their potential therapeutic application.