Antiproliferative activity and conversion of tachyzoite to bradyzoite of Toxoplasma gondii promoted by new zinc complexes containing sulfadiazine

Abstract

Here we describe the synthesis and biological effect against Toxoplasma gondii of two new zinc complexes containing sulfadiazine: [(SDZ)Zn(μ-BPA)₂Zn(SDZ)] 1 and [Zn(SDZ)(HSDZ)(Cl)(OH₂)] 2, where SDZ is the anion sulfadiazine. The complexes were characterized by elemental analysis, IR, ¹H NMR, UV-Vis, electrospray ionization ESI(+)-MS and tandem mass spectrometry ESI(+)-MS/MS. X-ray diffraction studies were performed for complex 1 revealing the presence of sulfadiazine molecules coordinated to the metal center, resulting in a dinuclear complex. The cytotoxic effects of both complexes on T. gondii infected LLC-MK2 host cells are presented and indicate that both reduced the growth of T. gondii in this cell. After 48 h of treatment, both compounds induced the formation of pseudocysts confirmed by fluorescence microscopy performed with Dolichos biflorus lectin, a cystic wall marker. Pseudocysts were not observed in untreated cells or after treatment with NaSDZ alone. These results suggest the effect of the metal and the ligand on the anti-toxoplasma activity. In silico molecular pharmacokinetics studies indicate poor permeability and oral bioavailability exhibited by complex 1. As complex 1 presents better antitoxoplasma activity than SDZ we suggest that complex 1 could be acting by a distinct mode of action compared to SDZ which until now was unclear.