Development, structural, spectroscopic and in silico investigation of new complexes relevant as anti-toxoplasma metallopharmacs

Toxoplasmosis is an endemic neglected disease spread throughout the southern hemisphere, affecting a large part of the population concentrated in these countries. Aiming to develop new coordination compounds with anti-toxoplasma activity, we report herein the reactions between the mononuclear complexes [Cu(HL1)Cl 2 ] (1) , [Fe(HL1)Cl 3 ] (2) , and [Zn(HL1)Cl 2 ] (3) ( HL1 is the ligand N-2[(pyridine-2ylmethyl)amino)ethanol)) and sodium sulfadiazine (NaSDZ), one of the current drugs used to treat toxoplasmosis. DFT data suggested that complexation reactions between complexes (1) - (3) and NaSDZ result in stable complexes (4)-(6) , containing SDZ - in their coordination spheres, based on EDA (Energy Decomposition Analysis), which indicate favorable interaction between the metallic centers of the complexes and the anion SDZ -. The EDA results also suggest that the SDZ - anion donates negative charge to the metal, weakening the M-Cl interaction, present in complexes (1)-(3) , and making the coordination with SDZ - anion easier. However, the reactions of (1) and (2) with NaSDZ were indeed ineffective, then complexes (4) and (5) were not obtained. Only the formation of [Zn(HL1)(SDZ)Cl] . 2H 2 O (6) was achieved, the product of the reaction between complex (3) and NaSDZ. Further analysis of DFT calculations and EDA data were carried out to understand the lack of the reactivity of compounds (1) and (2) . The data revealed higher lability for the chloro ligand present in complex (3) and better stabilization of complex (6) 's HOMO. Steric and stacking effects could also justify these experimental data. This parallel theoretic-experimental study allowed us to conclude that complex (6) is the most probable to be obtained synthetically, in agreement with the experimental behavior. Furthermore, a complete characterization employing spectroscopic and electrochemical is presented for all the complexes, with and without SDZ - anion, including X-ray diffraction studies for complexes (1) and (6) . The cytotoxic effects on T. gondii infecting LLC-MK2 host cells are presented and indicate that all the complexes reduced the parasite s acute accent ability to proliferate. These results suggest that these compounds are promising, especially complex (2) , which causes the death of the parasite.

Automated summary

Toxoplasmosis is a neglected disease that mainly affects the southern hemisphere. This study focuses on developing coordination compounds with anti-toxoplasma activity. Through experimental and theoretical analysis, it was found that complex (6) is the most likely compound to be obtained synthetically and shows promising inhibitory effects on the proliferation of Toxoplasma parasites.