Complexos de La 3+ , Eu 3+ e Gd 3+ coordenados à ampicilina: síntese, caracterização e investigação de atividades biológicas

Abstract

Ampicillin ((2S,5R,6R)-6-[[(2R)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane -2- sodium carboxylate) is a semi-synthetic β-lactam antimicrobial belonging to the penicillin group. This is the first semi-synthetic penicillin to exhibit activity against both Gram-positive and Gram-negative bacteria, in addition to having low cytotoxicity and not being mutagenic. However, ONU data describe that with the uncontrolled use of this antimicrobial, both Gram-positive and Gram-negative bacteria have developed resistance to ampicillin through the production of β-lactamase enzymes that deactivate its action. Literature data describe that the formation of coordination complexes with Ln3+ ions and drugs produces specific properties, as well as potentiating their effects since lanthanides possess biological activity. Thus, the main objective of this study was the synthesis of Ln3+ ion complexes (La3+, Eu3+, and Gd3+) coordinated with ampicillin for potential biological applications. The synthesis was carried out at a 1:3 molar ratio (metal:ligand), with the ligand in the form of sodium salt (NaL) and the metals in the form of lanthanide chlorides in an aqueous medium. After the synthesis process, the complexes acquired yellow coloration and become insoluble in water, methanol, ethanol, DMSO, DMF, acetone and hexane, unlike the ligand which is soluble in both solvents tested. Elemental analysis, complexometric titration, thermal analysis, Fourier-transform infrared spectroscopy (FTIR), and -ultraviolet-visible (UV-Vis) spectroscopy results were compatible with a proposed 2:2 (metal:ligand) coordination with the following coordination formulas: La2(L)2(Cl)4(H2O)4], [Eu2(L)2(Cl)4(H2O)4], [Gd2(L)2(Cl)4(H2O)2], Where L = C16H18N3SO4-. Photoluminescence spectroscopy analysis indicates that the Eu3+ ion is present in a heterogeneous chemical environment with mixed symmetries, suggesting the possible formation of a coordination polymer, as the 5D0 → 7F0 transition appears as broadband. The complexes were subjected to in vitro Minimum Inhibitory Concentration (MIC) tests, and the results indicate that the complexes were not active against bacteria [Staphylococcus aureus (clinical strain, resistant to ampicillin – Gram-positive) and Escherichia coli (NEWP0018 – Gram-negative, commercial strain, producing beta-lactamase]. These results may be attributed to the complexes’ insolubility in DMSO, the solvent used for the tests, as well as the possible formation of the coordination polymer. Cytotoxicity studies were also conducted, and the data show that the complexes exhibited activity against the B16-F10 (murine melanoma) cell lines, with their GI50 < 250 μg/mL; In the U251 (Glioma) cell line, only the EuL complex exhibited activity (GI50 < 250 μg/mL), and in the MCF7 (breast carcinoma) cell line, only the LaL and EuL complexes showed noticeable activity (GI50 < 250 μg/mL). However, when tested on the NIH – 3T3 cell lines, it is evident that the LaL, EuL, and GdL complexes are extremely active, as their GI50 values fall within the range 0.06 μg/mL <GI50> 5.9 μg/mL, and cytotoxic effects are observed, indicating high cytotoxicity in normal tissue cells and irrelevant selectivity indices.