Biological Activity of Triazolopyrimidine Copper(II) Complexes Modulated by an Auxiliary N-N-Chelating Heterocycle Ligands

Abstract

Novel complexes of type [Cu(N-N)(dmtp)2(OH2)](ClO4)2·dmtp ((1) N-N: 2,2′-bipyridine; (2) L: 1,10-phenantroline and dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine) were designed in order to obtain biologically active compounds. Complexes were characterized as mononuclear species that crystallized in the space group P-1 of the triclinic system with a square pyramidal geometry around the copper (II). In addition to the antiproliferative effect on murine melanoma B16 cells, complex (1) exhibited low toxicity on normal BJ cells and did not affect membrane integrity. Complex (2) proved to be a more potent antimicrobial in comparison with (1), but both compounds were more active in comparison with dmtp—both against planktonic cells and biofilms. A stronger antimicrobial and antibiofilm effect was noticed against the Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA). Both electron paramagnetic resonance (EPR) and Saccharomyces cerevisiae studies indicated that the complexes were scavengers rather than reactive oxygen species promoters. Their DNA intercalating capacity was evidenced by modifications in both absorption and fluorescence spectra. Furthermore, both complexes exhibited nuclease-like activity, which increased in the presence of hydrogen peroxide.

Insights into Structure and Biological Activity of Copper(II) and Zinc(II) Complexes with Triazolopyrimidine Ligands

“…The complexes’ spectra reveal the presence of two strong bands in the 1540–1635 cm −1 range, assigned to the stretching vibrations of the triazolopyrimidine moiety (νtp) and pyrimidine ring (νpym), respectively. These bands are slightly shifted to higher or lower wavenumbers for all complexes than for the free ligands, similar to other complexes with tpds coordinated through the N 3 atom [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. The additional low-intensity bands in the 455–480 cm −1 range can be assigned to the ν(M-N) stretching vibration [ 35 ].…”

“…Additional data consisting of EPR, FTIR, and UV-Vis spectra and redox behavior were also collected and are discussed in the following sections. Although the complexes ( 3 ) and ( 4 ) have been already characterized from the crystallographic and spectroscopic points of view [ 21 , 33 ], their EPR, UV-Vis, NMR, and cyclic voltammetry data are presented here for the first time together with their antimicrobial and antiproliferative activity.…”

“…Hence, in a continuous search for new antitumor drugs with reduced side effects and lower toxicity, the Cu(II) complexes are preferred, considering their reduced systemic toxicity [ 18 ]. Thus, several Cu(II) species were developed as non-toxic compounds for healthy tissue but with high activity in melanoma cells [ 33 , 39 , 40 ].…”

“…A broad spectrum of antimicrobial activity against both planktonic and biofilm-embedded strains, including methicillin-resistant Staphylococcus aureus (MRSA), was demonstrated by a series of complexes of 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidine (pmtp) with the M(pmtp)X 2 moiety (M: Cu, Zn; X: Cl [ 30 ], CH 3 COO [ 31 ] and ClO 4 [ 32 ]). Furthermore, the Cu(II) species with mixed ligands, pmtp or dmtp and 2,2’-bipyridine (bpy) or 1,10-phenanthroline, showed enhanced activity in comparison with both ligands against several planktonic and biofilm-embedded bacterial strains [ 21 , 33 ].…”

“…The acetate and perchlorate species of Cu(II) with pmtp exhibited moderate antiproliferative activity against the human colon adenocarcinoma cell line (HT 29) [ 31 , 32 ]. In contrast, Cu(II) complexes with pmtp/dmtp and bpy/phen as auxiliary ligands exhibited excellent activity against B16 melanoma cells, accompanied by a low toxicity in eukaryotic cells [ 21 , 33 ].…”