A Theoretical‐Experimental Study on the Structure and Activity of Certain Quinolones and the Interaction of Their Cu(II)‐Complexes on a DNA Model

Abstract

Theoretical electronic Structure methods have been employed to study the structure and activity of certain (free) quinolones and the interaction of their Cu(II)-complexes on a DNA model (Rhodamine 6G (rhod)). As a manner of assessing the generated geometries, the nalidixic acid geometrical parameters obtained were tested against the crystallographic ones and it was found that the average error in the calculated geometries is small. The present study allows us to (1) Rationalize the observed differences in antibiotic activities through their electronic hardnesses. (2) Suggest a plausible mechanism of action for these drugs through formation of a reactive intermediate (or carrier) which would consist of a quinolone anion coordinated to an adequate metal center (Cu(II) in this study). (3) We find that, through this model of DNA (modeled with rhod) the interaction seems to be mediated by an effective π-π stacking. (4) Finally, an in vitro experiment was designed so that the intercalation process in DNA could be experimentally modeled as well. The quenching of the rhod fluorescence is proportional to the strength of the Cu(II)-complex-rhod interaction and therefore provides a quantitative measurement of the “intercalating” capacity of the quinolones and their copper complexes. These results agree well with the theoretical total adduct formation energies.

Synthesis, characterization, antibacterial, antifungal and immunomodulating activities of gatifloxacin–metal complexes

“…The mechanism of gatifloxacin action involves inhibition of bacterial DNA gyrase, which is essential for DNA replication, and it has been proposed that metal complex intermediates are involved in this process [3,4]. A study on the structure and activity of certain quinolones and the interaction of their Cu(II) complexes on a DNA model, suggested that the intercalation of the quinolone complexed to a metal is an important step in the mechanism of action of these drugs [5]. Number of studies confirmed that DNA-affinity of the quinolone, modulated by Mg (II), plays an important role in poisoning the cleavable gyrase-DNA complex and, consequently, in eliciting antibacterial activity by this family of drugs [6].…”

Antibacterial studies, DNA oxidative cleavage, and crystal structures of Cu(II) and Co(II) complexes with two quinolone family members, ciprofloxacin and enoxacin

“…Some evidence suggests that these drugs interact directly with DNA, blocking the activity of DNA-gyrase repair enzymes [2,3]. Recent studies indicate an important role of metal ions in the mechanism of action of these drugs; from investigations of the structure and activity of certain quinolones and the interaction of their Cu(II) complexes on a DNA model, it was suggested that the intercalation of the quinolone complexed to a metal is an important step in these processes [4]. In the last few years, we have described the structure and chemical behaviour of several complexes of cinoxacin (a classic quinolone) and ciprofloxacin as well as the antimicrobial activity of some of their compounds [5][6][7][8][9][10][11][12].…”

Effect of metal ions on the in vitro availability of enoxacin, its in vivo implications, kinetic and antibacterial studies

“…From investigations of the structure and activity of certain quinolones and the interaction of their Cu(II) complexes on a DNA model, it was suggested that the intercalation of the quinolone complexed to a metal is an important step in their mechanisim of action. 3 Although reports indicate that the coordination of quinolones to metal ions such as Mg 2+ and Ca 2+ appears to be important for the activity of the quinolone antibiotics, 4 it has a detrimental effect on their absorption. 5 The interaction of metal ions with diverse deprotonated quinolones as ligands has been thoroughly studied.…”