A study on the formation of the nitro radical anion by ornidazole and its significant decrease in a structurally characterized binuclear Cu^(II)-complex: impact in biology

Abstract

An acetate-bridged binuclear Cu((II)) complex of the antiparasitic drug ornidazole was synthesized and characterized by different techniques. Single crystal X-ray diffraction revealed that the complex had a paddle wheel structure. Enzymatic assay experiments performed under anaerobic conditions on ornidazole and its Cu((II))-complex using xanthine oxidase as a model nitro-reductase showed that complex formation is able to cause a significant decrease in the reduction of the nitro group on the imidazole ring. Reduction products of 5-nitroimidazoles interact with DNA, causing destruction of the double helical structure and strands, leading to the inhibition of protein synthesis. Although not directly coordinated to the metal center, such a decrease in the generation of nitro radical anion through complex formation would result in decreased cytotoxicity of the complex, which could be a disadvantage from the standpoint of drug efficacy. For this reason, other aspects associated with the drug action of 5-nitroimidazoles, such as DNA binding, were studied. Experiments using cyclic voltammetry revealed that the binding of the complex was almost comparable to ornidazole. Bactericidal activity of ornidazole and the complex was studied on two separate bacterial strains, showing that the complex was comparable to ornidazole. Nitro radical anions are known to adversely affect the central nervous system, and this study showed that the Cu((II)) complex has the ability to decrease the generation of NO2˙(-) to an extent that struck the correct balance for beneficial activity, as cytotoxicity due to ornidazole was not affected.

Influence of ionic strength on the interaction of THA and its Cu(ii) complex with DNA helps to explain studies on various breast cancer cells

“…[39][40][41][42] The titration data from cyclic voltammetry was fitted to Eq. 10 and 11 provide values for K d (= 1/K app ) using non-linear curve fit analysis.…”

A ZnIIcomplex of ornidazole with decreased nitro radical anions that is still highly active onEntamoeba histolytica

“…[1][2][3][4][5][6][7][8] Their efficacy is attributed to the generation of the nitro-radical anion (R-NO 2 c À ). [1][2][3][4][5][6][7][8][9][10] In order to tackle infections caused by parasites, these molecules are rst reduced by the enzyme pyruvate ferredoxin oxidoreductase (PFOR) that acts as an electron sink. 9,10 Reduction of the nitro group prepares them for entry into cells by passive diffusion, creating a favorable concentration gradient.…”

“…R-NO 2 c À binds to DNA, disrupting or breaking strands, leading to cell death. 9, 10 As radiosensitizers, they interact with the radicals formed on DNA following the interaction of the latter with the products of the radiolysis of water, forming R-NO 2 c À , which thereaer enhances strand unwinding or strand breaks. [6][7][8] Unfortunately, the same R-NO 2 c À ion is associated with the neurotoxic side effects, particularly when there is prolonged use of such molecules.…”

Activity of CoII–Quinalizarin: A Novel Analogue of Anthracycline-Based Anticancer Agents Targets Human DNA Topoisomerase, Whereas Quinalizarin Itself Acts via Formation of Semiquinone on Acute Lymphoblastic Leukemia MOLT-4 and HCT 116 Cells

“…3,11−15 Therefore, it is necessary to strike a balance between therapeutic efficacy and toxic side effects with regard to the generation of these reactive intermediates. 16,17 Research has revealed that metal complexes of anthracyclines modulate the formation of semiquinone that helps to control cardiotoxicity. 18−20 However, in controlling the formation of semiquinone through complex formation in an attempt to check cardiotoxicity, efficacy of the molecule is often compromised.…”