Structure‐activity relationships in the haemolytic activity and nephrotoxicity of derivatives of 1,2‐ and 1,4‐naphthoquinone

Abstract

Naphthoquinone derivatives are under investigation as potential therapeutic agents. Some such compounds are known, however, to be toxic to both animals and humans. Many naphthoquinone derivatives are haemolytic agents, while others cause necrosis of tubular epithelial cells. In the present study, the short-term toxicity of 16 derivatives of 1,2- and 1,4-naphthoquinone has been examined in rats in order to give information on structure-activity relationships. All the naphthoquinones except one caused haemolytic anaemia, but only hydroxy and amino derivatives were nephrotoxic. Among derivatives of 2-amino-1,4-naphthoquinone, substitution in the 3-position decreased haemolytic activity and abolished nephrotoxicity. Methylation of the hydroxyl group of 2-hydroxy-1,4-naphthoquinone had a similar effect. In contrast, methylation of the amino group of 2-amino-1,4-naphthoquinone increased the severity of both haemolysis and renal damage. Among the 1,2-naphthoquinones tested, the 4-methoxy and 4-amino derivatives were more toxic than the corresponding 1,4-isomers, although 4-methyl-1,2-naphthoquinone was less toxic than 2-methyl-1,4-naphthoquinone. At present, the toxicity of naphthoquinone derivatives cannot accurately be predicted on the basis of their chemical structure. In developing naphthoquinone derivatives for use in humans, toxicological studies in animals should be conducted at an early stage, bearing in mind that clinical studies have shown that humans appear to be particularly vulnerable to the nephrotoxic action of these compounds, and that certain individuals are unusually susceptible to their haemolytic action.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…For example, structural alerts have been derived for the rat nephrotoxicity of 1,2-and 1,4-naphthoquinones (Munday et al, 2007), and a QSAR has been developed for the nephrotoxicity of haloalkenes (Jolivette et al, 2002). Haloalkenes are high-volume chemicals used in industrial, synthetic, and pharmaceutical applications and are common environmental pollutants.…”

2-Chloro-1,4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent

“…Since 1,4-naphthoquinones were reported toxic to erythrocytes 15,16 , we investigated the effect of 1 and its potential metabolite 2-chloro-3-hydroxy-[1,4]-naphthoquinone (compound 3) on osmotic fragility of isolated red blood cells. At the concentrations studied, no significant hemolytic effect of the compounds was observed (Figure 4).…”

“…Anti-inflammatory action of 1 is presented in the rat model of experimental colitis. In addition, the effect of 1 and of its potential metabolite 2-chloro-3-hydroxy- [1,4]-naphthoquinone (compound 3) on osmotic fragility of isolated red blood cells was investigated, since 1,4-naphthoquinones were reported toxic to erythrocytes 15,16 .…”

Anti-cancer activities of diospyrin, its derivatives and analogues

“…The third type, alkylating hydroquinones, undergo bioreductive alkylation leading to toxicity. The balance between detoxification and activation of oxidative stress via ROS generation depends on functional group chemistry, physicochemical properties of the hydroquinone generated [50], and the rate of auto-oxidation of the formed hydroquinone [57]. The rapid oxidation of hydroquinone leads to production of more free radicals leading to enhanced toxicity [58].…”