Reactivity and aquatic toxicity of aromatic compounds transformable to quinone-type Michael acceptors

Abstract

Reactive toxicity encompasses important endpoints such as skin and respiratory sensitization, hepatotoxicity and elevated acute aquatic toxicity. These adverse effects are initiated by, among others, electrophilic chemicals and those transformed into electrophiles; i.e. non-reactive chemicals activated into reactive electrophilic species by either a biotransformation (pro-electrophiles) or abiotic mechanism (pre-electrophiles). The presence of pro- and pre-electrophiles is important when developing quantitative structure-activity relationships (QSARs). In this study, the reactivity of potential pre-electrophile polyphenolics was investigated using an in chemico assay based on glutathione (GSH) depletion; in addition, the toxicity to Tetrahymena pyriformis was determined. For pre-electrophiles, no direct relationship between toxic potency and reactivity to GSH was obtained. The structural determinants for the pre-electrophile domain were characterized qualitatively by assessing structure-activity relationships (SARs). From this analysis, structural alerts for the pre-Michael acceptor domain (i.e. non-reactive chemicals activated into Michael acceptors) were extracted from the in chemico GSH data. A series of 10 structural alerts corresponding to 1,2- and 1,4-hydroxy and amino-substituted aromatics was developed. The relevance of the alerts was assessed by investigating the aquatic toxicity of these compounds. The structural alerts should help to identify and group pre-Michael acceptors and thus potent reactive toxicants.

Activity of 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines to Tetrahymena

“…The protozoacidal activity of the analogues was found to be highly 25 dependent on a 4-hydroxyl group at the 6-aryl ring, and a chiral 1-phenylethanamine substituent in posi- 26 tion 4. Further, the potency was affected by the aromatic substitution pattern of the phenylethanamine: 27 the unsubstituted, the meta-fluoro and the para-bromo substituted derivatives had the lowest minimum 28 protozoacidal concentrations (8)(9)(10)(11)(12)(13)(14)(15)(16) lg/mL). Surprisingly, both enantiomers were found to have high 29 potency suggesting that this compound class could have several modes of action.…”

Interspecies quantitative structure–activity–activity relationships (QSAARs) for prediction of acute aquatic toxicity of aromatic amines and phenols

“…The fact that the coefficient for substructures represented by the indicator variable h was relatively high (1.33) indicates that the toxicity of these pre-Michael acceptors [3] is higher for algae than for fish, at least in the context of the current training datasets. The positive multi-regression coefficient for indicator variable a (= aromatic nitrogen; e.g.…”

“…Indicator variable d in Figure 1 includes not only substructures covered by indicator variable c, but also aromatic hydrazine and amide substructures. Indicator variables g and h take into account the position of the hydroxyl or amino groups; the latter covers the substructure for preMichael acceptors [3]. Note that indicator variable j in Figure 1 is identical to the 125th MACCS key.…”

“…However, some aromatic amines and phenols are not categorised as polar narcotic chemicals, either because they have relatively high reactivity or their structures are not defined by the Verhaar scheme. For example, 1,2-or 1,4-hydroxy-substituted and 1,2-or 1,4-amino-substituted aromatics (Figure 1, indicator variable h), have pre-Michael acceptor substructures [3] and can react with biological molecules; thus, these compounds show high toxicity to aquatic organisms. Ramos et al [4] showed that anilines are substantially more toxic to Daphnia magna than other polar narcotic chemicals, although the excess toxicity is low in the case of 2-substituted aromatic amines.…”

Repeatability analysis of theTetrahymena pyriformispopulation growth impairment assay

“…For these reasons, it is therefore of little surprise that catechol and hydroquinone also demonstrate poor repeatability (CoV 4 0.5) (Figure 4b). Both of these compounds are pre-electrophiles (phenols) and are readily oxidized to quinones, exhibiting extremely fast reactions and high toxic potencies [48]. 2-Butyn-1-ol, within the pre-electrophile (alcohol) group (Figure 4c), also showed very poor repeatability (CoV ¼ 0.57).…”