Structure–activity relationships for aquatic toxicity to Tetrahymena: Halogen‐substituted aliphatic esters

Abstract

The toxicity of a series of 21 mono- and dihalogenated aliphatic monoesters has been evaluated using a Tetrahymena pyriformis population growth impairment assay. A structure-activity model has been developed for toxicity data (log(IGC50(-1))), using the 1-octanol/water partition coefficient (logKow) and the energy of the lowest unoccupied molecular orbital (ELUMO) as descriptors. A statistically robust plane (log of the inverse of the 50% growth inhibitory concentration (IGC50(-1)) = 0.34logKow - 0.84 (ELUMO) + 0.04; n = 15, r2 = 0.85, s = 0.26, F = 33, Pr > F = 0.0001) was found for monohalogen-substituted derivatives. These substances are thought to exhibit toxicity via the soft electrophilic mode of toxic action. This toxicity is imparted by the leaving ability of the halogen, which is enhanced when it is placed in close proximity to the carbonyl group. This leaving ability allows haloesters, especially alpha-haloesters, to undergo an SN2, addition-elimination substitution electro(nucleo)philic reaction. Outliers to the above model broadly fell into two groups: small reactive molecules (e.g., propylbromoacetate) that were more toxic than predicted and molecules in which the reactive center was sterically hindered by an alkyl group (e.g., ethyl-2-bromoisovalerate), which were less toxic than predicted.

Halogenated ligands and their interactions with amino acids: Implications for structure–activity and structure–toxicity relationships

“…Analysis of the interactions of each of the halogen types with their hydrogen bonding amino acids and water molecules indicated that bromine and iodine, due to their weaker electronegativity, could be considered better leaving groups and hence should be more toxic. This suggestion is consistent with the finding that addition of bromine atoms to haloesters increased the toxicity of the compound [24].…”

“…However, the presence of halogen bonds between the halogenated ligand and donor atoms significantly alters its affinity to the target protein receptor [23]. In fact, there is strong evidence that ahaloesters, when placed in close proximity to carbonyl groups, exhibit greater toxicity due to the increased ''leaving'' ability of the halogen atom [24]. This study also confirmed that increasing the number of halogen atoms altered the mechanism of toxic action from being baseline narcosis to that of direct electrophilicity [24,25], which concurs with our present results.…”

“…In fact, there is strong evidence that ahaloesters, when placed in close proximity to carbonyl groups, exhibit greater toxicity due to the increased ''leaving'' ability of the halogen atom [24]. This study also confirmed that increasing the number of halogen atoms altered the mechanism of toxic action from being baseline narcosis to that of direct electrophilicity [24,25], which concurs with our present results. Specifically, we found that the interaction parameters such as mean distance and angle of interaction between the halogen with nitrogen atoms differed significantly from that with oxygen atoms ( Table 2).…”

In silicoprediction of the aniline derivatives toxicities toTetrahymena pyriformisusing chemometrics tools

“…Thus, it is necessary to develop alternative methods and tools, such as in silico techniques for toxicity prediction, especially as a Level 1 screening for hazard potentials. Development of predictive models in the form of quantitative structure-toxicity relationships (QSTRs) as powerful tools to rapidly estimate and predict toxicity offers to fill data gaps in environmental risk assessment and regulatory concerns (De Weese and Schultz 2001). The use of QSTR has become increasingly helpful in understanding chemical-biological interactions in the areas of toxicology.…”

QSTR with extended topochemical atom (ETA) indices. 14. QSAR modeling of toxicity of aromatic aldehydes to Tetrahymena pyriformis

“…The toxicological experimentation and generation of data thereof is often time consuming and costly too. Development of predictive models in the form of quantitative structure-activity relationships (QSARs) offers a good opportunity to fill data gaps in environmental risk assessment and regulatory concerns in such cases [5]. QSAR uses chemical toxicity data of comparatively less number of compounds to predict the toxicity of a large number of compounds.…”