Reactivity-based toxicity modelling of five-membered heterocyclic compounds: application to Tetrahymena pyriformis.
A diverse set of 57 heterocyclic organic chemicals, consisting of a five-membered unsaturated ring of four carbon atoms and one oxygen (furans), or sulfur (thiophenes), or nitrogen (pyrroles) were evaluated for reactivity with thiol and acute aquatic toxicity assays using glutathione (GSH) as a model nucleophile and the ciliate Tetrahymena pyriformis, respectively. Reactivity was quantified by the RC₅₀ value, the concentration of test compound that produced 50% reaction of the GSH thiol groups in 2 hours. Under standard conditions, RC₅₀ values are mathematically proportional to reciprocal rate constants. Toxicity was quantified by the IGC₅₀, the concentration of the test compound that produces 50% inhibition of population growth in 40 hours. Pyrroles with polarized α,β-unsaturated substructures were found to be non-reactive with GSH and did not exhibit excess toxicity in the Tetrahymena assay. In contrast, those furans and thiophenes with polarized α,β-unsaturated substructures were reactive with GSH via the Michael addition mechanism and did exhibit excess acute aquatic toxicity in Tetrahymena. For furans and thiophenes, reactivity and toxicity varied with the number, type, and location on the ring of the π-bond-containing polarized moieties. Comparisons of reactivity and toxicity potency between furan and thiophene derivatives revealed furans to be twice as potent as thiophenes. QSAR analysis revealed that aquatic toxicity IGC₅₀ to Tetrahymena is correlated with RC₅₀ values: log (IGC₅₀(-1)) = 1.13 log (RC₅₀(-1)) + 1.43; n = 23, r²= 0.815, r²(adj) = 0.806, s = 0.41, F = 92.
The University of Tennessee, College of Veterinary Medicine, Department of Comparative Medicine, Knoxville, TN, USA.
T W
TW
Schultz
C L
CL
Sparfkin
A O
AO
Aptula
D005663:Furans / Q000737:chemistry / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000633:toxicity*; D008954:Models, Biological; D008956:Models, Chemical; D011758:Pyrroles / Q000737:chemistry / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D013769:Tetrahymena pyriformis / Q000187:drug effects* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*; D014874:Water Pollutants, Chemical / Q000737:chemistry / Q000633:toxicity*
D005663:Furans; D006571:Heterocyclic Compounds; D011758:Pyrroles; D013876:Thiophenes; D014874:Water Pollutants, Chemical; D005978:Glutathione