Predicting the Genotoxicity of Thiophene Derivatives from Molecular Structure

Abstract

We report several binary classification models that directly link the genetic toxicity of a series of 140 thiophene derivatives with information derived from the compounds' molecular structure. Genetic toxicity was measured using an SOS Chromotest. IMAX (maximal SOS induction factor) values were recorded for each of the 140 compounds both in the presence and in the absence of S9 rat liver homogenate. Compounds were classified as genotoxic if IMAX >or= 1.5 in either test or nongenotoxic if IMAX < 1.5 for both tests. The molecular structures were represented by numerical descriptors that encoded the topological, geometric, electronic, and polar surface area properties of the thiophene derivatives. The classification models used were linear discriminant analysis (LDA), k-nearest neighbor classification (k-NN), and the probabilistic neural network (PNN). These were used in conjunction with either a genetic algorithm or a generalized simulated annealing to find optimal subsets of descriptors for each classifier. The quality of the resulting models was determined by the number of misclassified compounds, with preference given to models that produced fewer false negative classifications. Model sizes ranged from seven descriptors for LDA to three descriptors for k-NN and PNN. Very good classification results were obtained with all three classifiers. Classification rates for the LDA, k-NN, and PNN models were 80, 85, and 85%, respectively, for the prediction set compounds. Additionally, a consensus model was generated that incorporated all three of the basic model types. This consensus model correctly predicted the genotoxicity of 95% of the prediction set compounds.

Scientific Opinion on Flavouring Group Evaluation 76, Revision 1 (FGE.76Rev1): Consideration of sulphur‐containing heterocyclic compounds evaluated by JECFA (59th meeting) structurally related to thiazoles, thiophene, thiazoline and thienyl derivatives from chemical group 29 and miscellaneous substances from chemical group 30 evaluated by EFSA in FGE.21Rev3

“…2-Acetylthiophene .040] was negative in microbial tests, using Salmonella typhimurium strains TA98 and TA100, with and without metabolic activation and in the SOS chromotest with metabolic activation. 2-Acetylthiophene was reported to be positive without metabolic activation in the SOS Escherichia coli chromotest (Mosier et al, 2003). In the same study, 2-acetyl-3-methylthiophene .037], thiophene-2-carbaldehyde .107] and 5-ethylthiophene-2-carbaldehyde [FL-no: 15.074] gave positive results without metabolic activation in the SOS E. coli chromotest.…”

Scientific Opinion on Flavouring Group Evaluation 21, Revision 5 (FGE.21Rev5): Thiazoles, thiophenes, thiazoline and thienyl derivatives from chemical groups 29 and 30

“…2-Acetylthiophene was reported to be positive without metabolic activation in the SOS Escherichia coli chromotest (Mosier et al, 2003). In the same study, the structurally related 2-acetyl-3-methylthiophene former In the second experiment, the concentrations of 2-acetyl-2-thiazoline .010] used in all strains in the absence and presence of S9 mix were 156.3, 312.5, 625.0, 1250, 2500 and 5000 µg/plate of 2-acetyl-2-thiazoline, and the pre-incubation method was used for treatments in the presence of S9.…”

Scientific Opinion on Flavouring Group Evaluation 93, Revision 1 (FGE.93Rev1): Consideration of sulphur containing heterocyclic compounds evaluated by JECFA (68th meeting) structurally related to thiazoles, thiophene, thiazoline and thienyl derivatives evaluated by EFSA in FGE.21Rev3

“…SOS Chromotest E. coli NR Negative with rat S9, positive without rat S9 (Mosier et al, 2003) Study endpoint inappropriate for the estimation of genotoxic potential. (Lee et al, 1994) Only two strains used but otherwise acceptable study.…”