Modelling physico-chemical properties of halogenated benzenes: QSAR optimisation through variables selection.

Abstract This paper describes the development of multivariate QSAR models for halogenated benzenes. Four physico-chemical properties have been modelled: Boiling Point (BP), Melting Point (MP), Flash Point (FP) and Density (D). For the multivariate characterisation of this class of compounds 90 topological indices derived from the chemical formula were used. The models were calibrated on training sets selected by a D-optimal design and were optimised by a statistical procedure of selection of the most informative variables. The predictive capacity of the resulting models measured in terms of the parameter SDEP (Standard Deviation of the Errors of Predictions) were as follows; MP: ± 21 ±C (with MP ranging from -48° to 181°C); BP: ±13°C (75° to 286°C); D: ±0.14 (1.02 to 2.52 g/cm(3)); FP: ±17°C (-12 to 126°C). These data were confirmed "experimentally", i.e., on external validation sets of compounds, the experimental values of the standard deviation of prediction errors were in fact as follows; MP: ±30°C; BP: ±16°C D: ±0.18 g/cm(3); FP: ±16°C. The developed models therefore provide a valuable tool for estimating physico-chemical properties relevant to environmental chemistry.

QSARs and pesticides design.

A multivariate analysis of phytotoxicity and measured ecotoxicity data of a set of 30 herbicidal triazines was carried out. Results indicate that it is feasible to design triazines that combine limited ecotoxicity with high herbicidal potency.

Herbicidal triazines: acute toxicity on Daphnia, fish, and plants and analysis of its relationships with structural factors.

The 24- and 48-hr EC50 immobilization test of Daphnia magna has been performed on 14 herbicidal triazines characterized by structural differences with respect to the substituent groups at the three carbon atoms in the s-triazinic ring. EC50 values of the tested compounds were found to vary within a factor of 6 to 7; such variations of toxicity have been analyzed in terms of structural variations concerning (i) the type of substituents, i.e., Cl, SCH3, or OCH3, at the carbon atom C-2, and (ii) the number and size of the alkyl groups at the aminic nitrogen atoms bound to the ring carbons C-4 and C-6. Literature data relative to the acute toxicity of the considered herbicides on fish and plants were also analyzed with reference to the above structural features. The possibility that separate contributions to toxic effects of triazines are provided by specific groups bound to the common structural moiety, constituted by the 1,3,5-triazinic ring, is examined and discussed.

Approaches to modeling toxic responses of aquatic organisms to aromatic hydrocarbons.

Acute toxic effects on Salmo gairdneri, Poecilia reticulata, Daphnia magna, and the growth inhibition of Selenastrum capricornutum were measured for eight aromatic hydrocarbons. Toxicity measurements were carried out following the OECD standard guidelines modified as appropriate in order to prevent hydrocarbon loss by volatilization; the concentrations of the substrates in the test solutions were periodically measured by HPLC. The toxic responses were analyzed in terms of the n-octanol/water partition coefficients, by means of linear regression analysis, and in terms of five molecular properties simultaneously, by means of the partial least squares analysis in latent variables (PLS). The univariate and multivariate quantitative structure-activity relationship models obtained by the two approaches are compared and discussed.

Effects of buffer composition on water stability of alkylating agents. The example of N-ethyl-N-nitrosourea.

The half-life of N-ethyl-N-nitrosourea (ENU) in water solution was measured at pH 6.1, 6.8 and 7.3 using buffer systems characterized by differences in quality and quantity of the component species. The decay of the concentration of ENU as a function of time was detected both indirectly, by measuring its residual capability of inducing alkali-labile sites in CHO DNA, and directly, by measuring its residual concentration by means of 1H-nmr spectroscopy. Under controlled pH, temperature, and buffering conditions, the rate of hydrolytic loss of ENU measured by the biological and chemical experiments compared quite well, whereas at constant pH and temperature, it was substantially dependent upon the concentration of the buffer. This was attributed to the occurrence of general base catalysis promoted by the nucleophilic anions present in the buffer systems. This conclusion, largely supported by analysis of previously reported data concerning the kinetics of ENU in water, suggests that buffering conditions may play a role in determining the actual levels of reactive substrates in in vitro assays and, therefore, that different buffering conditions may lead to poorly reproducible results.