Prediction of Lipophilicity and Pharmacokinetics of Chloroacetamides by Chemometric Approach.

In this study, the existence of biological potential of selected N-(substituted phenyl)-2-chloroacetamides was examined none empirically, as was the possibility of applying simple experimental technique in predicting essential properties which affect the biological activity of the compounds. By applying the Lipinski and Ghose's rules, it has been revealed that the examined chloroacetamides fulfill the theoretical requirements for bioactive compounds. In addition, lipophilicity was determined by applying the reversed-phase thin-layer chromatography (RPTLC18F254s) in the mixtures of water and two organic modifiers separately (methanol and acetone) and by using relevant software packages. The chromatographic retention parameters, RM0 and m, as the presumed criteria for the lipophilicity of the examined chloroacetamides were correlated by linear regression analysis, and the relevant chemometric methods (Cluster Analysis and Principal Component Analysis) with the standard measure of lipophilicity, log P, and with the selected pharmacokinetic predictors. Thus good correlations in both water-modifier systems (average correlation coefficients, r , 0.947 and 0.931) were obtained. The chemometric methods, as well as the classical correlation methods gave similar results which demonstrated that the chromatographic retention parameters, RM0 and m, can successfully describe the lipophilicity and the pharmacokinetics of the N-(substituted phenyl)-2-chloroacetamides in the first steps of preclinical research.

Multivariate assessment of azo dyes' biological activity parameters.

Lipophilicity as key molecular descriptor of potential biological activity for selected derivatives of azo dyes was determined mathematically, by using relevant software packages and by reversed-phase thin-layer chromatography (RPTLC) on C18 and cyano modified carriers in mixtures of water/n-propanol and water/acetone. The obtained chromatographic parameters, RM0 and m, of the examined azo dyes were correlated with the standard measure of lipophilicity, log P, important pharmacokinetic predictors and selected toxicity parameters applying linear regression analysis. Thereby, good correlations for each applied system were obtained (average correlation coefficient, r, 0.944, 0.885 and 0.919). Also, the correlations between the studied parameters of azo dyes were examined applying two multivariate methods (Cluster Analysis and Principal Component Analysis). It was shown that the polarity of the substituent, and to a lesser extent its electronic effects has the greatest influence on the studied parameters of the azo dyes derivatives. Multivariate methods pointed out the similarity of the chromatographic retention constant, RM0, with the parameters of lipophilicity, unlike the chromatographic parameter m, which exhibits better agreement with the toxicity parameters.

Establishing dependences between different lipophilic parameters of new potentially biologically active N-substituted-2-phenylacetamide derivatives by applying multivariate methods.

Lipophilicity, a very important parameter in the potential biological activities of molecules, was investigated for newly synthesized N-substituted-2-phenylacetamide derivatives. The determination was carried out in two ways: first experimentally, by applying thin-layer chromatography (TLC) on reversed-phase TLC (RPTLC) RP18F254s in the presence of one protic (methanol) and one aprotic solvent (acetonitrile) and then mathematically, by using different software packages. The intercept of the linear dependence between volume fractions of the organic solvent and the retention parameters obtained by TLC is known as the retention chromatographic constant, R(M)(0), while the slope represents the m value. In order to establish the dependences between the partition coefficient, log P as the standard measure of lipophilicity and the alternative lipophilic parameters obtained experimentally by TLC, R(M)(0) and m values, linear regression analysis and multivariate methods, cluster analysis (CA) and principal component analysis (PCA), were used. All applied methods gave approximately similar results. Although there is a linear dependence between the two chromatographic parameters, the retention constant, R(M)(0), and the m values, only R(M)(0) shows suitable similarity with the standard measure of lipophilicity of the investigated N-substituted-2-phenylacetamide derivatives at the given conditions. The existence of this resemblance proves that the chromatographic retention constant, R(M)(0), obtained by RPTLC could be successfully used for the description of lipophilicity of investigated compounds. On the other hand, the results confirmed that the applied linear regression analysis and the multivariate analysis (CA and PCA) have the ability to compare lipophilic parameters of the investigated phenylacetamide derivatives obtained in different ways.

Solvent and structural effects on the UV absorption spectra of N-(substituted phenyl)-2-cyanoacetamides.

UV absorption spectra of N-(substituted phenyl)-2-cyanoacetamides have been recorded in the range 200-400 nm in the set of selected solvents. The solute-solvent interactions were analyzed on the basis of linear solvation energy relationships (LSER) concept proposed by Kamlet and Taft. The effects of substituents on the absorption spectra were interpreted by correlation of absorption frequencies with Hammett substituent constant, σ. It was found that substituents significantly change the extent of conjugation. Furthermore, the experimental findings were interpreted with the aid of ab initio B3LYP/6-311G(d,p) method. Electronic energies was calculated by the use of 6-311++G(3df,3pd) methods with standard polarized continuum model (PCM) for inclusion of the solvent effect.

Multivariate analysis of chromatographic retention data and lipophilicity of phenylacetamide derivatives.

One of the most important physicochemical parameters of a molecule that determines its bioactivity is its lipophilicity. Cluster analysis (CA), principal component analysis (PCA), and sum of ranking differences (SRD) were used to compare the lipophilic parameters of twenty phenylacetamide derivatives, obtained experimentally as chromatographic retention data in the presence of different solvents and calculated by different mathematical methods. All the applied methods of multivariate analysis gave approximately similar grouping of the studied lipophilic parameters. In the attempt to group the investigated compounds in respect of their lipophilicity, the obtained results appeared to be dependent on the applied chemometric method. The CA and PCA, grouped the compounds on the basis of the nature of the substituents R1 and R2, indicating that they determine to a great extent the lipophilicity of the investigated molecules. Unlike them, the SRD method could not be used to group the studied compounds on the basis of their lipophilic character.