Free-Wilson Method Research Articles

Antimycobacterial 2-Arylamino-2-Thioxoacetamides

A series of 13 2-arylamino-2-thioxoacetamides was tested against Mycobacterium tuberculosis and M. kansasii. Structure-activity relationships were analyzed quantitatively using the Free-Wilson method. Evaluation of the antimycobacterial profile with regard to equipotency of both activities was accomplished by means of a recently proposed method for evaluation of activity profile with respect to intended therapeutical use.

Antituberculotic 4'-Cyclohexylthiobenzanilides: Combination of Free-Wilson Method in QSAR with Topliss Approach

On the basis of a preliminary study of antimycobacterial activity of thiobenzanilides against Mycobacterium kansasii, a group of 4'-cyclohexylthiobenzanilids have been prepared which exhibit a significant activity against the microorganism mentioned. The whole set of 35 thiobenzanilides was tested with Mycobacterium tuberculosis, and on the basis of QSAR analysis conclusions have been made with regard to prognostics of structures suitable for further studies. The problem was solved by the method by Free and Wilson combined with the Topliss approach and by a Hansch type analysis.

Modified Free-Wilson method for the analysis of biological activity data

Abstract A general approach to the analysis of biological activity data in terms of molecular constitution has been proposed. The algorithm is closely related to that of Free & Wilson [ J. Med. Chem. 7 , 395 (1964)]. The biological activity or its transform is split into the sum of contributions characteristic of different positions (segments) of the molecule, the segment contributions , the contributions characteristic of pairs of segments, the interaction contributions , and possibly higher order terms. The contributions are to be determined from a given set of biological activity data by a linear least-squares method. The analysis of the solution space of the resulting system of linear equations reveals that additional constraints must be imposed on the contributions in order that the problem be well-defined. One of the possible choices is to assign a standard substituent to each position in the molecule and define the segment (interaction) contributions relative to those of the standard substituents (pairs of substituents). This choice assures that the values obtained do not change formally when particular compounds are added or removed from the data set. In contrast to this, in the traditional Free-Wilson approach the segment contributions are defined relative to the average of all the segment contribution in a given position over the data set analyzed and therefore are shifted when the data set is changed. An algorithm has also been developed which handles cases when additional linear dependences occur between the contributions. A numerical example is presented.

Antagonists as “Affinity Probes” for Peptide Hormone Receptors: Qsar Studies on Oxytocin Receptor in the Rat Myometrium

The use of competitive antagonists in receptor investigations has been based mainly on empirically established abilities to suppress biological effects of certain agonists. This information serves primarily for classification of receptors according to ligand specificities. Methods of quantitative structure-activity analysis can extend their use for investigations of preference substituent in the desired position, estimates of ligand-receptor affinities, etc., when a set of antagonists differing solely in the substituents in that position and characterized by their pA2 values, is available. In the case of a multiple substitution, contributions of single substituents on individual positions can be estimated by the Free-Wilson method and then subjected to correlation analysis. The approach is demonstrated on a group of oxytocin analogues acting as uterotonic inhibitors of oxytocin; the "intramolecular force" descriptors are used for correlation analysis.

Factor analysis of in vitro antitumor activities of platinum complexes.

Factor analysis was applied to the data matrix of in vitro growth inhibitory activities of 52 platinum complexes against 9 tumor cell lines, L1210, P388, Lewis lung, AH66, AH66F, HeLa S3, KB, HT-1197 and HT-1376 cell lines. Three factors were obtained by the principal factor analysis method. After the varimax rotation of these three factors, tumor cell lines were classified into four groups according to their factor loadings. The platinum complexes were characterized by the factor scores. Cisplatin was situated in an extreme position as compared with the other platinum complexes. In vivo antitumor activities of the platinum complexes were tested against L1210 and LL murine tumor models. The in vivo activity against L1210 showed a negative correlation with that against LL. Factor 2 scores of the complexes obtained by factor analysis of in vitro antitumor activities showed a good correlation with these in vivo antitumor activities. Then, the structure-factor 2 score relationships among platinum complexes were analyzed by the Free-Wilson method. From this analysis, structure-activity relationships for carrier ligands and leaving groups are proposed. Factor analysis is suggested to be a useful method to establish an efficient screening system for platinum complexes.

Substituent-Group Effects on the Fluorescence of Aluminum–Schiff Base Complexes and Their Application to the Determination of Aluminum

Abstract The effects of the substituents in the Schiff-base N-salicylidene-o-aminophenol (SOAP) on the fluorescence of its aluminum complexes were investigated. N,N′-Disalicylideneethylenediamine (DSED) derivatives were used as aldehyde reagents for the condensation to prepare 25 different SOAP compounds, for these reagents can be conveniently hydrolyzed to yield salicylaldehyde derivatives. o-Aminophenol (OAP) derivatives were used as amine reagents for the SOAP compounds. A methoxyl group at the 4-position of the benzylidene group in the Schiff base and a sulfo group at the 5-position in the amine component increased the fluorescence intensity of the complex. The relationship between the fluorescence intensity and the structure of the complex was investigated by the Free-Wilson method of estimation, and good agreements were obtained between the experimental and the calculated values of the fluorescence intensities. The fluorometric determination procedure of aluminum was established by using 4,4′-dimethyl DSED and 4-sulfo OAP. Aluminum can be accurately determined in the range from 0.001 to 3 μg/25 ml under optimum conditions.

Quantitative relationships between chemical structure and technical properties of 4-aminoazobenzene sulphonic acid dyes

A series of new 4-aminoazobenzene dyes was synthesised. Absorption maxima and some important technical properties (lightfastness and fastness to washing) on nylon-6.6 and on wool were measured. A number of similar previously described structures were also prepared and characterised. Colour and constitution relationships in this series of dyes were established. A statistical analysis of their fastness properties by a modified Free-Wilson method was carried out. The validity of the additive model was confirmed and quantification of substituent contributions was obtained.

Application of the Free-Wilson technique to structurally related series of homologues. Quantitative structure-activity relationship studies of narcotic analgetics.

A series of benzomorphans with ED50 values determined in vivo by the hot-plate method in mice is analyzed by the modified Free-Wilson method. The QSAR yields 36 substituent constants (ai) with contributions to the overall activity in agreement with experimental data. Substituent constant values obtained for benzomorphans are used in calculating log (1/C) values for six morphinans. An excellent correlation is obtained (r = 0.95) between the six calculated and observed activities. The possibility of extending the Free-Wilson approach from one series of homologues to another is demonstrated.