Work

Fluorine-containing compounds are the important objects of medicinal chemistry which are currently under active study. In particular, in the recent years the focus of drug developers have been shifted to fluorinated cycloalkanes as the "building blocks" for biologically active molecules. This is due to the lack of representation of non-flat, "three-dimensional" molecules among the previously studied compounds in comparison to aromatic compounds, which are characterized by the dominance of planar cycles. Recently, some unusual correlations have been found between the lipophilicity of fluorinated cycloalkylamides and the number of fluorine atoms introduced into a molecule. For instance, the lipophilicity of methylamides does not change linearly depending on the number of hydrogen atoms in it, substituted by fluorine, but is characterized by a minimum for monofluoro-substituted compounds. A similar pattern was also found for the acidity constants of such amines. This complex nature of the dependence indicates that the additive method of calculating physicochemical parameters is insufficient to predict such parameters even for relatively small molecules. We believe that a more reliable prediction can be made (a) by considering conformations of the molecule instead of its structure only, and (b) including in the calculation the conformational ensemble present in the solution, instead of choosing only the most stable conformation. Using the methods of chemoinformatics and quantum chemistry, we plan to develop a procedure for rapid generation, clustering and filtering of possible conformers and accurate calculation of their physicochemical parameters. The aim of this work is to study the relationship between the structure of fluorine-containing cycloalkylamides and their physicochemical properties, in particular lipophilicity. The proposed theoretical study will allow prediction of these values for previously unknown compounds with high accuracy.