MOLECULAR LIPOPHILIC POTENTIAL ON VAN-DER-WAALS SURFACES AS A TOOL INTHE STUDY OF 4-ALKYLPYRAZOLES

A new method for the calculation and analysis of lipophilic properties on molecular surfaces is presented. In this method, both, the concept of molecular lipophilic potential developed by Audry and co-workers a nd the approach of Ghose and Crippen implying that the hydrophobicity of a molecule can be obtained as the sum of certain atomic contributio ns, are combined. Then, shape analysis methodology is applied to chara cterize the interrelation between this molecular lipophilic potential and the van der Waals surfaces of a family of pyrazoles, which are kno wn inhibitors of the enzyme liver alcohol dehydrogenase. In this study graphical representations and analytical methods are used. The mentio ned topological analysis provides certain codes which combine lipophil ic and steric information and are unique and characteristic of each py razole. These three-dimensional codes were correlated with the inhibit ory activity of this series of pyrazoles. The inhibitory power of 4-is opentylpyrazole was not known experimentally before this study was car ried out. Thus, by using these combined codes, the inhibitory activity of the isopentyl derivative was suggested to be lower than that of it s linear isomer. This hypothesis was confirmed after the synthesis of 4-isopentylpyrazole and its enzymatic evaluation.