EFFECT OF BRANCHING IN 4-ALKYLPYRAZOLES ON LIVER ALCOHOL-DEHYDROGENASE INHIBITION - A SHAPE-ANALYSIS STUDY

Shape analysis methodology is applied to the study of 4-alkylpyrazoles which are known inhibitors of liver alcohol dehydrogenase. Elongation of the alkyl chain increases the inhibitory power, whereas branching of the chain diminishes the activity. These two counterpoised effects are studied simultaneously in a selected set of 4-alkylpyrazoles. A sy stematic conformational analysis followed by topological characterizat ion of the van der Waals surfaces of all the local minima restricts th e conformational space to potential bioactive structures. The analysis of the interrelation between the molecular electrostatic potential an d van der Waals surfaces provides certain shape codes characteristic o f each 4-alkylpyrazole. In both topological analyses (van der Waals su rfaces and molecular electrostatic potential-van der Waals surface int errelations) graphical representations and analytical methods were use d. A good correlation between the shape codes and the inhibitory activ ity is found for the linear derivatives. For branched pyrazoles, a ten dency in their inhibitory power is predicted. Isopentylpyrazole is sug gested to have the same inhibitory profile as 4-butylpyrazole, the lin ear derivative with one less carbon atom.