Application of Hansch's Model to Guaianolide Ester Derivatives:  A Quantitative Structure−Activity Relationship Study

Abstract

A quantitative structure−activity study to evaluate the effect of lipophilia/aqueous solubility on etiolated wheat coleoptiles elongation has been carried out with 34 guaianolides having different numbers of hydroxyl groups and ester side chains of variable length and structure: linear, branched, aromatic, and unsaturated. Compounds have been tested in a range of concentrations between 10 and 1000 μM. Data show a strong influence of lipophilia, expressed as log P values. Specially, data from alkylic side chain ester derivatives adjust to the mathematical model based on Hansch's transport theory; hence, a quantitative structure−activity relationships (QSAR) correlation with a high degree of reliance is provided. Moreover, all active compounds fit the Lipinski's rule of five. Also, the presence of additional hydroxyl groups and their derivatives in the basic skeleton does not affect the mode of action but greatly influences the activity, as they modify the transport through membranes and aqueous phases. Finally, a second hydroxyl group enhances differences of activity between alkylic side chain derivatives by increasing differences in van der Waals interactions. Keywords: Guaianolide; sesquiterpene lactones; acyl derivatives; isozaluzanin C; 5α-hydroxyisozaluzanin C; wheat etiolated coleoptile; QSAR; Hansch's transport model; Lipinski's rule of five; log P; lipophilia; aqueous solubility; membranes