From the manual method of Topliss to a modified quantitative method.
The optimization of the properties of a lead compound is the first goal of most pre-clinical research projects. Optimization strategies may be applied to the synthesis of analogous compounds in order to minimize cost and time. One strategy of synthesis is the change of the substituents in the molecule. The manual method of Topliss was introduced for the prediction of the substituted compounds that will have the most potent activity in a series of aromatic substituted analogues. A modified Topliss method is proposed that consist of the quantitative correlation by a single regression equation of the activity of a series of 4 or 5 substituted aromatic compounds with the descriptor parameters: hydrophobic (pi), electronic (sigma) and sterics (Es and MR) and some combinations of them in order to predict future synthesis, or to obtain a training set of compounds to be used in the application of more advanced experimental design methods. These results when compared with those of multiple regression analysis applying the Hansch equation are very satisfactory.
Yunes
Rosendo A
RA
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, Brazil. ryunes@qmc.ufsc.br
Heinzen
Vilma E Fonseca
VE
Cechinel Filho
Valdir
V
Lazzarotto
Marcelo
M
D015195:Drug Design; D010600:Pharmacology / Q000379:methods*; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis