ANTILEISHMANIAL CHALCONES - STATISTICAL DESIGN, SYNTHESIS, AND 3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS

A large number of substituted chalcones have been synthesized and test ed for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR a nalyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppres sing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE m ethodology. The Smart Region Definition procedure with subsequent regi on selection as implemented in GOLPE reduced the number of variables t o approximately 1300 yielding 3D-QSAR models of high quality (lymphocy te-suppressing model, R-2 = 0.90, Q(2) = 0.80; antileishmanial model, R-2 = 0.73, Q(2) = 0.63). The coefficient plots indicate that steric i nteractions between the chalcones and the target are of major importan ce for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing a ctivity discloses significant differences which should make it possibl e to design chalcones having a high antileishmanial activity without s uppressing the proliferation of lymphocytes.