Nielsen, S F3; Christensen, S B5; Cruciani, G3; Kharazmi, A3; Liljefors, T3
1 Department of Psychology, Research School, Department of Psychology, Faculty of Social Sciences, Københavns Universitet2 Centre for Medical Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 SAXO-Institute - Archaeology, Ethnology, Greek & Latin, History, Faculty of Humanities, Københavns Universitet5 SAXO-Institute - Archaeology, Ethnology, Greek & Latin, History, Faculty of Humanities, Københavns Universitet
A large number of substituted chalcones have been synthesized and tested for antileishmanial and lymphocyte-suppressing activities. A subset of the chalcones was designed by using statistical methods. 3D-QSAR analyses using 67 (antileishmanial activity) and 63 (lymphocyte-suppressing activity) of the compounds for the training sets and 9 compounds as an external validation set were performed by using the GRID/GOLPE methodology. The Smart Region Definition procedure with subsequent region selection as implemented in GOLPE reduced the number of variables to approximately 1300 yielding 3D-QSAR models of high quality (lymphocyte-suppressing model, R2 = 0. 90, Q2 = 0.80; antileishmanial model, R2 = 0.73, Q2 = 0.63). The coefficient plots indicate that steric interactions between the chalcones and the target are of major importance for the potencies of the compounds. A comparison of the coefficient plots for the antileishmanial effect and the lymphocyte-suppressing activity discloses significant differences which should make it possible to design chalcones having a high antileishmanial activity without suppressing the proliferation of lymphocytes.
Journal of Medicinal Chemistry, 1998, Vol 41, Issue 24, p. 4819-32