Antileishmanial Chalcones:  Statistical Design, Synthesis, and Three-Dimensional Quantitative Structure−Activity Relationship Analysis

• Published in: Journal of medicinal chemistry Vol. 41; no. 24; pp. 4819 - 4832
• Main Authors: Nielsen, Simon Feldbæk, Christensen, Søren Brøgger, Cruciani, Gabriele, Kharazmi, Arsalan, Liljefors, Tommy
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.11.1998; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Cell Division - drug effects; Chalcone - analogs & derivatives; Chalcone - chemical synthesis; Chalcone - chemistry; Chalcone - pharmacology; Chemistry, Medicinal; Humans; In Vitro Techniques; Inhibitory Concentration 50; Leishmania donovani - drug effects; Life Sciences & Biomedicine; Lymphocytes - cytology; Lymphocytes - drug effects; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Reproducibility of Results; Science & Technology; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; POTENT ACTIVITY; LEISHMANIASIS; GOLPE; QSAR; PLS; Kinetoplastida; Human; Cell proliferation; Protozoa; Leishmania donovani; Benzene derivatives; In vitro; Modeling; Antiprotozoal agent; Three dimensional model; Structure activity relation; Parasiticid; Molecular model; Phenols; Inhibition; Chemical synthesis; Enone; Lymphocyte; Promastigote
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980410m

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, R 2 = 0.90, Q 2 = 0.80; antileishmanial model, R 2 = 0.73, Q 2 = 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.