14.
Kiralj R., Ferreira M. M. C., Pinheiro J. C., Romero O. A. S., “Combined QSAR, molecular graphics and modelling study on some C9, C10-substituted artemisinins with antimalarial activity against Plasmodium falciparum”. Bournemouth, United Kingdom, 08-13/09/2002: 14th European Symposium on QSAR: Designing Drugs and Crop Protectants - processes, problems and solutions, Proceedings, Session 5 Posters, Eds. M. Ford, D. Livingstone, J. Dearden, H. Van de Waterbeemd, Blackwell Publishing Ltd., Oxford, UK, pp. 308-310 (2003).
[Extended Abstract. More information about the meeting see at Notes.]

Abstract (from the Book of Abstracts).
At the present time, it is estimated that 40% of the world’s population is exposed to the risk of contracting malaria, and that every year about 2.7 million people die in consequence of that disease. The appearance of resistant strains of Plasmodium falciparum to some of drugs in common clinical usage has made necessary further investigation of new classes of compounds as artemisinin and its derivatives. The mechanism of artemisinin antimalarial activity includes heme-catalyzed artemisinin activation into a very reactive radical, which then could covalently bind to parasite proteins, heme, hemozoin, reduced glutathione or other parasite molecule. QSAR study [1] on 17 antimalarial C9, C10-substituted artemisinins against Plasmodium falciparum (biological activities from literature [2, 3]) was performed by means of quantum chemical (ab initio HF/6-31G* level), chemometric (Principal Component and Hierarchical Cluster Analyses, Partial Least Squares Regression) and molecular graphics and modeling methods. Prediction of antimalarial activities for 10 proposed C9, C10-substituted artemisinins was performed. Docking of some artemisinins to heme and hemoglobin, as well as structural studies on heme-receptor complexes, was carried out also. The PLS model with four latent variables explaining 91.61% of logIC50 variance (Q2 = 0.95 and R2 = 0.96) was obtained. Molecular descriptors were LUMO+1 energy, atomic charges in C9 and C10, the maximum number of hydrogen atoms that might make contacts with heme, and a WHIM-3D index related to molecular symmetry. Two from ten proposed artemisinin derivatives were predicted with antimalarial activities higher than the compounds reported in literature. The docking confirmed the PLS results and gave more insight into the nature of heme-artemisinin and hemoglobin-artemisinin interactions, and made it possible to explain why some artemisinins can be highly active.
[1] Pinheiro J. C., Ferreira M. M. C., Kiralj R., Reis R. M, Romero O. A. S. Submitted for
publication
[2] Acton N., Karle J. M., Miller R. E. J. Med. Chem. 1993; 36: 2552-7.
[3] Acton N., Klayman D. L. Planta Med. 1987; 53: 266-8.

Keywords.

Keywords Plus.