Artemisinin Derivatives with Antimalarial Activity against Plasmodium falciparum Designed with the Aid of Quantum Chemical and Partial Least Squares Methods Jose ¬ C. Pinheiro*, Rudolf Kiralj, Ma ¬rcia M. C. Ferreira** Laborato ¬rio de Quimiometria Teo ¬rica e Aplicada, Instituto de QuÌmica, Universidade Estadual de Campinas, 13083-974 Campinas, SP, Brazil Oscar A. S. Romero Departamento de QuÌmica, Centro de Cie √ncias Exatas e Naturais, Universidade Federal do Para ¬, 66075-110 Bele ¬m, PA, Brazil Full Paper Artemisinin derivatives with antimalarial activity against Plasmodium falciparum resistant to mefloquine are designed with the aid of Quantum Chemical and Partial Least Squares Methods. The PLS model with three principal components explaining 89.55% of total variance, Q 2  0.83 and R 2  0.92 was obtained for 14/5 molecules in the training/external validation set. The most important descriptors for the design of the model were one level above the lowest unoccupied molecular orbital energy (LUMO  1), atomic charges in atoms C9 and C11 (Q 9 ) and (Q 11 ) respectively, the maximum number of hydrogen atoms that might make contact with heme (NH) and RDF030 m (a radial distribution function centered at 3.0 ä interatomic distance and weighted by atomic mass- es). From a set of ten proposed artemisinin derivatives, a new compound (26), was predicted with antimalarial activity higher than the compounds reported in literature. Molecular graphics and modeling supported the PLS results and revealed heme-ligand and protein-ligand stereoelectronic relationships as important for antimalarial activity. The most active 26 and 29 in the prediction set possess substituents at C9 able to extend to hemoglobin exterior, what determines the high activity of these compounds. 1 Introduction Malaria has been known since ancient times. Hippocratic in his writings had already mentioned different manifestations of that disease as the enlargement of the spleen [1]. At the present time, some 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. There are four members of the Plasmodium gender that infect humans and all are transmitted through the bite of the Anofeles female mosquito. Most of the deaths are attributed to the parasite species falciparum. The severity of the disease caused by this species results primarily from its ability to modify the surface of infected red blood cells by inserting parasite proteins [2]. The enzymes in parasite digestive vacuole (cysteine and aspartic proteinases) break down hemoglobin into amino-acids and heme [3]. While all amino-acid contents is used for building parasite proteins, only a small portion of heme is incorporated into parasite hemoproteins; the rest of heme is detoxified (polymerized) caused by parasite enzymes [4]. A number of drugs have been investigated for their efficacy in the treatment of malaria [5], however, the appearance of resistant strains of falciparum to some of those drugs has made necessary further investigation of new classes of compounds which might have effective action against them [6 ± 10]. Also, computational [5, 11 ± 13] and quantitative structure-activ- ity relationship (QSAR) studies [6, 8, 14 ± 18] of any of those 830 QSAR Comb. Sci. 22 (2003) DOI: 10.1002/qsar.200330829 ¹ 2003 WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim * Permanent address: Laborato¬rio de QuÌmica Teo¬rica e Compu- tacional, Centro de Cie√ncias Exatas e Naturais, Universidade Federal do Para¬, 66075-110 Bele¬m, PA, Brasil ** Corresponding author: Laborato ¬rio de Quimiometria Teo ¬rica e Aplicada, Instituto de QuÌmica, Universidade Estadual de Campinas, 13081-970 Campinas, SP, Brasil; E-mail: marcia@iqm.unicamp.br; Phone:  551937883102; Fax:  551937883023 Key words: Artemisinin derivatives, Antimalarial activity, Plas- modium falciparum, Quantum Chemical Methods, PLS, QSAR, Molecular Graphics and Modeling J. C. Pinheiro et al. & Combinatorial Science