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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. May 2007, Volume 6, Number 5, 122-134 |
Modeling Artemisinin Derivatives with Potent Activity against P. falciparum Malaria
with Ab Initio and PLS Methods
Fábio José B. Cardoso, Rodrigo Bandeira da Costa, Antonio Florêncio de Figueiredo, Jardel Pinto Barbosa, Ilfran Nava Jr., José Ciríaco Pinheiro, and Oscar Augusto S. Romero
Internet Electron. J. Mol. Des. 2007, 6, 122-134
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Abstract:
Artemisinin (Qinghaosu) is a sesquiterpene containing the 1,2,4-trioxane-ring
system and it has been used in China for treatment of P. falciparum malaria, a
disease responsible for approximately 2.7 million deaths per year. A number of
drugs have been investigated for their efficiency in treating malaria. However, the
new strains of P. falciparum resistant to some of those drugs resulted in further
investigation of new classes of compounds effective in treating malaria. HF ab initio
and PLS methods were used to design the new artemisinin derivatives.
Potent artemisinin derivatives, with activity against chloroquine sensitive P. falciparum
malaria are proposed in this paper. The PLS model with three
principal components explaining 98.5% of total variance, Q2 = 0.592 and R2 = 0.774,
was obtained for 14 molecules. The most important descriptors in the
QSAR model were LUMO+1 energy, Q10, TSA, A5, and MAXDP. Also, the MEP
maps for artemisinin and artemisinin derivatives show that the compounds have
similar MEP around the trioxane ring. From a set of eleven proposed artemisinin
derivatives, one new compound is predicted with antimalarial activity higher than
the reported compounds in literature. Based on the HF ab initio calculations, MEP
maps, and PLS QSAR models we propose for chemical synthesis and biological
testing new artemisinin derivatives.
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