期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 9, 页码 4184-4191出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.06.021
关键词
Malaria; Plasmodium falciparum; Phenoxquinazolines; Trichloromethyl group
资金
- Centre National de la Recherche Scientifique (CNRS)
- Universite de la Mediterranee (Aix-Marseille II)
- Assistance Publique-Hopitaux de Marseille (APHM)
From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC(50) value of 1.1 mu M and a HepG2 CC(50) value of 50 mu M, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test. (C) 2011 Elsevier Masson SAS. All rights reserved.
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