Incorporation of a 3-(2,2,2-Trifluoroethyl)-纬-hydroxy-纬-lactam Motif in the Side Chain of 4-Aminoquinolines. Syntheses and Antimalarial Activities
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- 作者：Damien Cornut ; Hugues Lemoine ; Oleksandr Kanishchev ; Etsuji Okada ; Florian Albrieux ; Abdoul Habib Beavogui ; Anne-Lise Bienvenu ; St茅phane Picot ; Jean-Philippe Bouillon ; Maurice M茅debielle
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：January 10, 2013
- 年：2013
- 卷：56
- 期：1
- 页码：73-83
- 全文大小：444K
- 年卷期：v.56,no.1(January 10, 2013)
- ISSN：1520-4804
文摘
In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated 纬-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19鈥?0 nM with resistance indices in the range of 1.0鈥?.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 渭M. The most promising compounds (82 and 84) showed significant IC50 values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.