Antimalarial versus Cytotoxic Properties of Dual Drugs Derived From 4-Aminoquinolines and Mannich Bases: Interaction with DNA

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• 作者：Nicole I. Wenzel ; Natascha Chavain ; Yulin Wang ; Wolfgang Friebolin ; Louis Maes ; Bruno Pradines ; Michael Lanzer ; Vanessa Yardley ; Reto Brun ; Christel Herold-Mende ; Christophe Biot ; Katalin Tth ; Elisabet
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 22, 2010
• 年：2010
• 卷：53
• 期：8
• 页码：3214-3226
• 全文大小：1162K
• 年卷期：v.53,no.8(April 22, 2010)
• ISSN：1520-4804

文摘

The synthesis and biological evaluation of new organic and organometallic dual drugs designed as potential antimalarial agents are reported. A series of 4-aminoquinoline-based Mannich bases with variations in the aliphatic amino side chain were prepared via a three-steps synthesis. These compounds were also tested against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum and assayed for their ability to inhibit the formation of β-hematin in vitro using a colorimetric β-hematin inhibition assay. Several compounds showed a marked antimalarial activity, with IC₅₀ and IC₉₀ values in the low nM range but also a high cytotoxicity against mammalian cells, in particular a highly drug-resistant glioblastoma cell line. The newly designed compounds revealed high DNA binding properties, especially for the GC-rich domains. Altogether, these dual drugs seem to be more appropriate to be developed as antiproliferative agents against mammalian cancer cells than Plasmodium parasites.