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Imidazolopiperazines: hit to lead optimization of new antimalarial agents

Authors :
Chun Li
Véronique Dartois
Jeanette Wu
Suzanne Skolnik
Thierry T. Diagana
Thomas H. Keller
Advait Nagle
David Plouffe
Maria Tan
Matthias Rottmann
Xuena Lin
Arnab K. Chatterjee
Jonathan Chang
Elizabeth A. Winzeler
Suresh B. Lakshminarayana
Fenghua Liu
Kerstin Gagaring
John Isbell
Tao Wu
William Tan
Christopher Caldwell
Richard Glynne
Zhong Chen
Christoph Fischli
David C. Tully
Anne Goh
Tove Tuntland
Min Low Kang
Nicole Y. Ye
Jared Ek
Reto Brun
Hui Qing Ang
Rachel Borboa
Thomas Hollenbeck
Jianling Wang
Peiting Zeng
Kelli L. Kuhen
Caroline Francek
Source :
Journal of medicinal chemistry. 54(14)
Publication Year :
2011

Abstract

[Image: see text] Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.

Details

ISSN :
15204804
Volume :
54
Issue :
14
Database :
OpenAIRE
Journal :
Journal of medicinal chemistry
Accession number :
edsair.doi.dedup.....38d868962b7620c4673d34cdecd094cd