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Imidazolopiperazines: hit to lead optimization of new antimalarial agents.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Wu T,Nagle A,Kuhen K,Gagaring K,Borboa R,Francek C,Chen Z,Plouffe D,Goh A,Lakshminarayana SB,Wu J,Ang HQ,Zeng P,Kang ML,Tan W,Tan M,Ye N,Lin X,Caldwell C,Ek J,Skolnik S,Liu F,Wang J,Chang J,Li C,Hollenbe

doi

10.1021/jm2003359

subject

Has Abstract

pub_date

2011-07-28 00:00:00

pages

5116-30

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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