Discovery of Carbohybrid-Based 2-Aminopyrimidine Analogues As a New Class of Rapid-Acting Antimalarial Agents Using Image-Based Cytological Profiling Assay

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• 作者：Sukjun Lee ; Donghyun Lim ; Eunyoung Lee ; Nakyung Lee ; Hong-gun Lee ; Jonathan Cechetto ; Michel Liuzzi ; Lucio H. Freitas-Junior ; Jin Sook Song ; Myung Ae Bae ; Sangmi Oh ; Lawrence Ayong ; Seung Bum Park
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7425-7434
• 全文大小：509K
• ISSN：1520-4804

文摘

New antimalarial agents that exhibit multistage activities against drug-resistant strains of malaria parasites represent good starting points for developing next-generation antimalarial therapies. To facilitate the progression of such agents into the development phase, we developed an image-based parasitological screening method for defining drug effects on different asexual life cycle stages of Plasmodium falciparum. High-throughput screening of a newly assembled diversity-oriented synthetic library using this approach led to the identification of carbohybrid-based 2-aminopyrimidine compounds with fast-acting growth inhibitory activities against three laboratory strains of multidrug-resistant P. falciparum. Our structure鈥揳ctivity relationship study led to the identification of two derivatives (8aA and 11aA) as the most promising antimalarial candidates (mean EC₅₀ of 0.130 and 0.096 渭M against all three P. falciparum strains, selectivity indices >600, microsomal stabilities >80%, and mouse malaria ED₅₀ values of 0.32 and 0.12 mg/kg/day, respectively), targeting all major blood stages of multidrug-resistant P. falciparum parasites.