期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 17, 页码 7425-7434出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5009693
关键词
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资金
- Creative Research Initiative Grant [2014R1A3A2030423]
- Bio & Medical Technology Development Program [2012M3A9C4048780]
- Basic Research Laboratory - National Research Foundation of Korea (NRF) [2010-0019766]
- National Research Foundation of Korea (NRF) - Korea Government (MSIP) [2007-00559]
- Gyeonggi-do
- KISTI
- WCU-BK21 scholarship
- National Research Foundation of Korea [2010-0019766, 2007-00559] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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-activity 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 mu 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
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