Abstract
A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Cell Line
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Databases, Chemical
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Drug Resistance, Multiple
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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High-Throughput Screening Assays
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Humans
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Malaria / drug therapy
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Malaria / parasitology
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Male
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Mice
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Microsomes, Liver / metabolism
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Plasmodium berghei
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Plasmodium falciparum / drug effects
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / pharmacology
Substances
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Antimalarials
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Pyrimidines
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Thiophenes