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Bioorg Med Chem Lett. 2010 Jan 1;20(1):228-31. doi: 10.1016/j.bmcl.2009.10.133. Epub 2009 Oct 31.

Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines.

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  • 1Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.

Abstract

Two sets of diaminopyrimidines, totalling 45 compounds, were synthesized and assayed against Plasmodium falciparum. The SAR was relatively shallow, with only the presence of a 2-(pyrrolidin-1-yl)ethyl group at R(2) significantly affecting activity. A subsequent series addressed high LogD values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R(1)/R(2). A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF(3), however antiplasmodial activity decreased without any improvement in clearance. The C6-CF(3) group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4.

Copyright 2009 Elsevier Ltd. All rights reserved.

PMID:
19914064
[PubMed - indexed for MEDLINE]
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