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

Bioorg Med Chem Lett
Authors
Keywords
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.

Year of Publication
2010
Journal
Bioorg Med Chem Lett
Volume
20
Issue
1
Pages
228-31
Date Published
2010 Jan 01
ISSN
1464-3405
URL
DOI
10.1016/j.bmcl.2009.10.133
PubMed ID
19914064
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