Referenced in: none

Automatically associated channels: Kv11.1 , Kv4.1

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

Authors: Derek C Martyn, Amarjit Nijjar, Cassandra A Celatka, Ralph Mazitschek, Joseph F Cortese, Erin Tyndall, Hanlan Liu, Maria M Fitzgerald, Thomas J O'Shea, Sanjay Danthi, Jon Clardy

Journal, date & volume: Bioorg. Med. Chem. Lett., 2010 Jan 1 , 20, 228-31

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19914064

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.