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Bioorg Med Chem Lett DOI:10.1016/j.bmcl.2009.10.133

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

Publication TypeJournal Article
Year of Publication2010
AuthorsMartyn, DC, Nijjar, A, Celatka, CA, Mazitschek, R, Cortese, JF, Tyndall, E, Liu, H, Fitzgerald, MM, O'Shea, TJ, Danthi, S, Clardy, J
JournalBioorg Med Chem Lett
Date Published2010 Jan 01
KeywordsAnimals, Antimalarials, Ether-A-Go-Go Potassium Channels, Humans, Microsomes, Liver, Plasmodium falciparum, Pyrimidines, Rats, Structure-Activity Relationship

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.


Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID19914064