|Publication Type||Journal Article|
|Year of Publication||2010|
|Authors||Martyn, DC, Nijjar, A, Celatka, CA, Mazitschek, R, Cortese, JF, Tyndall, E, Liu, H, Fitzgerald, MM, O'Shea, TJ, Danthi, S, Clardy, J|
|Journal||Bioorg Med Chem Lett|
|Date Published||2010 Jan 01|
|Keywords||Animals, 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 Journal||Bioorg. Med. Chem. Lett.|