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Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines.
|Publication Type||Journal Article|
|Authors||Martyn, DC, Nijjar A., Celatka CA, Mazitschek R., Cortese JF, Tyndall E., Liu H., Fitzgerald MM, O'Shea TJ, Danthi S., and Clardy J.|
|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||Bioorganic & medicinal chemistry letters|
|Date Published (YYYY/MM/DD)||2010/01/01|