Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines |
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| 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 |
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| Affiliation: | 1. Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA;2. Drug and Biomaterial R&D, Genzyme Corporation, Waltham, MA 02451, USA;3. Center for Systems Biology, Massachusetts General Hospital, MA 02142, USA;4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA |
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| 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 R2 significantly affecting activity. A subsequent series addressed high Log D values by introducing more polar side groups, with the most active compounds possessing diazepine and N-benzyl-4-aminopiperidyl groups at R1/R2. A final series attempted to address high in vitro microsomal clearance by replacing the C6-Me group with CF3, however antiplasmodial activity decreased without any improvement in clearance. The C6-CF3 group decreased hERG inhibition, probably as a result of decreased amine basicity at C2/C4. |
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