Broad Institute Infectious Diseases Initiative, 7 Cambridge Center, Cambridge, MA 02142, USA.
Bioorg Med Chem Lett. 2010 Jan 1;20(1):228-31. doi: 10.1016/j.bmcl.2009.10.133. Epub 2009 Oct 31.
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.
两组二氨基嘧啶类化合物，共 45 个化合物，被合成并针对恶性疟原虫进行了检测。SAR 相对较浅，只有 R(2)上存在 2-(吡咯烷-1-基)乙基基团才能显著影响活性。随后的一系列研究通过引入更多极性侧基来解决高 LogD 值的问题，最活跃的化合物在 R(1)/R(2)上具有二氮杂环丁烷和 N-苄基-4-氨基哌啶基。最后一系列研究试图用 CF(3)取代 C6-Me 基团来解决体外高微粒体清除率的问题，但是抗疟活性降低，而清除率没有任何改善。C6-CF(3)基团降低了 hERG 抑制，可能是由于 C2/C4 上的胺碱性降低所致。
