Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II

A number of single-digit nanomolar, low-molecular-weight plasmepsin II aspa rtyl protease inhibitors have been identified using combinatorial chemistry and structure-based design. By identifying multiple, small-molecule inhibi tors using the parallel synthesis of several focused libraries, it was poss ible to select for compounds with desirable characteristics including enzym e specificity and minimal binding to serum proteins. The best inhibitors id entified have Ki's of 2-10 nM, molecular weights between 594 and 650 Da, be tween 3- and 15-fold selectivity toward plasmepsin II over cathepsin D, the most closely related human protease, good calculated log P values (2.86-4. 56), and no apparent binding to human serum albumin at 1 mg/mL in an in vit ro assay. These compounds represent the most potent non-peptide plasmepsin II inhibitors reported to date.