Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against .

In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against . Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.