biostudies-literatureWicht KJNIAID NIH HHS201-205https://www.ebi.ac.uk/biostudies/studies/S-EPMC5304302biostudies-literatureUnknown8(2)In a previous study, target based screening was carried out for inhibitors of ?-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against <i>Plasmodium falciparum</i>. 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 <i>P. falciparum</i> intracellular exchangeable (free) heme, correlating with decreased parasite survival for ?-hematin inhibiting derivatives.ACS medicinal chemistry lettersIdentification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against <i>Plasmodium falciparum</i>.PMC5304302R01 AI110329Wicht KJHunter RCombrinck JMEgan TJSmith PJfalseIdentification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against <i>Plasmodium falciparum</i>.In a previous study, target based screening was carried out for inhibitors of ?-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against <i>Plasmodium falciparum</i>. 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 <i>P. falciparum</i> intracellular exchangeable (free) heme, correlating with decreased parasite survival for ?-hematin inhibiting derivatives.2017-01-01T00:00:00Z2017 Feb2021-02-20T23:43:24Z2019-03-26T23:00:39ZS-EPMC53043022819731210.1021/acsmedchemlett.6b00416