Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against Plasmodium falciparum

Abstract

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 Plasmodium falciparum. 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 P. falciparum intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives.

Keywords: Antimalarial; Plasmodium falciparum; hemozoin; triarylimidazole.

Scheme 1. Preparation of the Triarylimidazole Derivatives 14a–g and 15

Figure 1

Linear correlation between the log of the parasite activity with the number of hydroxyl or methoxy substituents on the phenyl rings in a triarylimidazole given by log(NF54 IC₅₀) = −0.30(# of OH or OMe) + 1.23; (r² = 0.76, P = 0.0048).

Figure 2

Favorable (blue) and unfavorable (red) substituents for parasite activity within the triarylimidazole HTS hits and synthesized analogues.

Figure 3

Dose response curves for amount of free non-Hz heme (fg/cell) and the percent parasite survival for (a) 14f, showing a cross over near the IC₅₀, and (b) 14d, showing no increase in free heme with parasite growth inhibition.