A Diverse Range of Hemozoin Inhibiting Scaffolds Act on Plasmodium falciparum as Heme Complexes

• DOI: 10.1021/acsinfecdis.0c00680
• Publication Date: 2021-01-15T00:30:21Z
• Authors: Roxanne Openshaw; Keletso Maepa; Stefan J. Benjamin; Lauren Wainwright; Jill M. Combrinck; Roger Hunter; Timothy J. Egan
• Keywords: Hemozoin

A diverse series of hemozoin-inhibiting quinolines, benzamides, triarylimidazoles, quinazolines, benzimidazoles, benzoxazoles, and benzothiazoles have been found to lead exchangeable heme levels in cultured Plasmodium falciparum (NF54) that ranged over an order magnitude at the IC50. Surprisingly, less active compounds often exhibited higher than more ones. Quantities intracellular inhibitor measured using inoculum effect a linear correlation with heme, suggesting formation heme–inhibitor complexes parasite. In effort confirm this, presence Br atom one benzimidazole derivatives was exploited image its distribution parasite electron spectroscopic imaging Br, element not naturally abundant cells. This showed compound colocalized iron, consistent as complex. Direct evidence for this complex then obtained confocal Raman microscopy. Exchangeable were increase decreased rate killing, slow-acting time build up complexes. Lastly, some but all evidently cause pro-oxidant effects because their activity could be attenuated N-acetylcysteine potentiated t-butyl hydroperoxide. Collectively, these findings suggest hemozoin inhibitors act free each own unique activity.