Pyrido-Dibemequine Metabolites Exhibit Improved Druglike Features, Inhibit Hemozoin Formation in Plasmodium falciparum, and Synergize with Clinical Antimalarials.

Structural modification of existing chemical scaffolds to afford new molecules able to circumvent drug resistance constitutes one of the rational approaches to antimalarial drug discovery. Previously synthesized compounds based on the 4-aminoquinoline core hybridized with a chemosensitizing dibenzylmethylamine side group showed in vivo efficacy in Plasmodium berghei-infected mice despite low microsomal metabolic stability, suggesting a contribution from their pharmacologically active metabolites. Here, we report on a series of these dibemequine (DBQ) metabolites with low resistance indices against chloroquine-resistant parasites and improved metabolic stability in liver microsomes. The metabolites also exhibit improved pharmacological properties including lower lipophilicity, cytotoxicity, and hERG channel inhibition. Using cellular heme fractionation experiments, we also demonstrate that these derivatives inhibit hemozoin formation by causing a buildup of toxic "free" heme in a similar manner to chloroquine. Finally, assessment of drug interactions also revealed synergy between these derivatives and several clinically relevant antimalarials, thus highlighting their potential interest for further development.