Antimalarial Potential of Heme-Targeting Dimeric Compounds: Binding Efficacy vs. Membrane Retention Effects

Malaria, caused by Plasmodium parasites, remains a major global health burden with high morbidity and mortality rates. Despite the availability of treatments, the therapeutic arsenal is limited, and drug resistance poses a significant challenge. Thus, discovering new antimalarial compounds is critical, and understanding their mechanisms of action is key. One well-studied target is the heme group, which plays a central role in the degradation of the parasite's hemoglobin and infection success. This study describes the dimerization of 3-alkylpyridine derivatives, a class of compounds known to interact with heme, with the aim of enhancing their antimalarial activity. The dimers were analyzed for heme-binding affinity via UV-vis spectroscopy (<i>K</i> _d determination) and further investigated through semiempirical GFN2-xTB and with the B97-3c functional with double (def2-SVP) and triple (def2-TZVP) zeta basis set quality, confirming effective interaction. However, antimalarial assays revealed modest IC50 values (46-140 μM). In silico membrane permeation studies showed that the compounds penetrate lipid bilayers effectively. However, they remain trapped within the membrane for a long time, which may reduce their intracellular availability and limit their efficacy. Although these compounds exhibit strong target binding, their antimalarial activity is hindered by unfavorable pharmacokinetic properties. These findings emphasize the importance of physicochemical properties in antimalarial drug development and suggest that advanced drug delivery systems could overcome these limitations in future studies.