An innovative therapeutic approach based on the use of dicationic derivatives was previously designed to inhibit the biosynthesis of phosphatidylcholine in Plasmodium spp. Among these, bis-thiazolium salts were shown to block proliferation of the malaria parasite at concentrations in the low nanomolar range. However, due to unsuitable molecular properties such as the presence of the two polar heads and flexibility in the linker, these compounds have low oral bioavailability. To characterize the structural requirements of the linker that lead to more rigid analogues with fewer rotatable bonds but which retain antimalarial activity, a new series of compounds incorporating an aryl moiety and eventually oxygen atoms were prepared, and their biological activity was evaluated. Structure-activity relationships suggest that the optimal linker construct is an aromatic group with two n-butyl chains branched at the para position; two new leads (compounds 39 and 40) were selected for further development.