Antiplasmodial activity was determined in a CQ-resistant K1
strain of the P. falciparum parasite.17 The results of the antiplasmodial
activity of compounds 5–8 are shown in Table 1, along with
the value for the standard drug CQ and astemizole 2. With the
exception of 5, all compounds were 3–10 times more active than
CQ with optimum activity being seen in compound 6 (IC50
23 nM). Interestingly, the conformationally constrained aminopiperidine
linkers 7 and 8 also delivered potent K1 activity. This
is in contrast to a previously described series of CQ analogues
where acyclic linkers were found to deliver more potency that
those with a conformationally constrained piperidine or pyrrolidine
linker.16 Importantly, the hybrid analogues displayed good
cytotoxicity profiles, with all compounds showing >100-fold selectivity
for antiparasitic activity over cell-based cytotoxicity.