In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds <b>21</b>, <b>30</b>, and <b>33</b> displayed high activities against asexual blood stage parasites (<i>Pf</i>NF54 IC<sub>50</sub> = 0.025-0.043 μM), whereas amide compound <b>46</b> additionally showed activity against late-stage gametocytes (stage IV/V; <i>Pf</i>LG IC<sub>50</sub> = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (<b>46</b>, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.