We report the design, synthesis, and in vitro evaluation of novel polyspirocyclic structures, inspired by the antimalarial natural products, the aculeatins. A divergent synthetic strategy was conceived for the practical supply and has allowed the discovery of two novel and more potent analogues active on the Plasmodium falciparum 3D7 strain. Moreover, these compounds proved to be potent against Toxoplasma gondii. A number of features that govern these inhibitions were identified.