This study introduces third-generation derivatives of guttiferone A, designed to enhance both bioactivity and selectivity against Plasmodium falciparum and Trypanosoma brucei. Following an optimized synthetic route, two dioxolane derivatives of 3,16-oxyguttiferone A were prepared: 14-monodioxolane-3,16-oxyguttiferone A (3) and 13,14-bisdioxolane-3,16-oxyguttiferone A (4). Biological evaluation revealed compound 3 to be the most effective, with a selectivity index (SI) of 457.1 against Trypanosoma brucei brucei strain and 57.1 against P. falciparum, significantly outperforming its precursors. Compound 4 also demonstrated substantial activity with an SI of 143.8 against T. brucei. These results highlight the potential of targeted structural modifications, particularly monodioxolane substitution, to improve the pharmacological profile of guttiferone A derivatives.