Synthesis and In Vitro Activity of Hypofuran B and Analogs Against Plasmodium Falciparum and Trypanosoma Cruzi

Herein, the synthesis and biological evaluation of hypofuran B and a series of analogs against Trypanosoma cruzi and Plasmodium falciparum is described. The compounds are obtained through crossed aldol condensation between phenylacetaldehyde and furfural derivatives, using reaction conditions optimized according to the aromatic substituents. Yields ranged from 20% to 83%, with E/Z ratios between 89:11 and 98:2. Three compounds are isolated as single crystals suitable for X-ray diffraction, and their crystal structures are determined. The most active analogs showed IC₅₀ values of 5.35-10.35 µg mL^-1 and are further evaluated for cytotoxicity in L929 cells. For P. falciparum, a clear structure-activity-toxicity relationship is observed. The most promising compound displayed a CC₅₀ value above 400 µg mL^-1, indicating lower cytotoxicity than chloroquine. In silico predictions also supported favorable drug-like profiles. Overall, the moderate antiparasitic activity, low cytotoxicity, and consistent structure-activity trends highlight hypofuran B and related drynaran derivatives as promising antimalarial leads.