New derivatives of 6-nitrocoumarin-3-thiosemicarbazone exhibit improved antiparasitic activity in the placenta against and .

Congenital infections by and pose significant clinical challenges due to the lack of safe and effective treatments. This study evaluates eight novel 6-nitrocoumarin-3-thiosemicarbazone derivatives in an human placenta model, assessing their antiparasitic activity and impact on tissue integrity. Two therapeutic approaches were tested: pre-infection (preventive) and post-infection (therapeutic). and assays revealed strong activity trends. Compound was the most effective against (IC = 22.4 ± 0.8 µM, logP = 2.49), while compound exhibited the highest activity against (IC = 17.3 ± 0.5 µM, logP = 1.44). Unlike current treatments, none of the compounds induced placental tissue damage, preserving trophoblast function. Structure-activity relationship (SAR) analysis identified an inverse correlation between lipophilicity and antiparasitic activity in , where polar compounds were more effective. In , higher lipophilicity favored trypanocidal activity, suggesting differential cell permeability mechanisms. Mechanistic studies using electrochemistry and electron spin resonance (ESR) demonstrated that nitro group bioreduction promotes ROS generation, explaining activity against . By contrast, lower ROS levels in suggest alternative mechanisms. This study validates the human placenta model as a clinically relevant platform for antiparasitic drug screening. The findings highlight 6-nitrocoumarin-3-thiosemicarbazones as promising early-stage candidates that warrant further optimization to develop safer and more effective therapies for congenital infections.