Development of Diaryl Hydrazones for Alleviation of Mitochondrial Oxidative Stress in Preeclampsia.

Preeclampsia is a pregnancy-specific syndrome, linked to oxidative stress, affecting 5-8% of pregnancies, with no effective treatment available. Here, diaryl-hydrazones have been designed, synthesized, and investigated as mitochondria-targeting antioxidants to reduce placental oxidative stress and mitigate preeclampsia symptoms. The design, based on density functional theory studies, revealed that conjugated electron structure with the NH-motif appeared to explain their effect. Thirty compounds were synthesized and tested in three assays, where they exhibited excellent radical scavenging activity, significantly greater than that of the standard, Trolox. Based on the data, eight compounds were selected for cell-based assays. Oxidative stress was induced in human trophoblast cells and assessed whether the compounds reduced downstream antiangiogenic responses using ascorbic acid and MitoTEMPO as standards. The pretreatment with the hydrazones reduced mitochondrial superoxide and sFLT-1 production in H2O2-exposed trophoblast cells, indicating that mitochondrial oxidative stress and the anti-angiogenic response can be alleviated by these compounds.