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.