Impact of Structural Features on the Antioxidant Activity of Organofluorine Diaryl Hydrazones

Preeclampsia (PE) affects 2–8% of pregnancies, yet it lacks curative treatment options. Oxidative stress caused by the release of reactive oxygen and nitrogen species (ROS/RNS) in the placenta is common in abnormal placental development. It can cause downstream signaling and the formation of anti-angiogenic factors, e.g., soluble fms-like tyrosine kinase 1 (sFLT-1), leading to symptoms of PE, such as hypertension, proteinuria, and, in severe cases, eclampsia. Mitochondria-targeted antioxidants were developed to reduce oxidative stress and alleviate PE symptoms. Ten organofluorine diaryl hydrazones were designed as potential antioxidants, synthesized, and tested for their activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and oxygen radical absorbance capacity (ORAC) assays. Compounds 2, 3, 5, and 6 showed excellent antioxidant capacity in all three assays and were tested in an in vitro human trophoblast cell culture system mimicking PE in which the cells were exposed to oxidative stress inducing the release of sFLT-1. The anti-angiogenic factor sFLT-1 was greatly reduced in cells treated with antioxidants. Compounds 5 and 6 were more effective in preventing sFLT-1 release than 2 and 3. Density functional theory calculations of the electronic structures of compounds 2, 5, and 6 were conducted at the M06-2X/6-311G+(d,p) level to further understand the reactivity profile of these molecules. The electron density of delocalized bonds (EDDB(r)) was calculated to analyze the effect of delocalization on radical stabilization.