Neuroprotective and Anti-neuroinflammatory Properties of Ebselen Derivatives and Their Potential to Inhibit Neurodegeneration Article (Faculty180)

cited authors

  • Landgraf, Alexan D; Alsegiani, Am S; Alaqel, Saleh; Thanna, Sandeep; Shah, Z A; Sucheck, Steven J

description

  • Ebselen (EBS) is an organo-selenium-containing compound that has anti-inflammatory, antitumor, and antibacterial properties. EBS is being explored as a possible treatment for reperfusion injury and stroke and is under clinical trials as a mimetic of lithium for the treatment of bipolar disorder [Mota et al. 2020, 74 (7), 1-6] and noise-induced hearing loss as a result of these actives [Martini et al. 2019, 109, 107-117. Slusarczyk et al. 2019, 17 (7), 1255-1261. Thangamani et al. 2015, 10 (7), e0133877. Kil et al. 2017, 390 (10098), 969-979]. However, we wanted to characterize derivatives of EBS as neuroprotective, anti-neuroinflammatory, and antioxidant compounds. Recently, we have reported on a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N-substituted -halobenzamides to form ebselen derivatives with increased synthetic efficiency [Thanna et al. 2017, 82 (7), 3844-3854]. Our synthesis allows for the varying of the remote benzene ring with various substituents or replacing that ring with heterocyclic rings such as pyridine, pyrrole, thiophene, etc. In this study, we synthesized seven new heterocyclic EBS derivatives to further diversify our EBS library. These 21 compounds were then evaluated for their neuroprotective properties, with four compounds showing an equal or better neuroprotective profile than EBS. Compounds , , , and showed 73, 86, 80, 84% cell viability, respectively, at a 10 μM concentration. These studies were performed using human neuroblastoma SH-SY5Y cells in an oxygen and glucose deprivation (OGD) model of ischemia. At the same concentration, these compounds significantly inhibited lipopolysaccharide-induced nitric oxide and tumor necrosis factor alpha release from Human microglia clone 3 microglial cells. Compounds and showed significantly increased cell viability (84 and 80%, respectively) for SH-SY5Y cells exposed to microglia-activated media. These compounds showed only mild GPx-like reductive activity, with compounds , , , and (115, 96, 95, and 82%, respectively) showing a higher percent rate of oxidation of NADPH in a coupled reaction assay compared to ebselen. This research highlights several derivatives of ebselen that show improved activity as neuroprotective agents over the parent compound.

authors

publication date

  • 2020

published in

start page

  • 3008

end page

  • 3016

volume

  • 11