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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. Synapse 2020, 74 (7), 1-6] and noise-induced hearing loss as a result of these actives [Martini et al. J. Psychiatr. Res. 2019, 109, 107-117. Slusarczyk et al. Neural Regener. Res. 2019, 17 (7), 1255-1261. Thangamani et al. PLoS One 2015, 10 (7), e0133877. Kil et al. Lancet 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 ortho-halobenzamides to form ebselen derivatives with increased synthetic efficiency [Thanna et al. J. Org. Chem. 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 5, 9, 23, and 27 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 9 and 27 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 2, 7, 12, and 14 (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.

The six 1-n-pentyl-2-, 3-, 4-, 5-, 6- and 7-(2-naphthoyl)-indoles each have the same substituents attached to the indole ring, identical elemental composition (C24H23NO) yielding identical nominal and accurate masses. The electron ionization mass spectra of the 2-naphthoyl substituted isomers share equivalent major fragment ions resulting from cleavage of the groups attached to the central indole nucleus with some differences in relative abundances. These six regioisomers were successfully resolved on an Rtx-5 and Rxi-17Sil MS stationary phases and the molecules having both substituent groups on the same side of the indole ring (1,2- and 1,7-substituents) show the least retention. The more linear molecules have higher relative retention properties. A comparison of the GC properties of the 1-naphthoyl- and 2-naphthoyl groups attached at identical positions of the indole ring showed higher GC retention for the 2-naphthoyl substituted isomer in all cases evaluated. The amide inverse isomers (1-naphthoyl-3-n-pentylindoles) were separated from the 1-n-pentyl-3-naphthoyl-indoles on an Rtx-200 stationary phase. The two inverse amide isomers having the 1- and 2-naphthoyl groups substituted at the 1-position of the indole ring elute before either of the N-alkyl-indole isomers having the 1- and 2-naphthoyl groups substituted at the 3-position of the indole ring. The amide inverse isomers yield EI mass spectra easily distinguishing these amides from the ketone isomers having the naphthoyl groups at the indole 3-position.

Alzheimer’s disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation of damaged proteins β-amyloid (Aβ) and hyperphosphorylated tau outside and inside neurons, respectively. Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study, sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the synthesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was ULK-1 which has a significant role in autophagy.

The six regioisomeric 1-pentyl-3-dimethoxybenzoylindoles can be differentiated by a combination of EI-MS and FT-IR spectra. The six regioisomeric 1-n-pentyl-3-(dimethoxybenzoyl)-indoles represent potential designer modifications in the synthetic cannabinoid drug category. The analytical properties and methods of regioisomeric differentiation were developed in this study. The base peaks in these six spectra allow these compounds to be subdivided into three groups of two compounds each, the m/z 334 ion is the base peak for the 2,4- and 2,6-dimethoxybenzoyl isomers (compounds 2 and 4), the 2,3- and 2,5-dimethoxybenzoylindole isomers (compounds 1 and 3) show the m/z 200 ion of base peak intensity and the 3,4- and 3,5-isomers (compounds 5 and 6) show the molecular ion as the base peak, m/z 351. The four isomers having a methoxy group substituted at the ortho position show a unique fragment ion occurring at [M-17](+). An interesting fragment ion at m/z 200 is significant in the 2,3 and 2,5 isomers and completely absent in the 3,4 and 3,5 isomers. Minor peaks for m/z 200 appear in the mass spectra of the 2,4 and 2,6-isomers. This set of regioisomeric compounds was well resolved by capillary gas chromatography on a dimethylpolysiloxane stationary phase. The elution order appears related to the degree of substituent crowding in the dimethoxybenzoyl group. FTIR spectra provide useful data for differentiation among these regioisomeric compounds. Infrared absorption spectral data provide distinguishing and characteristic information to individualize the regioisomers in this set of compounds.