α-Aryl-N-alkyl Nitrones, as Potential Agents for Stroke Treatment: Synthesis, Theoretical Calculations, Antioxidant, Anti-inflammatory, Neuroprotective, and Brain–Blood Barrier Permeability Properties

Abstract

We report the synthesis, theoretical calculations, the antioxidant, anti-inflammatory, and neuroprotective properties, and the ability to cross the blood–brain barrier (BBB) of (Z)-α-aryl and heteroaryl-N-alkyl nitrones as potential agents for stroke treatment. The majority of nitrones compete with DMSO for hydroxyl radicals, and most of them are potent lipoxygenase inhibitors. Cell viability-related (MTT assay) studies clearly showed that nitrones 1–3 and 10 give rise to significant neuroprotection. When compounds 1–11 were tested for necrotic cell death (LDH release test) nitrones 1–3, 6, 7, and 9 proved to be neuroprotective agents. In vitro evaluation of the BBB penetration of selected nitrones 1, 2, 10, and 11 using the PAMPA-BBB assay showed that all of them cross the BBB. Permeable quinoline nitrones 2 and 3 show potent combined antioxidant and neuroprotective properties and, therefore, can be considered as new lead compounds for further development in specific tests for potential stroke treatment.

CholesteroNitrones for Stroke

“…[6][7][8] This background has supported our current efforts devoted to the search of new nitrones as neuroprotective agents for the development of new drugs for stroke. 9 In this context, and being aware that steroids have been also proposed as neuroprotective agents, able to prevent inflammation in the central nervous system, 10 we have considered the synthesis and biological evaluation of new steroid-nitrone hybrids (CholesteroNitrones, ChNs) as permeable suitable drugs for the treatment of stroke. Very surprisingly, although steroidal nitrones are readily available molecules, their biological activities have been scarcely documented, and particularly, in the field of stroke we are not aware of any previous reported research.…”

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke

“…Starting in 2008, the group led by Marco-Contelles (CSIC, Madrid, Spain) has designed, synthesized and developed a number of nitrones for the potential treatment of stroke, the most interesting compounds being RP19 (Figure 1; Chioua et al, 2012), and F2 (Ayuso et al, 2015; Figure 1), in collaboration with Dr. Dimitra J. Hadjipavlou-Litina (Aristotle University of Thessaloniki, Greece) and Dr. Alcázar (Hospital Ramón y Cajal, Madrid, Spain).…”

Styryl and functionalized aryl derivatives of lawsone through metal-free cross-coupling of its BF3-activated phenyliodonium ylide with cinnamaldehydes and arylaldehydes

“…Soybean Lipoxygenase, linoleic acid sodium salt, trolox and 2, 2 0 -Azobis(2-amidinopropane) dihydrochloride were obtained from Sigma Chemical, Co. 51,52 The compounds were dissolved in ethanol and incubated at room temperature with sodium linoleate (100 mM) and 0.2 mL of enzyme solution (1/9Â10 À4 w/v in saline). The conversion of sodium linoleate to 13-hydroperoxylinoleic acid at 234 nm was recorded and compared with the appropriate standard inhibitor (nordihydroguaeretic acid) ( 51,52 Production of conjugated diene hydroperoxide by oxidation of linoleic acid in an aqueous dispersion was monitored at 234 nm. 2, 2 0 -Azobis(2-amidinopropane) dihydrochloride (AAPH) is used as a free radical initiator.…”