Design, synthesis, and anti-neuroinflammatory activity of amidecontaining dithiolethiones

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination of neurons and neurodegeneration. Current MS therapies ameliorate inflammatory damage but are unable to address the degenerative aspects of the disease. Objective: In this report, we evaluate the ability of amide-based dithiolethiones (DTTs) to suppress neuroinflammation in microglia and increase anti-oxidant capacity neuron-like cells. Methods: A series of amide-containing DTTs were designed, synthesized, and assayed for ability to suppress proneuroinflammatory cytokines IL-12p40 and IL-23p19 induced by LPS in the BV2 microglial cell line. Lead analog 2c was identified and further characterized. Results: Structure-activity data revealed tolerance towards a variety of amides. Morpholine analog 2c dose-dependently reduced various other inflammatory cytokines and mediators, including TNF, IL-6, IL-1β, NOS2, and COX2. Additionally, 2c elevated cellular levels of glutathione in SH-SH5Y neuronal cell line. Furthermore, mechanistic studies showed 2c increased the expression of anti-inflammatory Nrf2 and HMOX proteins. Conclusion: The combination of anti-neuroinflammatory and anti-oxidant activities of amide-based DTTs suggest they are promising agents for the treatment of both demyelination and neurodegeneration in MS.