Synthesis and Evaluation of Novel Pyrazole Ethandiamide Compounds as Inhibitors of Human THP-1 Monocytic Cell Neurotoxicity.

Jordan A. McKenzie,Edward G. Neeland,Frederic Menard,Andis Klegeris,Kalun Boudreau,Reham F. Barghash,Azhaar T. Alsaggaf,Omkar Kulkarni

doi:10.3390/cells8070655

Abstract

Neuroinflammation and microglia-mediated neurotoxicity contribute to the pathogenesis of a broad range of neurodegenerative diseases; therefore, identifying novel compounds that can suppress adverse activation of glia is an important goal. We have previously identified a class of trisubstituted pyrazoles that possess neuroprotective and anti-inflammatory properties. Here, we describe a second generation of pyrazole analogs that were designed to improve their neuroprotective activity toward neurons under inflammatory conditions. Pyrazolyl oxalamide derivatives were designed to explore the effects of steric and electronic factors. Three in vitro assays were performed to evaluate the compounds’ anti-neurotoxic, neuroprotective, and cytotoxic activity using human THP-1, PC-3, and SH-SY5Y cells. Five compounds significantly reduced the neurotoxic secretions from immune-stimulated microglia-like human THP-1 monocytic cells. One of these compounds was also found to protect SH-SY5Y neuronal cells when they were exposed to cytotoxic THP-1 cell supernatants. While one of the analogs was discarded due to its interference with the cell viability assay, most compounds were innocuous to the cultured cells at the concentrations used (1–100 μM). The new compounds reported herein provide a design template for the future development of lead candidates as novel inhibitors of neuroinflammation and neuroprotective drugs.

Highlights

Alzheimer’s disease (AD) is characterized by inflammatory processes driven by non-neuronal cells, such as microglia [1]
A selection of unsymmetrical pyrazolyl oxalamide analogs were synthesized in a single, practical step (Figure 1)
The pyrazole derivatives 2 and 3 reported are part of a second generation of compounds that builds upon prior work [15,16]

Summary

Introduction

Alzheimer’s disease (AD) is characterized by inflammatory processes driven by non-neuronal cells, such as microglia [1]. As resident immune cells in the brain, microglia belong to the mononuclear phagocyte system and have been found to become activated in AD [2,3]. Considerable experimental and epidemiological evidence indicates that inhibiting adverse microglial activation in AD could be neuroprotective [5]. Both steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) have been tested as inhibitors of microglial adverse activation. These classes of anti-inflammatory medications have not been effective in most clinical trials performed [6].

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Conclusion