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

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.

Expression, Purification, Characterization and Cellular Uptake of MeCP2 Variants

“…A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) assay was performed as previously described [ 23 ] with slight modifications. On the day before treatment, NIH3T3 cells were seeded in a 96-well-plate (25,000 cells per well, Greiner, 655,180).…”

Neuroinflammatory response on a newly combinatorial cell–cell interaction chip

“…This indicated that the LPS activated the migratory behavior of THP-1 and caused the decrease of SH-SY5Y cell activity due to production of cytotoxic factors, demonstrating consistency with previous results. 32,33 Additionally, because the THP-1 cells were treated by live cell staining in advance, the mobility of the THP-1 cells could be observed by measuring the absorbance (OD 500 nm ) of the staining pigment in the culture medium (Fig. 6A).…”

Heterocyclic Compounds: Pharmacology of Pyrazole Analogs From Rational Structural Considerations

“…In light of this review, promising cytotoxic activities of some analogs against breast cancer cell lines (MCF-7 and MDA-MB-231) is expected to stimulate extensive evaluation of their effects on lung cancer (A-549), liver cancer (HepG-2), and brain cancer (HeLa) cell lines (Lv et al, 2016;Lehmann et al, 2017;Turkan et al, 2018;McKenzie et al, 2019;Bennani et al, 2020;Masaret, 2021). As a life-threatening health issue and one of the most lethal diseases known, cancer can be managed by targeting gene expression, certain protein synthesis, functions of organelles, pH, and electrolytes (Johnston and Strobel, 2020).…”

“…Chemically diverse pyrazole analogs have shown promising cellular or neuronal protections. The bulky dicyclohexylamide ( 9 ), smaller dimethylamide ( 10 ), and aminophenyl ( 11 ) (pyrazole analogs with sterically hindered substituents on amide) attenuated microglia-mediated neurotoxicity (IC 50 = 10–50 µM) better than compound 12 (IC 50 = 100 µM) with high susceptibility to electrophilic displacement ( McKenzie et al, 2019 ). This compound contains an allyl group on an electron-deficient amide.…”