Synthesis and Cytotoxic Evaluation of Some Substituted 5-Pyrazolones and Their Urea Derivatives

Abstract

In this paper, a series of new substituted-5-pyrazolones were first synthesized, then formulated by the Vilsmeier–Haack reaction to obtain substituted-4-carbaldehyde-5-pyrazolones. In the final step, when urea was reacted with formulated pyrazolones, we found that, instead of the C=N bond in azomethine form, the compounds tautomerized to form a series of novel pyrazole-4-ylidenemethylurea structures. The structures of these compounds were elucidated by FTIR, 1H, 13C NMR, LC-MS/MS, and elemental analysis methods. The cytotoxic and antioxidant effects of substituted 5-pyrazolones and their pyrazolone-urea derivatives were investigated in metastatic A431 and noncancerous HaCaT human keratinocytes by a mitochondrial activity test. The effects of the compounds on the migration of cancerous and noncancerous cell lines were investigated by using a cell scratch assay. The General Linear Model, Statistical Package for Social Sciences (SPSS v26) was used to determine if there was a statistically significant difference between the control and the treatment groups. Four of the nine compounds showed an antioxidant effect. All 5-pyrazolone-urea compounds showed higher toxicity (p < 0.05) in cancerous A431 cells compared to noncancerous cells at all time points. All compounds also showed a biphasic hormetic effect. Four of the nine compounds inhibited cell migration.

N-(3-Cyano-4,5,6,7-tetrahydrobenzothiophen-2-yl)-2-[[5-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)amino]-1,3,4-thiadiazol-2-yl]sulfanyl]acetamide

“…Antipyrine (1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one) structural motif is an important and valuable tool in modern medicinal chemistry [1][2][3]. Historically associated with antipyretic and anti-inflammatory properties, nowadays antipyrine-bearing molecules have been successfully studied and developed as potential modulators for the correction of various pathological processes [4,5]. Among them, the most successful example is Edaravone (brand names Radicava, Radicut), a close structural analog of antipyrine, which was was approved by the Food and Drug Administration (FDA) in 2017 as a neuroprotective antioxidant drug for used to help with recovery following a stroke and to treat amyotrophic lateral sclerosis and is considered by the FDA as a first-in-class medication [6,7] (Figure 1).…”