One of the powerful antioxidants used clinically is Edaravone (EDA). We synthesized a series of new EDA analogs, 4-aminopyrazol-5-ol hydrochlorides, including polyfluoroalkyl derivatives, via the reduction of 4-hydroxyiminopyrazol-5-ones. The primary antioxidant activity of the compounds in comparison with EDA was investigated in vitro using ABTS, FRAP, and ORAC tests. In all tests, 4-Amino-3-pyrazol-5-ols were effective. The lead compound, 4-amino-3-methyl-1-phenylpyrazol-5-ol hydrochloride (APH), showed the following activities: ABTS, 0.93 TEAC; FRAP, 0.98 TE; and ORAC, 4.39 TE. APH and its NH-analog were not cytotoxic against cultured normal human fibroblasts even at 100 μM, in contrast to EDA. According to QM calculations, 4-aminopyrazolols were characterized by lower gaps, IP, and η compared to 4-hydroxyiminopyrazol-5-ones, consistent with their higher antioxidant activities in ABTS and FRAP tests, realized by the SET mechanism. The radical-scavenging action evaluated in the ORAC test occurred by the HAT mechanism through OH bond breaking in all compounds, directly dependent on the dissociation energy of the OH bond. All the studied compounds demonstrated the absence of anticholinesterase activity and moderate inhibition of CES by some 4-aminopyrazolols. Thus, the lead compound APH was found to be a good antioxidant with the potential to be developed as a novel therapeutic drug candidate in the treatment of diseases associated with oxidative stress.
Background:
Formally belonging to the non-steroidal anti-inflammatory drug class
pyrazolones have long been used in medical practices.
Objective:
Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated
analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure
and evaluate biological activities of obtained compounds.
Methods:
In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity,
hyperalgesia, antipyretic activity, “open field” test) experiments. To suggest the mechanism
of biological activity, molecular docking of the synthesized compounds was carried out into the
tyrosine site of COX-1/2.
Conclusion:
The trifluoromethyl antipyrine represents a valuable starting point in design of the
lead series for discovery new antipyretic analgesics with anti-inflammatory properties.
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