Synthesis of 4-Aminopyrazol-5-ols as Edaravone Analogs and Their Antioxidant Activity

Abstract

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.

Structure–Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents

“…Structure-activity relationships (SARs) extension on IIa,b led to the isolation of pyrazole hydrochloride III (Figure 1) endowed with improved pharmacokinetic and antioxidant properties. Further statistical analysis and cytotoxicity studies confirmed the promising profile of the compound, which was taken as the lead structure for the development of effective agents against oxidative stress-related diseases [36]. More recently, 5-AP acylhydrazones Iva-d (Figure 2) proved to inhibit platelet aggregation and reactive oxygen species (ROS) production with IC50 values in the low micromolar range [37].…”

Amino-Pyrazoles in Medicinal Chemistry: A Review

“…Additional investigations confirmed the promising properties of 16, which was proposed as a lead structure for developing novel therapeutic drug candidates for treating oxidative stress-related diseases. Additional chemical modifications, such as conjugation to an anticholinesterase fragment, could be performed to obtain multifunctional drugs for treating neurodegenerative diseases [49].…”

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

“…[25] We are also actively carrying out research on the development of analgesics based on fluorine-containing pyrazoles. [26][27][28][29][30][31][32] Recently, we have synthesized polyfluoroalkylcontaining MeN-and MeO-derivatives of pyrazol-5-ols as analogues of antipyrine and celecoxib, [33] which revealed the pronounced analgesic activity in the hot plate test. Among the obtained derivatives, 5-methoxy-3-(trifluoromethyl)-1phenylpyrazole was distinguished by a combination of high analgesic activity in the in vivo hot plate test with low acute toxicity, which is a very important point for the development of new analgesics.…”

“…We are also actively carrying out research on the development of analgesics based on fluorine‐containing pyrazoles [26–32] . Recently, we have synthesized polyfluoroalkyl‐containing MeN‐ and MeO‐derivatives of pyrazol‐5‐ols as analogues of antipyrine and celecoxib, [33] which revealed the pronounced analgesic activity in the hot plate test.…”