| Autor: |
Burgart YV; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg 620108, Russia., Makhaeva GF; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severny proezd 1, Chernogolovka 142432, Russia., Krasnykh OP; Scientific and Educational Center for Applied Chemical-Biological Research, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Russia., Borisevich SS; Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Russia., Agafonova NA; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg 620108, Russia., Kovaleva NV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severny proezd 1, Chernogolovka 142432, Russia., Boltneva NP; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severny proezd 1, Chernogolovka 142432, Russia., Rudakova EV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severny proezd 1, Chernogolovka 142432, Russia., Shchegolkov EV; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg 620108, Russia., Triandafilova GA; Scientific and Educational Center for Applied Chemical-Biological Research, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Russia., Gazizov DA; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg 620108, Russia., Serebryakova OG; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (IPAC RAS), Severny proezd 1, Chernogolovka 142432, Russia., Ulitko MV; Institute of Natural Sciences and Mathematics of the Ural Federal University Named after the First President of Russia B. N. Yeltsin, Lenina Av., 51, Ekaterinburg 620083, Russia., Khursan SL; Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Russia., Saloutin VI; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg 620108, Russia., Richardson RJ; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA.; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.; Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.; Michigan Institute for Computational Discovery and Engineering, University of Michigan, Ann Arbor, MI 48109, USA. |
| Abstrakt: |
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. |
