2. Academic Validation
  3. Multiple biological active 4-aminopyrazoles containing trifluoromethyl and their 4-nitroso-precursors: Synthesis and evaluation

Multiple biological active 4-aminopyrazoles containing trifluoromethyl and their 4-nitroso-precursors: Synthesis and evaluation

  • Eur J Med Chem. 2020 Dec 15:208:112768. doi: 10.1016/j.ejmech.2020.112768.
Yanina V Burgart 1,  Natalia A Agafonova 2,  Evgeny V Shchegolkov 1,  Olga P Krasnykh 3,  Svetlana O Kushch 2,  Natalia P Evstigneeva 4,  Natalia A Gerasimova 4,  Vera V Maslova 3,  Galina A Triandafilova 3,  Sergey Yu Solodnikov 3,  Maria V Ulitko 5,  Galina F Makhaeva 6,  Elena V Rudakova 6,  Sophia S Borisevich 7,  Natalia V Zilberberg 4,  Nikolai V Kungurov 4,  Victor I Saloutin 8,  Oleg N Chupakhin 1
Affiliations

Affiliations

  • 1 Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg, 620108, Russia; Ural Federal University Named After the First President of Russia B.N. Yeltsin, Mira St. 19, Ekaterinburg, 620002, Russia.
  • 2 Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg, 620108, Russia.
  • 3 Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm, 614990, Russia.
  • 4 Ural Research Institute for Dermatology, Venereology and Immunopathology, Shcherbakova St., 8, Ekaterinburg, 620076, Russia.
  • 5 Ural Federal University Named After the First President of Russia B.N. Yeltsin, Mira St. 19, Ekaterinburg, 620002, Russia.
  • 6 Institute of Physiologically Active Compounds of the Russian Academy of Sciences, Severny Proezd 1, Chernogolovka, 142432, Russia.
  • 7 Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa, 450078, Russia.
  • 8 Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoi St., 22, Ekaterinburg, 620108, Russia; Ural Federal University Named After the First President of Russia B.N. Yeltsin, Mira St. 19, Ekaterinburg, 620002, Russia. Electronic address: [email protected].
PMID: 32932211 DOI: 10.1016/j.ejmech.2020.112768
Abstract

4-Nitroso-3-trifluoromethyl-5-alkyl[(het)aryl]pyrazoles were synthesized via one-pot nitrosation of 1,3-diketones or their lithium salts followed by treatment of hydrazines. Reduction of nitroso-derivatives made it possible to obtain 4-amino-3-trifluoromethylpyrazoles chlorides. According to computer-aided calculations, all synthesized compounds are expected to have acceptable ADME profile for drug design. Tuberculostatic, Antibacterial, antimycotic, antioxidant and cytotoxic activities of the compounds were evaluated in vitro, while their analgesic and anti-inflammatory action was tested in vivo along with acute toxicity studies. N-Unsubstituted 4-nitrosopyrazoles were the most effective tuberculostatics (MIC to 0.36 μg/ml) and Antibacterial agents against Streptococcus pyogenes (MIC to 7.8 μg/ml), Staphylococcus aureus,S. aureus MRSA and Neisseria gonorrhoeae (MIC to 15.6 μg/ml). 4-Nitroso-1-methyl-5-phenylpyrazole had the pronounced antimycotic action against a wide range of fungi (Trichophytonrubrum, T. tonsurans, T. violaceum, T. interdigitale, Epidermophytonfloccosum, Microsporumcanis with MIC 0.38-12.5 μg/ml). N-Unsubstituted 4-aminopyrazoles shown high radical-scavenging activity in ABTS test, ORAC/AAPH and oxidative erythrocyte hemolysis assays. 1-Methyl-5-phenyl-3-trifluoromethylpyrazol-4-aminium chloride revealed potential Anticancer activity against HeLa cells (SI > 1351). The pronounced analgesic activity was found for 4-nitroso- and 4-aminopyrazoles having phenyl fragment at the position 5 in "hot plate" test. The most of the obtained pyrazoles had a moderate acute toxicity.

Keywords

4-Hydroxyiminopyrazolines; ADME calculations; Acute toxicity; Analgesic activity; Antibacterial; Antimycotic; Antioxidant; Cytotoxic; Trifluoromethyl-containing 4-amino- and 4-nitrosopyrazoles; Tuberculostatic.

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