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Synthesis and Biological Evaluation of Polyfluoroalkylated Antipyrines and their Isomeric O-Methylpyrazoles

Author(s):

Natalya Agafonova, Evgeny Shchegolkov*, Yanina Burgart, Victor Saloutin, Alexandra Trefilova, Galina Triandafilova, Sergey Solodnikov, Vera Maslova, Sophia Borisevich, Olga Krasnykh and Sergey Khursan   Pages 1 - 16 ( 16 )

Abstract:


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. Results: We developed the convenient methods for regioselective methylation of 1-aryl-3- polyfluoroalkylpyrazol-5-ols leading to the synthesis N-methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time, the biological properties of new derivatives were investigated in vitro and in vivo. Conclusion: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties.

Keywords:

Polyfluoroalkyl-containing antipyrine , Analgesic and anti-inflammatory activities, Toxicity, Permeability , Molecular docking

Affiliation:

Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoy Str., 22, Ekaterinburg 620990, Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoy Str., 22, Ekaterinburg 620990, Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoy Str., 22, Ekaterinburg 620990, Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskoy Str., 22, Ekaterinburg 620990, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990, Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078



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