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, Olga Krasnykh, Sophia Borisevich, Sergey Khursan.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 5 , 2019

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Graphical 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: Methylation, 1H-pyrazol-5-ols, polyfluoroalkyl-containing antipyrine, analgesic and anti-inflammatory activities, toxicity, permeability, molecular docking, COX-1/2 inhibitor.

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Year: 2019
Page: [521 - 536]
Pages: 16
DOI: 10.2174/1573406414666181106145435
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