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The Synthesis and Anti-inflammatory Studies of New Pyrimidine Derivatives, Inhibitors of Cyclooxygenase Isoforms

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Abstract—

Using the molecular docking approach the simulation of the complex formation of 17 uracil derivatives containing cyclic and acyclic sulfur- and oxygen substituents in the pyrimidine cycle with active centers of cyclooxygenase isoforms (COX) was performed. Of the set tested, two leading compounds were identified, namely, conjugates of 5-hydroxy-1,3,6-trimethyluracil with N-phthalyl-L-amino acids, which can be effective inhibitors of COX isoforms induced during inflammatory processes in the organism with an increased selectivity towards COX-2. The synthesized compounds were evaluated in vivo on the models of inflammation caused by carrageenan, lidocaine, egg white, and formalin. The conjugates of 5-hydroxy-1,3,6-trimethyluracil with N-phthalyl alanine and N-phthalyl methionine displayed pronounced anti-inflammatory activities with the efficacy comparable to that of Ortofen. The isoenzyme-specific inhibition of COX isoforms was assessed and the pronounced anti-inflammatory activity of the synthesized compounds was found.

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Funding

The work was supported by the Russian Scientific Foundation, project no. 19-73-20073 and state tasks of Ufa Institute of Chemistry, Russian Academy of Sciences, projects nos. 122031400278-2 and 122031400274-4.

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Authors and Affiliations

  1. Ufa Institute of Chemistry, Structural Subdivision of the Federal State Budgetary Scientific Institution, Ufa Federal Research Center, Russian Academy of Sciences, 450054, Ufa, Russia

    Y. Z. Khazimullina, A. R. Gimadieva & A. G. Mustafin

  2. Federal State Budgetary Educational Institution of Higher Education Bashkir State University, 450076, Ufa, Russia

    V. R. Khairullina & A. G. Mustafin

  3. Institute of Biochemistry and Genetics, Separate Structural Subdivision of the Federal State Budgetary Scientific Institution, Ufa Federal Research Center, Russian Academy of Sciences, 450054, Ufa, Russia

    L. F. Zainullina & Y. V. Vakhitova

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  1. Y. Z. Khazimullina
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  4. L. F. Zainullina
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Correspondence to Y. Z. Khazimullina.

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Translated by E. Shirokova

Abbreviations: COX, cyclooxygenase; IC50, a concentration when 50% inhibition is achieved; NSAIDs, nonsteroidal anti-inflammatory drugs.

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Khazimullina, Y.Z., Gimadieva, A.R., Khairullina, V.R. et al. The Synthesis and Anti-inflammatory Studies of New Pyrimidine Derivatives, Inhibitors of Cyclooxygenase Isoforms. Russ J Bioorg Chem 48, 1027–1035 (2022). https://doi.org/10.1134/S1068162022050107

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