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Pharm Sci. 2021;27(3): 353-365.
doi: 10.34172/PS.2020.100
  Abstract View: 163
  PDF Download: 38

Research Article

Synthesis, Anti-Inflammatory Activity and Molecular Docking Studies of 1,4,5,6-Tetrahydropyrimidine-2-Carboxamides

Volodymyr Ya. Horishny 1, Pavlo V. Zadorozhnii 2* ORCID logo, Ivanna V. Horishnia 1, Vasyl S. Matiychuk 3 ORCID logo

1 Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv, 79010, Ukraine.
2 Department of Pharmacy and Technology of Organic Substances, Ukrainian State University of Chemical Technology, Gagarin Ave., 8, Dnipro 49005, Ukraine.
3 Department of Organic Chemistry, Ivan Franko National University of Lviv, 6 Kyryla і Mefodia, Lviv, 79005, Ukraine.

Abstract

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. The widespread use of NSAIDs is associated with a number of serious side effects and complications observed for both selective and non-selective COX inhibitors. Therefore, the search for new COX inhibitors, which along with their effectiveness will have minimal side effects, is a very important and urgent task.
Methods: This work studied the synthesis of new 1,4,5,6-tetrahydropyrimidine-2-carboxamides based on the reaction of 2-morpholin-4-yl-N-(het)aryl-2-thioxoacetamides with 1,3-diaminopropane. All obtained compounds were tested for anti-inflammatory activity in vitro and in silico conditions. All synthesized 1,4,5,6-tetrahydropyrimidine-2-carboxamides were tested for influence on the course of the exudative phase of the inflammatory process based on the carrageenan model of paw edema of laboratory nonlinear heterosexual white rats weighing 220-250 g, using Diclofenac as a reference. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package.
Results: The target products were obtained with yields of 71-98% and easily isolated from the reaction mixture. The best anti-inflammatory activity was found in N-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine-2-carboxamide and in N-[4-chloro-3-(trifluoromethyl)phenyl]-1,4,5,6-tetrahydropyrimidine-2-carboxamide, suppression of the inflammatory response was 46.7 and 46.4%, respectively. The results of molecular docking with COX-1 and COX-2 enzymes were in good agreement with the experimental data, R2 ˃ 0.92 and R2 ˃ 0.83, respectively.
Conclusion: The compounds under study were shown to be promising as potential anti-inflammatory agents.
Keywords: Tetrahydropyrimidine, COX-1, COX-2, Antiinflammatory activity, SAR analysis, Molecular docking
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Submitted: 26 Sep 2020
Revision: 26 Nov 2020
Accepted: 18 Dec 2020
ePublished: 18 Dec 2020
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