1 Laboratory of Thermodynamics and Physical Chemistry of the Environment, NANGUI ABROGOUA University, Abidjan, Republic of Côte-d'Ivoire.
2 Biological Sciences Department, Université Peleforo Gon Coulibaly, Korhogo, Republic of Côte-d'Ivoire.
3 Ivorian Research Group in Disease Modeling (GIR2M), Abidjan, Ivory Coast.
Research Article
World Journal of Advanced Research and Reviews, 2024, 24(02), 2676–2691
Received on 07 October 2024; revised on 28 November 2024; accepted on 30 November 2024
Three pyrimidine derivatives, namely 4-[4-(dimethylamino)phenyl]-6-(pyridin-4-yl)pyrimidin-2-amine (DMPN), 4-(4-aminophenyl)-6-[4-(dimethylamino)phenyl]pyrimidin-2-ol (DMPO) and 4-(4-aminophenyl)-6-[4-(dimethylamino)phenyl]pyrimidine-2-thiol (DMPS), with analgesic properties established by a QSAR study, were subjected to reactivity parameter studies using the DFT method, at the B3LYP/6-311++G(d,p) level of theory. Studies of the docking of these molecules to cyclooxygenases 1 (PDB ID: 5U6X) and 2 (PDB ID: 5F19) were also carried out using the CB-Dock online program. Reactivity parameter calculations revealed that the three derivatives are less stable to internal electron transfer, with the lowest energy gap ∆E ranging from 3.63 eV to 3.88 eV, compared with 6.03 eV for ibuprofen (IBP). These derivatives possess the lowest chemical hardnesses η from 1.81eV to 1.94eV versus 3.02eV for IBP and are better electrophiles than IBP with chemical electrophilicity index values ω from 3.20eV to 3.88eV versus 2.64eV for IBP. These derivatives possess greater chemical reactivity than ibuprofen. All three derivatives also feature electrophilic and nucleophilic attack sites. The docking results show that all three derivatives react with cyclooxygenases in the same areas of reactivity as most NSAIDs. These ligands are more active on COX-2 than COX-1, according to complex stability scores which are stronger with COX-2 than with COX-1. In addition, all three derivatives are more active on COX-2 than ibuprofen, with stability score values of -8.6 kcal/mol for DMPN, -9.2 kcal/mol for DMPO, -8.9 kcal/mol for DMPS and -7.6 kcal/mol for IBP. The DMPO ligand forms the most stable complex with COX-2. These three derivatives thus appear to be selective COX-2 inhibitors, with higher stability scores than ibuprofen. All three derivatives also have good absorption, distribution, metabolism and toxicity properties. They can therefore be used as drugs.
Pyrimidine Derivatives; Analgesic; Molecular Docking; Cyclooxygenase; DFT.
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Jean Missa Ehouman, Georges Stéphane Dembélé, Mamadou Guy-Richard Koné, Donourou Diabaté, Yafigui Traoré and Nahossé Ziao. Reactivity of three pyrimidine derivatives, potential analgesics, by the DFT method and study of their docking on cyclooxygenases-1 and 2. World Journal of Advanced Research and Reviews, 2024, 24(2), 2676-2691. Article DOI: https://doi.org/10.30574/wjarr.2024.24.2.3497