Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies
The heterocyclic ring system of pyrido [2,3-<i>d</i>]pyrimidines is a privileged scaffold in medicinal chemistry, possessing several biological activities. The synthesis of the pyrimidine derivatives was performed via the condensation of a suitable <i>α,β</i>-unsaturated keto...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/28/9/3913 |
| _version_ | 1797602112571441152 |
|---|---|
| author | Malama Myriagkou Evangelia Papakonstantinou Georgia-Eirini Deligiannidou Alexandros Patsilinakos Christos Kontogiorgis Eleni Pontiki |
| author_facet | Malama Myriagkou Evangelia Papakonstantinou Georgia-Eirini Deligiannidou Alexandros Patsilinakos Christos Kontogiorgis Eleni Pontiki |
| author_sort | Malama Myriagkou |
| collection | DOAJ |
| description | The heterocyclic ring system of pyrido [2,3-<i>d</i>]pyrimidines is a privileged scaffold in medicinal chemistry, possessing several biological activities. The synthesis of the pyrimidine derivatives was performed via the condensation of a suitable <i>α,β</i>-unsaturated ketone with 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate in glacial acetic acid. Chalcones were synthesized, as starting materials, via the Claisen–Schmidt condensation of an appropriately substituted ketone and an appropriately substituted aldehyde in the presence of aqueous KOH 40% <i>w/v</i> in ethanol. All the synthesized compounds were characterized using IR, <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, LC-MS and elemental analysis. The synthesized compounds were evaluated for their antioxidant (DPPH assay), anti-lipid peroxidation (AAPH), anti-LOX activities and ability to interact with glutathione. The compounds do not interact significantly with DPPH but strongly inhibit lipid peroxidation. Pyrimidine derivatives <b>2a</b> (IC<sub>50</sub> = 42 μΜ), <b>2f</b> (IC<sub>50</sub> = 47.5 μΜ) and chalcone <b>1g</b> (IC<sub>50</sub> = 17 μM) were the most potent lipoxygenase inhibitors. All the tested compounds were found to interact with glutathione, apart from 1h. Cell viability and cytotoxicity assays were performed with the HaCaT and A549 cell lines, respectively. In the MTT assay towards the HaCaT cell line, none of the compounds presented viability at 100 μM. On the contrary, in the MTT assay towards the A549 cell line, the tested compounds showed strong cytotoxicity at 100 μM, with derivative <b>2d</b> presenting the strongest cytotoxic effects at the concentration of 50 μΜ. |
| first_indexed | 2024-03-11T04:11:18Z |
| format | Article |
| id | doaj.art-98efeab15707416e9653a92dfe72cffa |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T04:11:18Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-98efeab15707416e9653a92dfe72cffa2023-11-17T23:25:09ZengMDPI AGMolecules1420-30492023-05-01289391310.3390/molecules28093913Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling StudiesMalama Myriagkou0Evangelia Papakonstantinou1Georgia-Eirini Deligiannidou2Alexandros Patsilinakos3Christos Kontogiorgis4Eleni Pontiki5Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceLaboratory of Hygiene and Environmental Protection, School of Medicine, Democritus University of Thrace, 25510 Alexandroupoli, GreeceLaboratory of Hygiene and Environmental Protection, School of Medicine, Democritus University of Thrace, 25510 Alexandroupoli, GreeceDepartment of Drug Chemistry and Technology, Sapienza University, 00185 Rome, ItalyLaboratory of Hygiene and Environmental Protection, School of Medicine, Democritus University of Thrace, 25510 Alexandroupoli, GreeceDepartment of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceThe heterocyclic ring system of pyrido [2,3-<i>d</i>]pyrimidines is a privileged scaffold in medicinal chemistry, possessing several biological activities. The synthesis of the pyrimidine derivatives was performed via the condensation of a suitable <i>α,β</i>-unsaturated ketone with 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate in glacial acetic acid. Chalcones were synthesized, as starting materials, via the Claisen–Schmidt condensation of an appropriately substituted ketone and an appropriately substituted aldehyde in the presence of aqueous KOH 40% <i>w/v</i> in ethanol. All the synthesized compounds were characterized using IR, <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, LC-MS and elemental analysis. The synthesized compounds were evaluated for their antioxidant (DPPH assay), anti-lipid peroxidation (AAPH), anti-LOX activities and ability to interact with glutathione. The compounds do not interact significantly with DPPH but strongly inhibit lipid peroxidation. Pyrimidine derivatives <b>2a</b> (IC<sub>50</sub> = 42 μΜ), <b>2f</b> (IC<sub>50</sub> = 47.5 μΜ) and chalcone <b>1g</b> (IC<sub>50</sub> = 17 μM) were the most potent lipoxygenase inhibitors. All the tested compounds were found to interact with glutathione, apart from 1h. Cell viability and cytotoxicity assays were performed with the HaCaT and A549 cell lines, respectively. In the MTT assay towards the HaCaT cell line, none of the compounds presented viability at 100 μM. On the contrary, in the MTT assay towards the A549 cell line, the tested compounds showed strong cytotoxicity at 100 μM, with derivative <b>2d</b> presenting the strongest cytotoxic effects at the concentration of 50 μΜ.https://www.mdpi.com/1420-3049/28/9/3913antioxidantanti-inflammatorycytotoxicityHaCaTpyrimidine derivativesLOX inhibition |
| spellingShingle | Malama Myriagkou Evangelia Papakonstantinou Georgia-Eirini Deligiannidou Alexandros Patsilinakos Christos Kontogiorgis Eleni Pontiki Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies Molecules antioxidant anti-inflammatory cytotoxicity HaCaT pyrimidine derivatives LOX inhibition |
| title | Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies |
| title_full | Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies |
| title_fullStr | Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies |
| title_full_unstemmed | Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies |
| title_short | Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies |
| title_sort | novel pyrimidine derivatives as antioxidant and anticancer agents design synthesis and molecular modeling studies |
| topic | antioxidant anti-inflammatory cytotoxicity HaCaT pyrimidine derivatives LOX inhibition |
| url | https://www.mdpi.com/1420-3049/28/9/3913 |
| work_keys_str_mv | AT malamamyriagkou novelpyrimidinederivativesasantioxidantandanticanceragentsdesignsynthesisandmolecularmodelingstudies AT evangeliapapakonstantinou novelpyrimidinederivativesasantioxidantandanticanceragentsdesignsynthesisandmolecularmodelingstudies AT georgiaeirinideligiannidou novelpyrimidinederivativesasantioxidantandanticanceragentsdesignsynthesisandmolecularmodelingstudies AT alexandrospatsilinakos novelpyrimidinederivativesasantioxidantandanticanceragentsdesignsynthesisandmolecularmodelingstudies AT christoskontogiorgis novelpyrimidinederivativesasantioxidantandanticanceragentsdesignsynthesisandmolecularmodelingstudies AT elenipontiki novelpyrimidinederivativesasantioxidantandanticanceragentsdesignsynthesisandmolecularmodelingstudies |