Novel Pyrimidine Derivatives as Antioxidant and Anticancer Agents: Design, Synthesis and Molecular Modeling Studies

Abstract

The heterocyclic ring system of pyrido [2,3-d]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 α,β-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% w/v in ethanol. All the synthesized compounds were characterized using IR, 1H-NMR, 13C-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 2a (IC50 = 42 μΜ), 2f (IC50 = 47.5 μΜ) and chalcone 1g (IC50 = 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 2d presenting the strongest cytotoxic effects at the concentration of 50 μΜ.

Synthesis and Antioxidant Activities of Novel Pyrimidine Acrylamides as Inhibitors of Lipoxygenase: Molecular Modeling and In Silico Physicochemical Studies

“…The absorbance was recorded at 517 nm after 20 and 60 min at room temperature ( Table 2 ). The test follows our previous published methods [ 31 , 73 ].…”

“…A considerable number of clinically used drugs such as minoxidil, phenobarbital, primidone, zidovudine, stavudine, 5-flurouracil, methotrexate, imatinib, dasatinib, pazopanib, nilotinib, cytarabine, uramustine, tegafur, risperidone, sulfamethazine and trimethoprim contain the pyrimidine heterocyclic scaffold [ 14 , 15 ]. In recent years, diverse biological activities of pyrimidine derivatives, including anticancer [ 16 , 17 ], antibacterial [ 18 , 19 , 20 ], antifungal [ 21 ], antitubercular [ 21 , 22 ], antimalarial [ 23 ], antiviral [ 24 , 25 , 26 ], analgesic [ 27 ], antioxidant [ 28 , 29 ], anti-lipoxygenase [ 30 , 31 ] and anti-inflammatory activities have been reported [ 32 , 33 ]. Thus, the pyrimidine ring can be considered as a promising pharmacophoric scaffold for the synthesis of novel bioactive molecules for the treatment of various diseases.…”

A review on pyrimidine‐based derivatives: Synthesis and their biological application

“…Recently, Pontiki's group observed that some pyrimidine compounds showed limited interaction with DPPH but exhibited significant inhibition of lipid peroxidation (Figure 21) [101]. In this study, samples (e.g., compound 71) were tested using AAPH (2,2 0 -Azobis(2-methylpropionamidine) dihydrochloride) to generate peroxy radicals, with sodium linoleate undergoing peroxidation.…”

Synthesis, photophysical properties, anticancer evaluation, and molecular docking studies of new pyrimidine linked 4‐arylidene‐thiazolidin‐4‐ones as potent anticancer agents

“…Analogues based on pyrimidine and its annulated heterocyclic compounds have garnered significant interest due to their diverse biological properties, including antimicrobial [1][2][3], anti-inflammatory [4,5], antioxidant [6,7], antiviral [8], and antitumour [9][10][11][12] effectiveness.…”