Exploring the Antiproliferative Potency of Pyrido[2,3-d]Pyrimidine Derivatives: Studies on Design, Synthesis, Anticancer Evaluation, SAR, Docking, and DFT Calculations.

Autor: Abd-Alsalam E; Chemistry Department, Faculty of Science, Ain shams University, Abbassia, 11566, Cairo, Egypt., Hafez HN; National Research Center, Photochemistry Department (Heterocyclic Unit), Dokki, 12622, Cairo, Egypt., Assay MG; Chemistry Department, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt., Ali AK; Chemistry Department, Faculty of Science, Ain shams University, Abbassia, 11566, Cairo, Egypt., El-Farargy AF; Chemistry Department, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt., Abbass EM; Chemistry Department, Faculty of Science, Ain shams University, Abbassia, 11566, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Chemistry & biodiversity [Chem Biodivers] 2024 Feb; Vol. 21 (2), pp. e202301682. Date of Electronic Publication: 2024 Jan 11.
DOI: 10.1002/cbdv.202301682
Abstrakt: Herein, an efficient method for the synthesis of a new series of pyrido[2,3-d]pyrimidine derivatives has been adopted through the reaction of hydrazinyl pyrido[2,3-d] pyrimidine derivative (1) with different electrophilic species, such as ethyl cyanoacetate and different 1,3 diketone derivatives, gave the corresponding derivatives (2-5). Meanwhile, pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines (6-11) were synthesized via reaction of hydrazine derivative 1 with phenylisothiocyanate, potassium thiocyanate, and carbon disulfide. Compound 1 was also submitted to react with different carbonyl compounds to afford pyrido-pyrimidine derivatives (12-15). All the newly synthesized compounds were tested in vitro for their antiproliferative activities against HCT-116 and MCF-7 cell lines. Compounds 2, 3, 7, and 8 displayed very strong inhibitory activity against the two cell lines compared with the standard drug doxorubicin. Furthermore, a docking study of the most active compounds was performed with the thymidylate synthase enzyme (PDB: Code 6qxg). Moreover, DFT calculation was carried out for the most biologically active compounds and a reference drug (Doxorubicin) using the B3LYP/6-31G+(d,p) level of theory. The calculated E HOMO and E LUMO energies were used to calculate the global reactivity parameters. Finally, Molecular electrostatic potential (MEP) and structure activity relationship (SAR) were studied to correlate the relation between chemical structure and reactivity.
(© 2023 Wiley-VHCA AG, Zurich, Switzerland.)
Databáze: MEDLINE
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