Anticancer activity of new triazolopyrimidine linked coumarin and quinolone hybrids: Synthesis, molecular modeling, TrkA, PI3K/AKT and EGFR inhibition

• Published in: Journal of molecular structure Vol. 1305; p. 137790
• Main Authors: Batran, Rasha Z., Ahmed, Eman Y., Nossier, Eman S., Awad, Hanem M., Abdel Latif, Nehad A.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.06.2024
• Subjects: Anticancer; Coumarin: Quinolone; EGFR; Molecular docking; PI3K/AKT; TrkA; Coumarin: Quinolone; TrkA; Anticancer; EGFR; Molecular docking; PI3K/AKT
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2024.137790

•A series of coumarin and quinolone based pyrazolopyrimidines was synthesized.•The new compounds showed promising anticancer effect against HCT-116, HepG2 and MCF-7 cell lines.•One of the quinolone derivatives 4e showed significant inhibition activity towards TrKA, EGFR and PI3K/AKT, induced apoptosis and arrested the cell cycle.•Molecular docking of 4e, showed the ability of the derivative to interact with the key amino acids in the target proteins binding sites.•Compound 4e exhibited favorable physicochemical properties and pharmacokinetic parameters. A series of coumarin and quinolone based triazolopyrimidines was designed and synthesized utilizing molecular hybridization approach, the derivatives were examined for their antiproliferative activity against HCT-116, HepG2, MCF-7 and normal cells using the LDH assay. The results revealed that most of the synthesized compounds exhibited notable activity towards cancer cells with no cytotoxicity on normal cells. Compounds 4a and 4e were investigated for their Trk, PI3K/AKT and EGFR inhibitory activities. The results suggested that compound 4e demonstrated better inhibitory activity than compound 4a on the target proteins and was capable of arresting the cell cycle at G1 phase and inducing apoptosis. Furthermore, the promising compounds displayed a remarkable binding mode into the target proteins binding site as indicated by the molecular docking study. The in silico physicochemical properties of compounds 4a and 4e were studied, as well. [Display omitted]