Synthesis of 2-amino-4H-chromenes catalyst-free via sequential Knoevenagel-Michael reaction and evaluation of biological activity in tumor cells

This work focuses on investigating solvents for the catalyst-free synthesis of 2-amino-4H-chromenes from salicylaldehydes and malononitrile through the Knoevenagel-Michael sequential reaction. The use of ethanol under reflux conditions resulted in the production of several 2-amino-4H-chromenes 5(a-g...

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Published in:Medicinal chemistry research 2023-10, Vol.32 (10), p.2234-2244
Main Authors: de Abrantes, Poliana Gomes, de Abrantes, Paloma Gomes, dos Santos Silva, Damião Alves, Magalhães, Renata Rodrigues, da Silva, Paulo Bruno Norberto, Militão, Gardenia Carmen Gadelha, de Menezes, Renata Priscila Barros, Scotti, Luciana, Scotti, Marcus Tullius, Vale, Juliana Alves
Format: Article
Language:English
Subjects:
Anticancer properties
Antitumor activity
Antitumor agents
BCR-ABL protein
Biochemistry
Biological activity
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Catalysts
Chemical synthesis
Chronic myeloid leukemia
Ethanol
Fusion protein
Imatinib
Inorganic Chemistry
Kinases
Leukemia
Malononitrile
Medicinal Chemistry
Michael reaction
Molecular docking
Myeloid leukemia
Original Research Article
Pharmacology/Toxicology
Tumor cells
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Summary:This work focuses on investigating solvents for the catalyst-free synthesis of 2-amino-4H-chromenes from salicylaldehydes and malononitrile through the Knoevenagel-Michael sequential reaction. The use of ethanol under reflux conditions resulted in the production of several 2-amino-4H-chromenes 5(a-g) with high isolated yields (75-93%) within a short reaction time (60-300 min). Notably, four new compounds, 2-amino-4H-chromenes 5(b,d,e,g), were synthesized for the first time. Virtual screening was performed on the most promising molecules (5b, 5e, and 5 f) against cell lines H-116 and K-562, with 5e demonstrating the most potential in antitumor activity. The in vitro assays validated the high potential exhibited by the 5e molecule, corroborating the in silico findings. Molecular docking analysis suggested a possible mechanism of action for the 5e molecule involving inhibition of the mutant T315l Abl protein. Mutations in the kinase domain of Bcr-Abl commonly lead to resistance to imatinib therapy in chronic myelogenous leukemia patients. This study represents the first investigation into the biological activity of this compound class, offering a promising starting point developing of new antitumor agents.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-023-03131-w