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

• 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
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-023-03131-w

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.