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

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Abstract

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.

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Acknowledgements

The authors are grateful National Institute of Science and Technology on Molecular Sciences (INCT-CiMol), Grant CNPq 406804/2022-2, the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, 88887.824150/2023-00), and projeto de produtividade-PROPESQ/PRPG/UFPB (PVA13317-2020) for their financial support.

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Authors and Affiliations

  1. Department of Chemistry, CCEN, Federal University of Paraiba, João Pessoa, 58051-900, PB, Brazil

    Poliana Gomes de Abrantes, Paloma Gomes de Abrantes, Damião Alves dos Santos Silva, Renata Rodrigues Magalhães & Juliana Alves Vale

  2. Department of Physiology and Pharmacology, Bioscience Center, Federal University of Pernambuco, Recife, PE, 50670-901, Brazil

    Paulo Bruno Norberto da Silva & Gardenia Carmen Gadelha Militão

  3. Post-Graduate Program in Natural Synthetic Bioactive Products, Federal University of Paraiba, João Pessoa, 58051-900, PB, Brazil

    Renata Priscila Barros de Menezes, Luciana Scotti & Marcus Tullius Scotti

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  1. Poliana Gomes de Abrantes
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de Abrantes, P.G., de Abrantes, P.G., dos Santos Silva, D.A. et al. Synthesis of 2-amino-4H-chromenes catalyst-free via sequential Knoevenagel-Michael reaction and evaluation of biological activity in tumor cells. Med Chem Res 32, 2234–2244 (2023). https://doi.org/10.1007/s00044-023-03131-w

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