Синтез 1-нафтиламідів 2-іміно-2Н-хромен-3-карбонових кислот та їхній вплив на проліферацію клітинних культур ракових пухлин

I. Ye. Bylov; S. M. Kovalenko; S. V. Baiurka

doi:10.14739/2409-2932.2026.2.355802

Authors

I. Ye. Bylov National University of Pharmacy, Kharkiv, Ukraine https://orcid.org/0000-0001-7685-465X
S. M. Kovalenko V. N. Karazin Kharkiv National University, Ukraine https://orcid.org/0000-0003-2222-8180
S. V. Baiurka National University of Pharmacy, Kharkiv, Ukraine https://orcid.org/0000-0001-7505-6322

DOI:

https://doi.org/10.14739/2409-2932.2026.2.355802

Keywords:

organic synthesis, 2-imino-2H-chromenes, coumarin-3-carboxylic acid, 1-naphthylamides, antiproliferative activity, antitumor agents

Abstract

Aim. The study aimed to identify new pharmacologically active compounds among derivatives of 2-imino-2H-chromene-3-carboxylic acids, specifically through the synthesis of 1-naphthylamides of these acids and evaluation of their effects on cancer cell proliferation.

Materials and methods. Organic synthesis was performed, and the structures of the synthesized compounds were confirmed using instrumental analytical techniques. Pharmacological screening was subsequently conducted.

Results. N-(1-naphthyl)cyanoacetamide was obtained by reacting 1-naphthylamine with ethyl cyanoacetate under heating. This intermediate was then converted into N-(1 naphthyl)amides of 2-imino-2H-chromene-3-carboxylic acids via Knoevenagel condensation with salicylic aldehydes. The reaction was carried out in 2-propanol with piperidine as a catalyst. The in vitro antiproliferative activity of the synthesized compounds was tested against cell lines of common human tumors: leukemia (6 lines), lung cancer (9), colon cancer (7), renal cancer (8), ovarian cancer (6), prostate cancer (2), breast cancer (8), CNS tumors (6), and melanoma (8). Activity was assessed by comparing the optical density of cell cultures stained with sulforhodamine B before and after exposure to the test compounds dissolved in dimethyl sulfoxide.

Conclusions. In vitro testing revealed that 7-hydroxy-2-imino-2H-chromene-3-[N-(1-naphthyl)]carboxamide (4d) exhibited the highest activity, significantly inhibiting the growth of most cultures (GI₅₀ 1.5–4.5 μM), with potency equal to or exceeding that of the reference drug. Furthermore, 6-methoxy-2-imino-2H-chromene-3-[N-(1-naphthyl)]carboxamide (4b) showed pronounced selectivity and efficacy against breast cancer cell lines MDA MB 435 (GI₅₀ 0.32 μM) and MDA N (GI₅₀ 0.46 μM), surpassing the reference drug severalfold. These findings experimentally confirm that the presence of a hydroxyl group at the 7^th position of the 2H-chromene ring enhances activity, consistent with literature reports on the ability of related amides to inhibit tyrosine kinase enzymes.

Author Biographies

I. Ye. Bylov, National University of Pharmacy, Kharkiv

PhD, Associate Professor of the Department of General Chemistry

S. M. Kovalenko, V. N. Karazin Kharkiv National University

PhD, DSc, Professor of the Department of Organic Chemistry, School of Chemistry

S. V. Baiurka, National University of Pharmacy, Kharkiv

PhD, DSc, Professor of the Department of Pharmaceutical Chemistry

References

Bylov IE, Vasylyev MV, Bilokin YV. Synthesis and Anti-inflammatory Activity of N-substituted 2-oxo-2H-1-benzopyran-3-carboxamides and Their 2-iminoanalogs. Eur J Med Chem. 1999;34(11):997-1001. doi: https://doi.org/10.1016/s0223-5234(99)00119-1
| |
Bylov IE, Zhuravel IO, Bryzytska OA, Kolisnyk SV, Baiurka SV. Synthesis of phenyl esters 2-oxo-2H-1-benzopyran-3-carboxylic acids as promising antimicrobial agents. Voprosy khimii i khimicheskoi tekhnologii. 2024;(3):30-6. doi: https://doi.org/10.32434/0321-4095-2024-154-3-30-36
|
Asadipour A, Alipour M, Jafari M, Khoobi M, Emami S, Nadri H, et al. Novel coumarin-3-carboxamides bearing N-benzylpiperidine moiety as potent acetylcholinesterase inhibitors. Eur J Med Chem. 2013;70:623-30. doi: https://doi.org/110.1016/j.ejmech.2013.10.024
| |
Mesiti F, Gaspar A, Chavarria D, Maruca, A Rocca R, Martins EG, et al. Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas? J Med Chem. 2021;64:11169-82. doi: https://doi.org/10.1021/acs.jmedchem.1c00510
| |
Robert S, Bertolla C, Masereel B, Dogne´ J-M, Pochet L. Novel 3-Carboxamidecoumarins as Potent and Selective FXIIa Inhibitors. J Med Chem. 2008;51(11):3077-80. doi: https://doi.org/10.1021/jm8002697
| |
Çelik-onar H, Bayramoğlu G, Mataraci-kara E. Synthesis and antimicrobially activities of coumarin-3-carboxamide derivatives. Rev Roum Chim. 2023;68(1-2):85-9. doi: https://doi.org/10.33224/rrch.2023.68.1-2.08
|
Yu X, Teng P, Zhang YL, Xu ZJ, Zhang MZ, Zhang WH. Design, synthesis and antifungal activity evaluation of coumarin-3-carboxamide derivatives. Fitoterapia. 2018;127(6):387-95. doi: https://doi.org/10.1016/j.fitote.2018.03.013
| |
Shaheen HM, Nyemb JN, Segueni N, George J, Patil VR, Batiha GE. Anticancer Properties and Clinical Trials of Coumarins: A Review. Free Radicals Antioxid. 2022;12(2):41-8. doi: https://doi.org/10.5530/fra.2022.2.8
Weber US, Steffen B, Siegers CP. Antitumor activities of coumarin, 7-hydroxycoumarin and its glucuronide in several human tumor cell lines. Res Commun Molec Pathol Pharmacol. 1998;99(2):193-206.
Burke TR, Lim B, Marquez VE, Zhen-Hong L, Bolen JB, Stefanova I, et al. Byciclic compounds as ring-contrained inhibitors of protein – tyrosine kinase p56lck1. J Med Chem. 1993;36(4):425-32. doi: https://doi.org/10.1021/jm00056a001
| |
Huang CK, Wu FY, Ai YX. Polyhydroxylated 3-(N-phenyl) carbamoyl-2-iminochromene derivatives as potent inhibitors of tyrosine kinase p60c-src. Bioorg Med Chem Lett. 1995;5(20):2423-8. doi: https://doi.org/10.1016/0960-894X(95)00422-P
|
Koley M, Han J, Soloshonok VA, Mojumder S, Javahershenas R, Makarem A. Latest developments in coumarin-based anticancer agents: mechanism of action and structure-activity relationship studies. RSC Med Chem. 2023;15(1):10-54. doi: https://doi.org/10.1039/d3md00511a
| |
Lakshmi Ranganatha V, Zameer F, Meghashri S, Rekha ND, Girish V, Gurupadaswamy HD, et al. Design, synthesis, and anticancer properties of novel benzophenone-conjugated coumarin analogs. Arch Pharm (Weinheim). 2013;346(12):901-11. doi: https://doi.org/10.1002/ardp.201300298
| |
Rawat A, Vijaya Bhaskar Reddy A. Recent advances on anticancer activity of coumarin derivatives Eur J Med Chem Rep. 2022;5:100038. doi: https://doi.org/10.1016/j.ejmcr.2022.100038
|
Phutdhawong W, Chuenchid A, Taechowisan T, Sirirak J, Phutdhawong WS. Synthesis and Biological Activity Evaluation of Coumarin-3-Carboxamide Derivatives. Мolecules. 2021;26(6):1653. doi: https://doi.org/10.3390/molecules26061653
| |
Shi J, Lu W, Chen J, Sun L, Yang S, Zhou M, et al. Synthesis, antiproliferative activities, and DNA binding of coumarin-3-formamido derivatives. Arch Pharm. 2021;354(2):2000236. doi: https://doi.org/10.1002/ardp.202000236
| |
Toolabi M, Basiri A, Yaghouti FD, Safdarian M, Ayati A, Mojaddami A. Coumarin derivatives as potential anticancer agents: Synthesis, antiproliferative activity, apoptosis, and molecular docking studies. Results Chem. 2025;16:102442. doi: https://doi.org/10.1016/j.rechem.2025.102442
|
Bhat AA, Kaur G, Tandon N, Tandon R, Singh I. Current advancements in synthesis, anticancer activity, and structure–activity relationship (SAR) of coumarin derivatives Inorganic Chemistry Communications 2024;167(9):112605 doi: https://doi.org/10.1016/j.inoche.2024.112605
|
Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology, Updates, vol. 3. Philadelphia: Lippincott; 1989:1-12.