Synthesis, structural characterization and antitumor activity of new chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazole derivatives

Authors

DOI:

https://doi.org/10.15587/2519-4852.2025.341796

Keywords:

anticancer activity, thiopyrano[2,3-d]thiazoles, Knoevenagel condensation, hetero-Diels–Alder reaction, domino reaction

Abstract

The development of heterocyclic compounds with significant biological activity remains a priority in modern medicinal chemistry. The use of cascade domino reactions, such as Knoevenagel condensation combined with hetero-Diels-Alder cyclization, enables the efficient construction of complex structures with potential anticancer properties.

The aim of the study. To synthesize a series of thiopyrano[2,3-d]thiazole derivatives via a cascade Knoevenagel–hetero-Diels–Alder reaction followed by N3-alkylation and evaluate their in vitro antitumor activity in the NCI-60 human cancer cell line panel.

Materials and methods. Structural identification of the compounds was carried out using NMR spectroscopy in DMSO-d₆ with tetramethylsilane (TMS) as the internal standard, and LC-MS analysis with an APCI mass-selective detector. Biological activity was assessed using the NCI-60 screening program, which includes a panel of 60 human cancer cell lines of various origins. Key parameters such as growth inhibition (GI₅₀), lethal concentration (LC₅₀), and cytotoxicity at micromolar concentrations were determined.

Results. A series of thiopyrano[2,3-d]thiazole derivatives were synthesized through a two-step domino Knoevenagel condensation and intramolecular hetero-Diels–Alder cyclization between 4-thioxo-2-oxothiazolidinone and O-alkylated salicylaldehyde derivatives bearing allylic or propargyl substituents. Subsequent N3-alkylation yielded compounds 3.1 (60.0%), 3.2 (67.0%), and 4 (58.0%). Introduction of a piperidine moiety enabled the synthesis of water-soluble methanesulfonate salt 5 (70.0%). Reaction with 2,5-(2-propynyloxy)benzaldehyde led to in situ aromatization and the formation of a stable compound 8. Four compounds were tested for anticancer activity. Compound 8 showed the highest efficacy, causing complete cell death in OVCAR-4 (Ovarian Cancer, LC₅₀ = 29.5 μM) and strong growth inhibition in SR (Leukemia, GI₅₀ = 0.676 μM), 786-0 (Renal Cancer, GI₅₀ = 0.696 μM), A498 (Renal Cancer, GI₅₀ = 0.528 μM), and BT-549 (Breast Cancer, GI₅₀ = 0.666 μM) cells.

Conclusions. The proposed synthetic methodology enables efficient preparation of structurally diverse thiopyrano[2,3-d]thiazole derivatives in high yields. N3-alkylation and incorporation of a piperidine fragment allowed for the synthesis of a water-soluble methanesulfonate salt 5. Among the tested compounds, compound 8 exhibited the most promising cytotoxicity and selectivity towards several cancer cell lines, suggesting its potential as a lead compound for further preclinical development of novel anticancer agents

Supporting Agency

  • Research project "Search for novel potential anticonvulsant agents for the treatment of post-traumatic epilepsy in military personnel and the civilian population", funded by the Ministry of Education and Science of Ukraine (Project registration number: 0125U001794)

Author Biographies

Mykhailo Hoidyk, Danylo Halytsky Lviv National Medical University

PhD Student

Department of Pharmaceutical, Organic and Bioorganic Chemistry

Andriy Karkhut, Lviv Polytechnic National University

PhD, Associate Professor

Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology

Sviatoslav Polovkovych, Lviv Polytechnic National University

Doctor of Chemical Sciences, Professor

Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology

Roman Lesyk, Danylo Halytsky Lviv National Medical University

Doctor of Pharmaceutical Sciences, Professor

Department of Pharmaceutical, Organic and Bioorganic Chemistry

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Synthesis, structural characterization and antitumor activity of new chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazole derivatives

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2025-10-31

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Hoidyk, M., Karkhut, A., Polovkovych, S., & Lesyk, R. (2025). Synthesis, structural characterization and antitumor activity of new chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazole derivatives. ScienceRise: Pharmaceutical Science, (5 (57), 37–49. https://doi.org/10.15587/2519-4852.2025.341796

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