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In Vitro Anticancer Activity and In Silico Target Profiling of 5-(Piperazin-1-ylsulfonyl)-1,3-oxazole-4-carbonitriles
Oleksandr O Severin1,2, Denys Bondar1,3, Olga Bragina1
1Department of Chemistry and Biotechnology, Tallinn University of Technology (TalTech), 15 Akadeemia Rd., 12618 Tallinn, Estonia.
International Journal of Molecular Sciences
|February 27, 2026
Summary
New anticancer agents, oxazole-4-carbonitriles, show potent activity against neuroblastoma and other cancer cells. Lead compounds exhibit high selectivity and a promising kinase-directed mechanism, warranting further investigation.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Biology
Background:
- Novel anticancer agents are crucial for overcoming drug resistance and improving patient outcomes.
- Piperazine-substituted oxazole-carbonitriles represent a class of compounds with potential therapeutic applications.
Purpose of the Study:
- To synthesize and evaluate sulfonylated 5-piperazine-substituted 1,3-oxazole-4-carbonitriles for in vitro anticancer activity.
- To identify lead compounds with potent and selective cytotoxicity against various cancer cell lines.
- To investigate the potential mechanism of action and pharmacokinetic properties of the lead compounds.
Main Methods:
- Synthesis of sulfonylated 5-piperazine-substituted 1,3-oxazole-4-carbonitriles.
- In vitro cytotoxicity assays using a panel of human cancer cell lines (hepatocellular, breast, cervical, melanoma, neuroblastoma) and a non-malignant control (HEK293).
- In silico molecular docking studies to predict interactions with cancer-associated proteins (e.g., Aurora A kinase, CDKs).
- Assessment of predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties.
Main Results:
- Compounds 7a, 7b, and 8aa were identified as lead structures with significant in vitro anticancer activity.
- Compound 7b demonstrated potent activity against neuroblastoma cells (Kelly) with an IC50 of 1.3 µM and low toxicity to HEK293 cells (IC50 > 10 µM).
- In silico analysis predicted favorable interactions with Aurora A kinase and cyclin-dependent kinases, suggesting a kinase-directed mechanism.
- Predicted ADMET properties were comparable to doxorubicin, though the compounds showed limited biodegradability.
Conclusions:
- Sulfonylated 5-piperazine-substituted 1,3-oxazole-4-carbonitriles are promising anticancer candidates.
- Compound 7b exhibits a favorable selectivity profile and potent activity against neuroblastoma.
- The identified compounds possess a potential kinase-directed mechanism of action, supporting further preclinical development.
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