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image of New 4-Benzenesulfonamide Derivatives of Pyrazolo[1,5-a][1,3,5]triazine as Purine Bioisosteres: Development, Synthesis, and Anticancer Perspective
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Abstract

Introduction

Seven new 4-[2-(dichloromethyl)pyrazolo[1,5-][1,3,5]triazine derivatives were investigated for anticancer activity, possible molecular mechanisms of anticancer action, and ADMET properties.

Methods

The 4-benzenesulfonamide derivatives of pyrazolo[1,5-][1,3,5]triazine were synthesized using the condensation of -(2,2-dichloro-1-cyanovinyl)-amides IV with 1-pyrazol-5-amine. Compound antitumor activities were evaluated using the NCI-60 human cancer cell line. AutoDockTools and AutoDock Vina software were used for molecular modeling. Using the ADMETlab 3.0 and pkCSM web sources, the ADMET properties of compounds , , and were calculated.

Results

Seven new pyrazolo[1,5-][1,3,5]triazine derivatives were synthesized. The compounds , , and exhibit high activity >1 µM against leukemia, colon, and renal cancer. Compound 4 exhibited the most potent activity, with IC values of 0.32  µM against leukemia, 0.49-0.89  µM against colon cancer, and 0.92  µM against renal cancer. Molecular modeling has demonstrated a potential antitumor mechanism involving CDK. The predicted ADMET profile of compounds , , and is favorable.

Discussion

The seven novel pyrazolo[1,5-][1,3,5]triazines, as purine bioisosteres, were developed, synthesized, and investigated by and methods.

Conclusion

Seven novel pyrazolo[1,5-][1,3,5]triazine derivatives exhibited anticancer activity against the NCI-60 cancer cell lines. The compounds , , and demonstrated strong anticancer activity, with growth inhibition (GI) values exceeding 50% across all nine cancer types tested. The most active compound, , is against leukemia, colon cancer, renal cancer, and lung cancer. All compounds exhibit low toxicity, with LC values of 100 µM or greater. The molecular docking of compounds , , and revealed the potential to inhibit cancer-associated cyclin-dependent kinases. The predicted ADMET profiles of their compounds are favorable, providing a basis for further improvement of their anticancer activity.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-07-31
2025-11-04

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New 4-Benzenesulfonamide Derivatives of Pyrazolo[1,5-a][1,3,5]triazine as Purine Bioisosteres: Development, Synthesis, and Anticancer Perspective
Bentham Science Publishers ; https://doi.org/10.2174/0109298673385989250711112625
/content/journals/cmc/10.2174/0109298673385989250711112625
/content/journals/cmc/10.2174/0109298673385989250711112625
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  • Article Type:     Research Article
Keywords: benzenesulfonamide ; purine bioisosteres ; CDK2 ; anticancer agent ; cancer ; cyclin-dependent kinase ; Pyrazolo[1,5-a][1,3,5]triazine

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