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

INTRODUCTION

Seven new 4-[2-(dichloromethyl)pyrazolo[1,5-a][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-a][1,3,5]triazine were synthesized using the condensation of N-(2,2-dichloro-1-cyanovinyl)-amides IV with 1H-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 4, 5, and 7 were calculated.

RESULTS

Seven new pyrazolo[1,5-a][1,3,5]triazine derivatives were synthesized. The compounds 4, 5, and 7 exhibit high activity >1 μM against leukemia, colon, and renal cancer. Compound 4 exhibited the most potent activity, with IC50 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 4, 5, and 7 is favorable.

DISCUSSION: The seven novel pyrazolo[1,5-a][1,3,5]triazines, as purine bioisosteres, were developed, synthesized, and investigated by in vitro and in silico methods.

CONCLUSION

Seven novel pyrazolo[1,5-a][1,3,5]triazine derivatives exhibited anticancer activity against the NCI-60 cancer cell lines. The compounds 4, 5, and 7 demonstrated strong anticancer activity, with growth inhibition (GI) values exceeding 50% across all nine cancer types tested. The most active compound, 4, is against leukemia, colon cancer, renal cancer, and lung cancer. All compounds exhibit low toxicity, with LC50 values of 100 μM or greater. The molecular docking of compounds 4, 5, and 7 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.