Synthesis, in Vitro Anticancer Evaluation, and Structure–Activity Relationships of Novel C4- and C7-Aryl-Substituted Pyrazolo[1,5-a][1,3,5]triazines
Year: 2026
Type: article
Abstract: A series of pyrazolo[1,5-a][1,3,5]triazine derivatives is synthesized and characterized to assess their anticancer potential. Among the tested compounds, 2-(dichloromethyl)-7-(4-methylphenyl)-4-(pyridin-3-yl)pyrazole[1,5-a][1,3,5]triazine (4) and its analogue 2-(dichloromethyl)-7-phenyl-4-pyridin-3-ylpyrazolo[1,5-a][1,3,5]triazine (7) showed the highest activity. In contrast to the other derivatives, which displayed only weak growth-inhibitory effects, compounds 4 and 7 contain a 3-pyridyl substituent at the C4 position of the pyrazolotriazine scaffold. Both compounds demonstrated broad-spectrum antiproliferative activity in the NCI-60 human cancer cell line panel. Compound 4 exhibited GI50 values of 0.32–2.22 μM, with the highest potency against NSCLC, breast cancer, and leukemia cell lines. Compound 7 was even more potent, showing GI50 values of 0.03–3.04 μM and selective activity against renal cancer, breast cancer, and leukemia cell lines. In most cases, LC50 values exceeded 100 μM, indicating low overall cytotoxicity despite strong growth inhibition. ADMET predictions suggested favorable drug-like properties, including high intestinal absorption, CNS permeability, weak P-gp substrate behavior, and probable P-gp inhibition. Structure–activity relationship (SAR) analysis identified the 2-dichloromethyl group as a key determinant of activity, while the C4 substituent effect followed the order 3-pyridyl > 2-methylphenyl ≈ 2-fluorophenyl > phenyl ≈ 4-tert-butyl.
Source: SynOpen
DOI: 10.1055/a-2873-3153
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $340
Award: G504715729
OpenAlex ID: W7160618498
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