Synthesis of New Pyrazolo[1,5‐ a ]Pyrazin‐4(5 H )‐One Derivatives and Effects on PI3K Protein Levels in A549 Lung Adenocarcinoma Cell Line
Year: 2025
Type: article
Abstract: ABSTRACT Molecular targeted therapies have significantly advanced non‐small cell lung cancer (NSCLC) treatment; however, acquired resistance in advanced stages remains a critical challenge. To overcome this, novel therapeutic targets or combination strategies are urgently needed. In this study, a new series of pyrazolo[1,5‐ a ]pyrazin‐4(5 H )‐one derivatives (compounds 12–41 ) was designed and synthesized. Their antiproliferative activities were assessed in the A549 NSCLC cell line. Compounds 15 , 16 , 21 , and 26 – 28 showed strong cytotoxicity, with IC 50 values of 8.19 µM (compound 27 ) and 7.01 µM (compound 28 ). Notably, compounds 21 and 26 – 28 significantly reduced phosphoinositide 3‐kinase (PI3K) protein levels in A549 cells. To better understand their mode of action, molecular docking studies were performed using the crystal structure of PI3K (PDB ID: 4XE0), revealing favorable binding affinities and conserved interactions within the active site. Compounds 27 and 28 , which showed the strongest in vitro activity, also exhibited the most stable binding modes and docking scores, consistent with the biological data. Structure–activity relationship (SAR) analysis indicated that a high electron‐density benzene ring on the pyrazole moiety and a low electron‐density ring on the pyrazine enhanced cytotoxic activity. Drug‐likeness and pre–absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluations suggested favorable pharmacokinetic properties.
Source: Chemistry & Biodiversity
Authors: Burak Kuzu, Ege Arzuk, Meltem Tan‐Uygun
Institutions: Van Yüzüncü Yıl Üniversitesi, Ege University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Award: G3811437787
OpenAlex ID: W4416664513