Abstract:
Background/Objectives: Glioblastoma multiforme (GBM), an aggressive anddeadly brain tumour, presents significant challenges in achieving effective treatment dueto its resistance to current therapies and poor prognosis. This study aimed to synthesiseand evaluate 23 novel analogues of 3,4-dihydroquinolin-2(1H)-one, designed to enhancedruggability and solubility, and to investigate their potential as VEGFR2 inhibitors forGBM treatment. Methods: The synthesised compounds were analysed using in silicomethods, including molecular docking and dynamics studies, to assess their interactionswith key residues within the VEGFR2 binding pocket. In vitro evaluations were performedon U87-MG and U138-MG GBM cell lines using MTT assays to determine the IC50 valuesof the compounds. Results: Among the tested compounds, 4u (IC50 = 7.96 μM), 4t(IC50 = 10.48 μM), 4m (IC50 = 4.20 μM), and 4q (IC50 = 8.00 μM) demonstrated significantantiproliferative effects against both the U87-MG and U138-MG cell lines. Thesecompounds exhibited markedly higher efficacy compared to temozolomide (TMZ), whichshowed IC50 values of 92.90 μM and 93.09 μM for U87-MG and U138-MG, respectively.Molecular docking and dynamics studies confirmed strong interactions between the compoundsand VEGFR2 kinase, supporting their substantial anti-cancer activity. Conclusions:This study highlights the promising potential of 3,4-dihydroquinolin-2(1H)-one analogues,particularly 4m, 4q, 4t, and 4u, as VEGFR2-targeting therapeutic agents for GBM treatment.Further detailed research is warranted to validate and expand upon these findings.
Keywords: glioblastoma multiforme; 3,4-dihydroquinolin-2(1H)-one; therapeutic efficacy;molecular docking; molecular dynamics; VEGFA–VEGFR2 pathway; anti-cancer
