Akademik Veri Yönetim Sistemi
JOURNAL OF MOLECULAR STRUCTURE, cilt.1352, 2026 (SCI-Expanded, Scopus)
A series of novel thieno[3,2-d]pyrimidine derivatives were designed, synthesized, and evaluated for their anticancer potential against A549 lung cancer cells. In vitro cytotoxicity assays identified urea compounds (12-14) as the most potent, with compound 13 (p-Me substituted) exhibiting the highest activity (IC50 = 3.49 mu M) and remarkable selectivity over BEAS-2B (SI = 36.7) and HUVEC (SI = 24.7) normal cells. The structure-activity relationship (SAR) analysis highlighted the critical role of the urea moiety in mediating bidentate hydrogen bonding, while substituents fine-tune hydrophobic and electrostatic interactions, optimizing potency and selectivity. To gain mechanistic insight into their action, molecular docking and MM-GBSA analyses were performed against VEGFR 1-2 and EGFR, revealing that 13 forms stable hydrogen bonds with key residues (Asp1040, Glu-878 in VEGFR 1 and Cys-919, Asp-1046, Glu-885 in VEGFR 2), along with it-it stacking interactions that anchor the ligand within the active site. On the other hand, the compounds were observed not to exhibit significant interactions with EGFR. 500 ns molecular dynamics simulations confirmed the stability of these complexes, as reflected by low RMSD and RMSF values and persistent ligand-protein interactions throughout the trajectories. ADME predictions indicated favorable pharmacokinetic properties. The combination of in vitro cytotoxicity, SAR insights, molecular docking, MD simulations, and ADME profiling highlights compound 13 as a promising anticancer agent and potential VEGFR inhibitor.