In vitro and in silico evaluation of synthesized 4-Anilinoquinazoline derivatives as potential anticancer agents

Twenty-three 4-anilinoquinazoline derivatives were successfully synthesized, including six new compounds (8, 9, 12, 17, 19, 20) and seventeen known compounds. Seventeen derivatives (10-26) were evaluated for cytotoxic activity against three cancer cell lines (A549, HepG2, and SH-SY5Y) using the MTT assay. The results showed that compound 13 exhibited high selectivity toward the SH-SY5Y cell line with an IC₅₀ value of 13.1 µM, while compound 26 displayed good inhibition against A549 and SH-SY5Y with IC₅₀ values of 24.1 and 14.8 µM, respectively. The ADME analysis further indicated that compounds 13 and 26 possess favorable drug-like and pharmacokinetic properties, supporting their potential suitability for further investigation. Furthermore, molecular docking and molecular dynamics simulations were performed on these two compounds (13 and 26) targeting phosphoglycerate dehydrogenase (PHGDH). The docking results revealed that the fluorine atom exhibited halogen interactions with Tyr173, and the -NH group formed hydrogen bonds with Asp174. Additional hydrogen bond interactions were observed for the nitro group of compound 13 with Gly156 and for the amine group of compound 26 with Leu152. Other interactions were dominated by van der Waals, π-π, π-sigma, alkyl, and π-alkyl contacts with the aromatic N-anilinoquinazoline scaffold. The molecular dynamics simulation demonstrated consistent RMSD, Rg, RMSF, hydrogen bond, and binding energy profiles, confirming the stability and reliability of the PHGDH-ligand complexes in aqueous solution. Notably, compound 13 maintained more persistent hydrogen bonding interactions and induced localized flexibility around the active site compared to compound 26.