Prio Santoso, Ade Danova, Chanat Aonbangkhen, Jaruwan Chatwichien, Dessy Natalia, Elvira Hermawati, Warinthorn Chavasiri, Anita Alni
Globally, cancer is the second leading cause of death after cardiovascular diseases and represents a significant public health challenge. Despite advancements in cancer treatments, new and effective anticancer agents that can specifically target cancer cells while minimizing side effects on normal cells remain urgent. This study aimed to address this requirement by focusing on the design and synthesis of quinazoline derivatives. Sixteen quinazoline derivatives (4a-p) were synthesized and evaluated for their anticancer properties. The synthesized compounds were confirmed using FT-IR, 1H NMR, 13C NMR, and mass spectrometry analysis. The antiproliferative activities of all synthesized compounds were tested against three cancer cell lines, namely A549 (lung cancer), HepG2 (liver cancer), and SH-SY5Y (neuroblastoma), as well as normal cell line (L929), using the MTT assay. Compounds 4a and 4f were identified as the most active against the HepG2 cell line, with IC50 values of 2.4 ± 1.4 and 13.4 ± 5.2 μM, respectively. Additionally, compound 4a also exhibited anticancer activity against the A549 cell line with an IC50 of 4.9 ± 0.9 μM. ADMET studies showed that both 4a and 4f comply with Lipinski's rule of five, indicating their potential as cancer drug candidates. Docking studies revealed consistency with the biological assays. Molecular dynamics studies show that compounds 4a and 4f are stable in aqueous solvent systems in the active pocket of EGFR and VEGFR-2, which is indicated by RMSD values less than 2 Å. The RMSF data showed that the amino acid residues play a role in the activeness of the hinge and hydrophobic region are stable during the simulation. © 2025
Chemistry Department, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Jl. Ganesa 10, Bandung, Indonesia; Chemistry Department, Faculty of Sciences, Institut Teknologi Sumatera, Jl. Terusan Ryacudu, South Lampung, Indonesia; Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Bangkok, 10330, Thailand; Program in Chemical Sciences, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand