In this work, the design, synthesis, biological evaluation, and molecular dynamics studies of compounds consisting of quinazoline, ibuprofen, and amino acids were carried out, showing cytotoxic effects in vitro and anti-inflammatory effects in vivo. Molecule 6 emerged as a candidate for an antineoplastic drug.

Abstract

In this research work, a series of 16 quinazoline derivatives bearing ibuprofen and an amino acid were designed as inhibitors of epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) and cyclooxygenase-2 (COX-2) with the intention of presenting dual action in their biological behavior. The designed compounds were synthesized and assessed for cytotoxicity on epithelial cancer cells lines (AGS, A-431, MCF-7, MDA-MB-231) and epithelial non-tumorigenic cell line (HaCaT). From this evaluation, derivative 6 was observed to exhibit higher cytotoxic potency (IC₅₀) than gefitinib (reference drug) on three cancer cell lines (0.034 μM in A-431, 2.67 μM in MCF-7, and 3.64 μM in AGS) without showing activity on the non-tumorigenic cell line (>100 μM). Furthermore, assessment of EGFR-TKD inhibition by 6 showed a discreet difference compared to gefitinib. Additionally, 6 was used to conduct an in vivo anti-inflammatory assay using the 12-O-tetradecanoylphorbol-3-acetate (TPA) method, and it was shown to be 5 times more potent than ibuprofen. Molecular dynamics studies of EGFR-TKD revealed interactions between compound 6 and M793. On the other hand, one significant interaction was observed for COX-2, involving S531. The RMSD graph indicated that the ligand remained stable in 50 ns.