Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti‐Inflammatory Effects

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.

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