1. Academic Validation
  2. Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti-Inflammatory Effects

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

  • ChemMedChem. 2024 Feb 14:e202300651. doi: 10.1002/cmdc.202300651.
Luis Roberto Garduño-Villavicencio 1 Ulises Martínez-Ortega 1 Elizabeth Ortiz-Sánchez 2 José Manuel Tinajero-Rodríguez 2 Francisco Hernández-Luis 1
Affiliations

Affiliations

  • 1 Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U., Coyoacán, CDMx, 04510, Mexico.
  • 2 E. Ortiz-Sánchez, J. M. Tinajero-Rodríguez, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaria de Salud, Av. San Fernando 22, Belisario Domínguez, CDMx, 14080, Mexico.
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.

Keywords

COX-2; EGFR; amino acid; antiproliferative activity; ibuprofen; quinazoline.

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