Synthesis of Quinazoline-1,3,4-Oxadiazole Linked 1,2,3-Triazole Hybrids as Potent EGFR Targeting Antilung Cancer Agents: In Vitro, In Silico, and DFT Studies

Abstract

This research focuses on the design and synthesis of novel quinazoline-1,3,4-oxadiazole linked 1,2,3-triazoles. Subsequently, it investigates their in vitro inhibitory effects on EGFR kinases and anticancer efficacy against lung cancer cell lines A-549 and H1299. Compared to the primary compound, erlotinib, most tested compounds demonstrated superior efficacy. The compounds 2-(((1-(3,5-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)sulfonyl)-5-(quinazoline-5-yl)-1,3,4-oxadiazole, 2-(((1-(3,5-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)sulfonyl)-5-(quinazolin-5-yl)-1,3,4-oxadiazole, and 2-(((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)sulfonyl)-5-(quinazoline-5-yl)-1,3,4-oxadiazole showed strong anticancer activity against both cancer cell lines with IC₅₀ values ranging from 2.62 ± 0.65 to 4.21 ± 0.24 µM. The compounds exhibited notable kinase inhibitory activity with EGFR IC₅₀ values of 0.34 ± 0.03, 0.36 ± 0.04, and 0.43 ± 0.02 µM, respectively. In Silico docking experiments were conducted to assess the molecular interactions of more potent drugs with the human epidermal growth factor receptor, EGFR (PDB: 4HJO) proteins, which included a co-crystallized ligand (erlotinib). The results indicated that six active compounds exhibited significantly higher binding energies compared to standard medications. SWISS/ADME was used to estimate the in Silico pharmacokinetic profile of potent compounds. Geometric optimization was also used to determine the structural characteristics of compound 2-(((1-(3,5-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)sulfonyl)-5-(quinazolin-5-yl)-1,3,4-oxadiazole. The molecular electrostatic potential (MEP) and HOMO-LUMO energy gap were determined.