Design and Synthesis of Novel Imidazole-Bearing 1,2,3-Triazoles as Potent Anticancer Agents: Drug-Likeness, Pharmacophore, and Molecular Docking Exploration

Abstract

Objective: A novel series of imidazole-based 1,2,3-triazole derivatives (VIa–VIk) was designed and synthesized as potential broad-spectrum anticancer agents. Methods: These compounds were obtained via a well-established copper(I)-catalyzed azide–alkyne cycloaddition (“click chemistry”), starting from (E)-2-butyl-4-chloro-1-methyl-1H-imidazole-5-carbaldehyde oxime. The structures of the synthesized compounds were confirmed using standard spectroscopic techniques, including infrared (IR), proton (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR), and mass spectrometry (MS). Results and Discussion: The antiproliferative activities of the final compounds were evaluated against human lung adenocarcinoma (PC-9) and human colorectal carcinoma (HCT-116) cell lines, along with in vitro inhibitory assays targeting the epidermal growth factor receptor (EGFR). Compounds (VId) and (VIh) exhibited potent cytotoxic activity against the PC-9 cell line, with IC₅₀ values of 4.87 ± 0.4 and 3.74 ± 0.3 μM, respectively, surpassing the reference drug doxorubicin (IC₅₀ = 6.32 ± 0.3 μM). Molecular docking studies predicted that compounds (VId) and (VIj) bind favorably to the active site of EGFR, with IC₅₀ values of 0.76 and 0.25 μM, respectively. Docking results revealed that (VId) forms highly stable hydrogen bonds with amino acid residues Phe82, Met80, His18, and Gln42, which play key roles in ligand binding within the EGFR crystal structure associated with lung cancer mutations (PDB ID: 1M17). Furthermore, computational ADMET profiling was carried out using SwissADME and ADMETlab 2.0 to evaluate the pharmacokinetic properties and drug-likeness of the synthesized triazole compounds. Conclusions: In this study, a series of novel EGFR inhibitors incorporating 1,2,3-triazole scaffolds linked to oxime/imidazole moieties were successfully designed and synthesized.