New 1,2,3-Triazole-Containing Hybrids as Antitumor Candidates: Design, Click Reaction Synthesis, DFT Calculations, and Molecular Docking Study

Abstract

In an effort to improve and achieve biologically active anticancer agents, a novel series of 1,2,3-triazole-containing hybrids were designed and efficiently synthesized via the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of substituted-arylazides with alkyne-functionalized pyrazole-[1,2,4]-triazole hybrids. The structure geometry of these new clicked 1,2,3-triazoles was explored by density functional theory (DFT) using the B3LYP/6-311++G(d,p) level; also, the potential activity of the compounds for light absorption was simulated by time-dependent DFT calculations (TD-DFT). The antitumor impacts of the newly synthesized compounds were in vitro estimated to be towards the human liver cancer cell line (HepG-2), the human colon cancer cell line (HCT-116), and human breast adenocarcinoma (MCF-7). Among the tested compounds, conjugate 7 was the most potent cytotoxic candidate towards HepG-2, HCT-116, and MCF-7, with IC₅₀ = 12.22, 14.16, and 14.64 µM, respectively, in comparison to that exhibited by the standard drug doxorubicin (IC₅₀ = 11.21, 12.46, and 13.45 µM). Finally, a molecular docking study was conducted within the epidermal growth factor receptor (EGFR) active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that analogies 7, 6, and 5 could be considered as decent lead candidate compounds for anticancer agents.

Keywords: 1,2,3-triazole; DFT calculation; antitumor activity; click chemistry; cycloaddition reaction; molecular docking; pyrazole.

Figure 1

Representative samples of bioactive triazoles.

Scheme 1

Reagents and conditions: (a) NaBH₄, dry MeOH, stirring, rt, 1 h; (b) propargyl bromide, DMF, K₂CO₃, reflux/ stirring, 6 h; (c) Na-ascorbate, CuSO₄·5H₂O, DMF: H₂O (6:1), stirring, 60–70 °C, 5–7 h.

Figure 2

Optimized structure of 8 and 9 derivatives at the B3LYP/6-311++G(d,p) level of theory in the gas phase.

Figure 3

(A) Simulated absorption spectra of compounds 7 and 9 calculated by TD-DFT in the gas phase and H₂O, (B) Simulated absorption spectra of 9 in the gas phase and H₂O at longer wavelength

Figure 4

In vitro anticancer effects of the target compounds on the HepG-2, HCT-116, and MCF-7 cell lines.

Figure 5

Docking of lapatinib within the ATP binding site of EGFR: (A) 3D binding mode; (B) 2D binding mode.

Figure 6

Docking of compound 7 within the ATP binding site of EGFR: (A) 3D binding mode; (B) 2D binding mode.