N-phenethyl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives: Synthesis, crystal structure and molecular docking studies against SARS-CoV-2

• Published in: Journal of molecular structure 2025-02, Vol.1321, p.140167, Article 140167
• Main Authors: Cedillo–Cruz, Alberto, Villalobos–López, Diana Cecilia, Kuri Cruz, Abraham, Aguilar, María Isabel, Lara–Almazán, Nancy, Martínez–Otero, Diego, Cuevas–Yañez, Erick
• Format: Article
• Language: English
• Subjects: Click chemistry; Crystal structure; Molecular docking; SARS-CoV-2 inhibitors; Triazole derivatives
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140167

•The N-phenethyl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives were synthesized via click chemistry.•The new compounds were confirmed by SCXRD, MS, FTIR and NMR.•Molecular geometries were optimized using DFT method and HOMO–LUMO were calculated.•Molecular docking studies were performed on SARS-CoV-2 proteases 3CLpro and PLpro and Helicase.•Compounds 9, 26 and 12 exhibited excellent binding energy. Novel N-phenethyl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives were synthesized via Copper(I)-catalyzed 1,3-dipolar azide-alkyne cycloaddition, commonly known as CuAAC. These triazoles were then characterized using Nuclear Magnetic Resonance (NMR), Fourier Transform Infrared Spectroscopy (FTIR), and Mass Spectrometry (MS). The crystal structures of ten compounds were elucidated through single-crystal X-ray diffraction (SCXRD). Computational calculations, based on Density Functional Theory (DFT), were employed to optimize the molecular structures. The energy levels of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were also determined. Additionally, molecular docking studies revealed the binding interactions of the most potent triazole with the active sites of key molecular targets. The findings indicated that the newly synthesized triazoles exhibit promising inhibitory activity against SARS-CoV-2 proteases 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), and helicase, outperforming the co-crystallized ligand.