Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel 1,2,4-Triazole-Functionalized Benzene-Sulfonate Derivatives as Potential Enzyme Inhibitors and Cytotoxicity in HepG2 Cells.
6 affiliations
- 1Department of Chemistry, Faculty of Sciences, Karadeniz Technical University, 61080 Trabzon, Türkiye.
- 2Department of Basic Sciences, Faculty of Dentistry, Iğdır University, 76000 Iğdır, Türkiye.
- 3Department of Basic Medical Science, Medical of Faculty, Nakhchivan State University, AZ 7012 Nakhchivan, Azerbaijan.
- 4Department of Molecular Biology and Genetics, Faculty of Science, Karadeniz Technical University, 61080 Trabzon, Türkiye.
- 5Department of Medical Services and Techniques, Health Services Vocational School, Iğdır University, 76000 Iğdır, Türkiye.
- 6Department of Chemistry, Graduate School of Natural and Applied Science, Karadeniz Technical University, 61080 Trabzon, Türkiye.
Abstract
Background/Objectives: In this study, novel benzenesulfonate derivatives containing a 1,2,4-triazole ring were synthesized. Methods: Their molecular structures were characterized by IR, ¹H NMR, and ¹³C NMR spectroscopy, together with Q-TOF LC/MS analyses. For compounds 5b and 5d, the available mass spectrometric data were not used for structural confirmation, and their structural assignments were based primarily on the spectroscopic data. The inhibitory effects of the synthesized compounds (3-5) against acetylcholinesterase (AChE) and glutathione S-transferase (GST) enzymes were evaluated. Results: Comparison of the results with the reference inhibitors, donepezil and ethacrynic acid, showed that compound 3e exhibited the highest AChE inhibitory activity among the tested compounds, with an IC₅₀ value of 1.60 ± 0.198 μM. In addition, compound 4a showed remarkable GST inhibitory activity, with an IC₅₀ value of 1.95 ± 0.492 μM, demonstrating greater potency than the reference inhibitor. The cytotoxic effects of the selected compounds were further assessed against the HepG2 cell line after 24 and 48 h of treatment. Overall, the synthesized molecules exhibited potent enzyme inhibitory activities together with promising cytotoxic effects, highlighting their potential as lead candidates for further biological investigations. In silico analyses were performed to elucidate the molecular basis of the experimentally observed acetylcholinesterase (AChE) inhibitory activity of the synthesized derivatives. Molecular docking against human AChE (PDB ID: 4EY7) identified compound 3e as the most favorable binder among the synthesized series, while 3f also exhibited a strong binding profile. Subsequent 100 ns molecular dynamics simulations of the hAChE-3e, hAChE-3f, and hAChE-donepezil complexes demonstrated stable protein conformations and persistent ligand accommodation within the catalytic gorge. MM/GBSA calculations further indicated a more favorable binding-energy profile for 3e than for 3f, whereas donepezil showed the most favorable overall calculated binding energy. Per-residue decomposition highlighted key gorge residues, including Trp86, Trp286, Tyr337, Tyr341, Phe295, and Phe297, as important contributors to ligand stabilization. Conclusions: Collectively, these computational findings provide structural and energetic support for the experimentally observed AChE inhibitory activity of the lead derivatives.
Related
- Synthesis, Antioxidant Activity, In Silico Evaluation, and Cytotoxicity of Novel Polyphenolic–Methyliden–Hydrazono–Thiazole Derivatives
- Design, Synthesis, In Vitro and In Silico Evaluation of Triazole–Benzimidazole Hybrid Derivatives as Potential Inhibitors of EGFR, EGFR-L858R, and EGFR-L858R/T790M
- Synthesis, in silico study and cytotoxic evaluation of new benzimidazole derivatives as potential aromatase inhibitors
- Design, synthesis, and biological evaluation of novel 4,5-diaryl-1,2,3-thiadiazole derivatives: anticancer activity and molecular docking studies
- Synthesis and Evaluation of Aryloxy-Acetamide Derivatives as CBX2 Inhibitors
BibTeX
@article{unver2026synthesis,
title = {{Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel 1,2,4-Triazole-Functionalized Benzene-Sulfonate Derivatives as Potential Enzyme Inhibitors and Cytotoxicity in HepG2 Cells.}},
author = {Yasemin Ünver and Fikret Türkan and Halil İbrahim Güler and Ercan Oguz and Tuğba Usta and Fatih Çelik},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/ph19101645},
url = {https://europepmc.org/article/MED/42943342},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel 1,2,4-Triazole-Functionalized Benzene-Sulfonate Derivatives as Potential Enzyme Inhibitors and Cytotoxicity in HepG2 Cells.
AU - Yasemin Ünver
AU - Fikret Türkan
AU - Halil İbrahim Güler
AU - Ercan Oguz
AU - Tuğba Usta
AU - Fatih Çelik
PY - 2026
DA - 2026/10/19
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101645
UR - https://europepmc.org/article/MED/42943342
AB - Background/Objectives: In this study, novel benzenesulfonate derivatives containing a 1,2,4-triazole ring were synthesized. Methods: Their molecular structures were characterized by IR, ¹H NMR, and ¹³C NMR spectroscopy, together with Q-TOF LC/MS analyses. For compounds 5b and 5d, the available mass spectrometric data were not used for structural confirmation, and their structural assignments were based primarily on the spectroscopic data. The inhibitory effects of the synthesized compounds (3-5) against acetylcholinesterase (AChE) and glutathione S-transferase (GST) enzymes were evaluated. Results: Comparison of the results with the reference inhibitors, donepezil and ethacrynic acid, showed that compound 3e exhibited the highest AChE inhibitory activity among the tested compounds, with an IC₅₀ value of 1.60 ± 0.198 μM. In addition, compound 4a showed remarkable GST inhibitory activity, with an IC₅₀ value of 1.95 ± 0.492 μM, demonstrating greater potency than the reference inhibitor. The cytotoxic effects of the selected compounds were further assessed against the HepG2 cell line after 24 and 48 h of treatment. Overall, the synthesized molecules exhibited potent enzyme inhibitory activities together with promising cytotoxic effects, highlighting their potential as lead candidates for further biological investigations. In silico analyses were performed to elucidate the molecular basis of the experimentally observed acetylcholinesterase (AChE) inhibitory activity of the synthesized derivatives. Molecular docking against human AChE (PDB ID: 4EY7) identified compound 3e as the most favorable binder among the synthesized series, while 3f also exhibited a strong binding profile. Subsequent 100 ns molecular dynamics simulations of the hAChE-3e, hAChE-3f, and hAChE-donepezil complexes demonstrated stable protein conformations and persistent ligand accommodation within the catalytic gorge. MM/GBSA calculations further indicated a more favorable binding-energy profile for 3e than for 3f, whereas donepezil showed the most favorable overall calculated binding energy. Per-residue decomposition highlighted key gorge residues, including Trp86, Trp286, Tyr337, Tyr341, Phe295, and Phe297, as important contributors to ligand stabilization. Conclusions: Collectively, these computational findings provide structural and energetic support for the experimentally observed AChE inhibitory activity of the lead derivatives.
SN - 1424-8247
ER -