Synthesis, Biological Evaluation, and Molecular Docking of Pyridine-Containing Squaramides as DNase I Inhibitors
9 affiliations
- 1Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
- 2Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria
- 3Department of General and Inorganic Chemistry, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria
- 4Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bontchev Str., Bl. 9, 1113 Sofia, Bulgaria
- 5Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria
- 6Department of Pharmacy, Faculty of Medicine, University of Niš, Blvd. Dr Zorana Đinđića 81, 18000 Niš, Serbia
- 7Department of Chemistry, Faculty of Medicine, University of Niš, Blvd. Dr Zorana Đinđića 81, 18000 Niš, Serbia
- 8Institute of Mineralogy and Crystallography, “Akad. Ivan Kostov”, Bulgarian Academy of Sciences, Acad. Georgi Bonchev Str., Bl. 107, 1113 Sofia, Bulgaria
- 9Center of Competence “Personalized Innovative Medicine”—2 PERIMED—2, Vasil Aprilov Blvd. 15A, 4002 Plovdiv, Bulgaria
Abstract
Background: DNase I inhibitors may be useful as biochemical tools and as potential leads for investigating pathological processes associated with excessive DNA degradation. Squaramides represent attractive scaffolds for drug discovery owing to their rigid, highly polarized structure and versatile hydrogen-bonding properties. Methods: Four novel pyridine-containing squaramides (5a–5d), comprising two symmetric and two asymmetric derivatives, were synthesized and structurally characterized by spectroscopic methods and, for 5a and 5b, single-crystal X-ray diffraction. Their DNase I inhibitory activity and cytotoxicity were evaluated experimentally. Comparative structure–activity analysis, molecular docking, molecular descriptor calculations, and in silico ADME profiling were additionally performed. Results: All compounds inhibited bovine pancreatic DNase I, with IC50 values ranging from 34.42 ± 5.86 to 61.95 ± 9.61 μM. Compound 5a showed the highest inhibitory activity within the present series (IC50 = 34.42 ± 5.86 μM). Comparison with five previously reported structurally related derivatives identified preliminary structure–activity trends, with 5a exhibiting the highest activity among the nine compounds considered. Molecular docking predicted a common preferred binding region within the major DNA-contact/catalytic region of DNase I and suggested possible noncovalent ligand–enzyme interactions. Molecular descriptor calculations revealed differences in the electronic properties of selected compounds, while in silico ADME analysis predicted generally favorable physicochemical and absorption-related properties together with potential pharmacokinetic liabilities. No measurable cytotoxicity was observed against the investigated cancer cell lines at the tested concentrations. Conclusions: Pyridine-containing squaramides represent a promising scaffold for further investigation as DNase I inhibitors, with 5a providing a useful starting point for subsequent structural optimization and mechanistic studies.
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BibTeX
@article{atanasova2026synthesis,
title = {{Synthesis, Biological Evaluation, and Molecular Docking of Pyridine-Containing Squaramides as DNase I Inhibitors}},
author = {Mariyana Atanasova and Nina Ruseva and Georgi Tirolski and Simeon Stoyanov and Ana Marković and Andrija Šmelcerović and Magdalena Angelova and Hristina Sbirkova-Dimitrova and Adriana Bakalova and Rositsa Mihaylova and Emiliya Cherneva},
journal = {Molecules (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/molecules31193548},
url = {https://europepmc.org/article/PMC/PMC13667282},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synthesis, Biological Evaluation, and Molecular Docking of Pyridine-Containing Squaramides as DNase I Inhibitors
AU - Mariyana Atanasova
AU - Nina Ruseva
AU - Georgi Tirolski
AU - Simeon Stoyanov
AU - Ana Marković
AU - Andrija Šmelcerović
AU - Magdalena Angelova
AU - Hristina Sbirkova-Dimitrova
AU - Adriana Bakalova
AU - Rositsa Mihaylova
AU - Emiliya Cherneva
PY - 2026
DA - 2026/10/01
JO - Molecules (Basel, Switzerland)
DO - 10.3390/molecules31193548
UR - https://europepmc.org/article/PMC/PMC13667282
AB - Background: DNase I inhibitors may be useful as biochemical tools and as potential leads for investigating pathological processes associated with excessive DNA degradation. Squaramides represent attractive scaffolds for drug discovery owing to their rigid, highly polarized structure and versatile hydrogen-bonding properties. Methods: Four novel pyridine-containing squaramides (5a–5d), comprising two symmetric and two asymmetric derivatives, were synthesized and structurally characterized by spectroscopic methods and, for 5a and 5b, single-crystal X-ray diffraction. Their DNase I inhibitory activity and cytotoxicity were evaluated experimentally. Comparative structure–activity analysis, molecular docking, molecular descriptor calculations, and in silico ADME profiling were additionally performed. Results: All compounds inhibited bovine pancreatic DNase I, with IC50 values ranging from 34.42 ± 5.86 to 61.95 ± 9.61 μM. Compound 5a showed the highest inhibitory activity within the present series (IC50 = 34.42 ± 5.86 μM). Comparison with five previously reported structurally related derivatives identified preliminary structure–activity trends, with 5a exhibiting the highest activity among the nine compounds considered. Molecular docking predicted a common preferred binding region within the major DNA-contact/catalytic region of DNase I and suggested possible noncovalent ligand–enzyme interactions. Molecular descriptor calculations revealed differences in the electronic properties of selected compounds, while in silico ADME analysis predicted generally favorable physicochemical and absorption-related properties together with potential pharmacokinetic liabilities. No measurable cytotoxicity was observed against the investigated cancer cell lines at the tested concentrations. Conclusions: Pyridine-containing squaramides represent a promising scaffold for further investigation as DNase I inhibitors, with 5a providing a useful starting point for subsequent structural optimization and mechanistic studies.
SN - 1420-3049
ER -