Chloro-substituted pyridine squaramates as new DNase I inhibitors: Synthesis, structural characterization, in vitro evaluation and molecular docking studies

Nina Ruseva; Mariyana Atanasova; Hristina Sbirkova-Dimitrova; Ana Marković; Žaklina Šmelcerović; Andrija Šmelcerović; Emiliya Cherneva; Adriana Bakalova

doi:10.1016/j.cbi.2023.110772

Chloro-substituted pyridine squaramates as new DNase I inhibitors: Synthesis, structural characterization, in vitro evaluation and molecular docking studies

Chem Biol Interact. 2023 Dec 1:386:110772. doi: 10.1016/j.cbi.2023.110772. Epub 2023 Oct 28.

Authors

Nina Ruseva¹, Mariyana Atanasova¹, Hristina Sbirkova-Dimitrova², Ana Marković³, Žaklina Šmelcerović⁴, Andrija Šmelcerović⁵, Emiliya Cherneva⁶, Adriana Bakalova⁷

Affiliations

¹ Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000, Sofia, Bulgaria.
² Institute of Mineralogy and Crystallography "Akad. Ivan Kostov", Bulgarian Academy of Sciences, Acad. G. Bonchev Bl. 107, 1113, Sofia, Bulgaria.
³ Department of Pharmacy, Faculty of Medicine, University of Niš, Bulevar Zorana Ðindića 81, 18000, Niš, Serbia.
⁴ Center for Biomedicinal Science, Faculty of Medicine, University of Niš, Bulevar Zorana Ðindića 81, 18000, Niš, Serbia.
⁵ Department of Chemistry, Faculty of Medicine, University of Niš, Bulevar Zorana Ðindića 81, 18000, Niš, Serbia. Electronic address: andrija.smelcerovic@medfak.ni.ac.rs.
⁶ Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000, Sofia, Bulgaria; Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113, Sofia, Bulgaria.
⁷ Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000, Sofia, Bulgaria. Electronic address: a_bakalova@pharmfac.mu-sofia.bg.

PMID: 37898285
DOI: 10.1016/j.cbi.2023.110772

Abstract

Having continued our recent study on the synthesis and DNase I inhibition of several monosquaramides, two new chloro-substituted pyridine squaramates were synthesized and their structure was identified by X-ray. Their inhibitory properties towards deoxyribonuclease I (DNase I) and xanthine oxidase (XO) were evaluated in vitro. 3-(((6-Chloropyridin-3-yl)methyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione (compound 3a) inhibited DNase I with an IC₅₀ value of 43.82 ± 6.51 μM, thus standing out as one of the most potent small organic DNase I inhibitors tested to date. No cytotoxicity to human tumor cell lines (HL-60, MDA-MB-231 and MCF-7) was observed for the tested compounds. In order to investigate the drug-likeness of the squaramates, the ADME profile and pharmacokinetic properties were evaluated. Molecular docking was performed to reveal the binding mode of the studied compounds on DNase I.

Keywords: DNase I inhibition; Docking studies; Squaramates; XO inhibition.

MeSH terms

Cell Line, Tumor
Deoxyribonuclease I* / metabolism
Enzyme Inhibitors / chemistry
Humans
Molecular Docking Simulation
Molecular Structure
Pyridines* / pharmacology
Structure-Activity Relationship

Substances

Pyridines
Deoxyribonuclease I
Enzyme Inhibitors