Synthesis and analysis of 4-oxothiazolidines as potential dual inhibitors of deoxyribonuclease I and xanthine oxidase

• Published in: Chemico-biological interactions 2021-08, Vol.345, p.109536-109536, Article 109536
• Main Authors: Gajić, Mihajlo, Džambaski, Zdravko, Ilić, Budimir S., Kocić, Gordana, Bondžić, Bojan P., Šmelcerović, Andrija
• Format: Article
• Language: English
• Subjects: DNases; Enzyme inhibition; Molecular dynamics; Oxidoreductases; Thiazolidinones
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2021.109536

In this study, seven new 4-oxothiazolidine derivatives were synthesized and assayed, along 7 known derivatives, for inhibitory properties against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. Among tested compounds, (5Z)-Ethyl-2-(2-(cyanomethylene)-4-oxothiazolidin-5-yliden)acetate (6) exhibited inhibitory activity against both enzymes (DNase I IC50 = 67.94 ± 5.99 μM; XO IC50 = 98.98 ± 13.47 μM), therefore being the first reported dual inhibitor of DNase I and XO. Observed DNase I inhibition qualifies compound 6 as the most potent small organic DNase I inhibitor reported so far. Derivatives of 2-alkyliden-4-oxothiazolidinone (1) inhibited DNase I below 200 μM, while the other tested 4-oxothiazolidine derivatives remained inactive against both enzymes. The molecular docking and molecular dynamics simulations into the binding sites of DNase I and XO enzyme allowed us to clarify the binding modes of this 4-oxothiazolidine derivative, which might aid future development of dual DNase I and XO. •4-Oxothiazolidine derivative (6) is the first reported dual DNase I/XO inhibitor.•Compound 6 is the most potent small organic DNase I inhibitor reported so far.•Binding modes of reported dual inhibitor with DNase I and XO are predicted.