Xanthine oxidase inhibitory properties and anti-inflammatory activity of 2-amino-5-alkylidene-thiazol-4-ones

• Published in: Chemico-biological interactions 2015-03, Vol.229, p.73-81
• Main Authors: Smelcerovic, Zaklina, Veljkovic, Andrej, Kocic, Gordana, Yancheva, Denitsa, Petronijevic, Zivomir, Anderluh, Marko, Smelcerovic, Andrija
• Format: Article
• Language: English
• Subjects: 2-Amino-5-alkylidene-thiazol-4-ones; Amination; Animals; Anti-inflammatory activity; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Cattle; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Molecular docking; Molecular Docking Simulation; NF-kappa B - antagonists & inhibitors; NF-κB inhibition; Rats; Thiazoles - chemistry; Thiazoles - pharmacology; Xanthine Oxidase - antagonists & inhibitors; Xanthine oxidase inhibition
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2015.01.022

[Display omitted] •2-Amino-5-alkylidene-thiazol-4-ones are potent XO inhibitors.•Correlation between data on XO inhibition and antioxidant activity.•Studied compounds showed significant anti-inflammatory activity.•Studied compounds meet criteria for good solubility and permeability, and do not fall into PAINS category.•Some compounds give a promise to be used in the treatment of gout. Thirty 2-amino-5-alkylidene-thiazol-4-ones were assayed for inhibitory activity against commercial enzyme xanthine oxidase (XO) in vitro and XO in rat liver homogenate as well as for anti-inflammatory response on human peripheral blood mononuclear cells (PBMCs). 4-((2-Benzylamino-4-oxothiazol-5(4H)-ylidene)-methyl)benzonitrile showed the most potent inhibitory effect against commercial XO (IC50=17.16μg/mL) as well as against rat liver XO (IC50=24.50μg/mL). All compounds containing the 4-cyanobenzylidene group or (indol-3-yl)methylene group at the position 5 of thiazol-4-one moiety were moderately potent inhibitors of commercial XO. The assayed compounds were docked into the crystal structures of XO enzyme complexes with three diverse inhibitors (PDB codes: 1FIQ, 1VDV, and 1V97) using OEDocking software. Our results strongly point to a correlation between the data on inhibitory activity against commercial XO and data on antioxidant activity of studied compounds, screened using a lipid peroxidation (LP) method. 2-(Benzylamino)-5-((thiophen-2-yl)methylene)thiazol-4(5H)-one showed the highest anti-inflammatory response on PBMCs, exerted most probably through the NF-κB inhibition. Studied 2-amino-5-alkylidene-thiazol-4-ones obey the “Rule of five” and meet all criteria for good solubility and permeability.