title: Xanthine oxidase inhibitory properties and anti-inflammatory activity of 2-amino-5-alkylidene-thiazol-4-ones.
abstract: 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 = 17.16 μg/mL) as well as against rat liver XO (IC50 = 24.50 μg/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.
authors.affiliation: Center for Biomedicinal Science, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 Nis, Serbia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Smelcerovic
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 Nis, Serbia.
authors.forename: Andrej
authors.initials: A
authors.lastname: Veljkovic
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 Nis, Serbia.
authors.forename: Gordana
authors.initials: G
authors.lastname: Kocic
authors.affiliation: Laboratory of Structural Organic Analysis, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Build. 9, 1113 Sofia, Bulgaria.
authors.forename: Denitsa
authors.initials: D
authors.lastname: Yancheva
authors.affiliation: Faculty of Technology, University of Nis, Bulevar oslobodjenja 124, 16000 Leskovac, Serbia.
authors.forename: Zivomir
authors.initials: Z
authors.lastname: Petronijevic
authors.affiliation: Department of Pharmaceutical Chemistry, University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Slovenia. Electronic address: marko.anderluh@ffa.uni-lj.si.
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.affiliation: Department of Chemistry, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 Nis, Serbia. Electronic address: a.smelcerovic@yahoo.com.
authors.forename: Andrija
authors.initials: A
authors.lastname: Smelcerovic
mesh_terms: D000586:Amination; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D051381:Rats; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D013844:Thiazoles; D014969:Xanthine Oxidase
keywords: 2-Amino-5-alkylidene-thiazol-4-ones; Anti-inflammatory activity; Molecular docking; NF-κB inhibition; Xanthine oxidase inhibition