Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents

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Figueiredo , J , Serrano , J L , Cavalheiro , E , Keurulainen , L , Yli-Kauhaluoma , J T , Moreira , V M , Ferreira , S , Domingues , F C , Silvestre , S & Almeida , P 2018 , ' Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents ' , European Journal of Medicinal Chemistry , vol. 143 , pp. 829-842 . https://doi.org/10.1016/j.ejmech.2017.11.070

Title: Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents
Author: Figueiredo, Joana; Serrano, João L.; Cavalheiro, Eunice; Keurulainen, Leena; Yli-Kauhaluoma, Jari Tapani; Moreira, Vânia M.; Ferreira, Susana; Domingues, Fernanda C.; Silvestre, Samuel; Almeida, Paulo
Contributor: University of Helsinki, Pharmaceutical Design and Discovery group
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Pharmaceutical Design and Discovery group
Date: 2018-01-01
Language: eng
Number of pages: 14
Belongs to series: European Journal of Medicinal Chemistry
ISSN: 0223-5234
URI: http://hdl.handle.net/10138/308822
Abstract: Barbituric and thiobarbituric acid derivatives have become progressively attractive to medicinal chemists due to their wide range of biological activities. Herein, different series of 1,3,5-trisubstituted barbiturates and thiobarbiturates were prepared in moderate to excellent yields and their activity as xanthine oxidase inhibitors, antioxidants, antibacterial agents and as anti-proliferative compounds was evaluated in vitro. Interesting bioactive barbiturates were found namely, 1,3-dimethyl-5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6c) and 1,3-dimethyl-5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6e), which showed concomitant xanthine oxidase inhibitory effect (IC50 values of 24.3 and 27.9 mu M, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC50 values of 18.8 and 23.8 mu M, respectively). In addition, 5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6d) also revealed DPPH radical scavenger effect, with an IC50 value of 20.4 mu M. Moreover, relevant cytotoxicity against MCF-7 cells (IC50 = 13.3 mu M) was observed with 5-[[(2-chloro-4-nitrophenyl)amino]methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (7d). Finally, different 5-hydrazinylethylidenepyrimidines revealed antibacterial activity against Acinetobacter baumannii (MIC values between 12.5 and 25.0 mu M) which paves the way for developing new treatments for infections caused by this Gram-negative coccobacillus bacterium, known to be an opportunistic pathogen in humans with high relevance in multidrug-resistant nosocomial infections. The most promising bioactive barbiturates were studied in silico with emphasis on compliance with the Lipinski's rule of five as well as several pharmacokinetics and toxicity parameters. (C) 2017 Elsevier Masson SAS. All rights reserved.
Subject: 317 Pharmacy
Barbiturates
Xanthine oxidase inhibition
Antioxidant
Antibacterial
Cytotoxicity
ASSAY INTERFERENCE COMPOUNDS
ONE-POT SYNTHESIS
EFFICIENT SYNTHESIS
ACID-DERIVATIVES
MULTICOMPONENT REACTIONS
AQUEOUS-MEDIA
IN-SILICO
CYCLOADDITION
TOXICITY
ANALOGS
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