期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 143, 期 -, 页码 829-842出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.11.070
关键词
Barbiturates; Xanthine oxidase inhibition; Antioxidant; Antibacterial; Cytotoxicity
资金
- FEDER funds through the POCI - COMPETE - Operational Programme Competitiveness and Internationalization in Axis I - Strengthening research, technological development and innovation [POCI-01-0145-FEDER-007491]
- FCT - Foundation for Science and Technology [UID/Multi/00709/2013]
- Fundação para a Ciência e a Tecnologia [UID/Multi/00709/2013] Funding Source: FCT
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.
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