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

  • Eur J Med Chem. 2018 Jan 1:143:829-842. doi: 10.1016/j.ejmech.2017.11.070.
Joana Figueiredo  1 ,  João L Serrano  1 ,  Eunice Cavalheiro  1 ,  Leena Keurulainen  2 ,  Jari Yli-Kauhaluoma  2 ,  Vânia M Moreira  3 ,  Susana Ferreira  4 ,  Fernanda C Domingues  1 ,  Samuel Silvestre  5 ,  Paulo Almeida  1
Affiliations
  • 1. CICS-UBI - Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; Department of Chemistry, University of Beira Interior, 6201-001 Covilhã, Portugal.
  • 2. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (PO Box 56), FI-00014, University of Helsinki, Helsinki, Finland.
  • 3. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, Viikinkaari 5 E (PO Box 56), FI-00014, University of Helsinki, Helsinki, Finland; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
  • 4. CICS-UBI - Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal.
  • 5. CICS-UBI - Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-517 Coimbra, Portugal. Electronic address: [email protected].
PMID: 29223098 DOI: 10.1016/j.ejmech.2017.11.070
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 μM, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC50 values of 18.8 and 23.8 μM, 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 μM. Moreover, relevant cytotoxicity against MCF-7 cells (IC50 = 13.3 μM) 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 μM) 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.

Keywords
Antibacterial; Antioxidant; Barbiturates; Cytotoxicity; Xanthine oxidase inhibition.