Trisubstituted barbiturates and thiobarbiturates : synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and antiproliferative agents

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Figueiredo, Joana and Serrano, João L. and Cavalheiro, Eunice and Keurulainen, Leena and Yli-Kauhaluoma, Jari and Moreira, Vânia M. and Ferreira, Susana and Domingues, Fernanda C. and Silvestre, Samuel and Almeida, Paulo (2018) Trisubstituted barbiturates and thiobarbiturates : synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and antiproliferative agents. European Journal of Medicinal Chemistry, 143. pp. 829-842. ISSN 0223-5234 (https://doi.org/10.1016/j.ejmech.2017.11.070)

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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.

ORCID iDs

Figueiredo, Joana, Serrano, João L., Cavalheiro, Eunice, Keurulainen, Leena, Yli-Kauhaluoma, Jari, Moreira, Vânia M. ORCID logoORCID: https://orcid.org/0000-0001-6169-5035, Ferreira, Susana, Domingues, Fernanda C., Silvestre, Samuel and Almeida, Paulo;
CORE (COnnecting REpositories)