Synthesis, biological evaluation, and metabolic stability of phenazine derivatives as antibacterial agents

Maddeboina Krishnaiah, Nathalia Rodrigues de Almeida, Venkatareddy Udumula, Zhongcheng Song, Yashpal Singh Chhonker, Mai M. Abdelmoaty, Valter Aragao do Nascimento, Daryl J Murry, Martin Conda Sheridan

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Drug-resistant pathogens are a major cause of hospital- and community-associated bacterial infections in the United States and around the world. These infections are increasingly difficult to treat due to the development of antibiotic resistance and the formation of bacterial biofilms. In the paper, a series of phenazines were synthesized and evaluated for their in vitro antimicrobial activity against Gram positive (methicillin resistant staphylococcus aureus, MRSA) and Gram negative (Escherichia coli, E. coli) bacteria. The compound 6,9-dichloro-N-(methylsulfonyl)phenazine-1-carboxamide (18c) proved to be the most active molecule (MIC = 16 μg/mL) against MRSA whereas 9-methyl-N-(methylsulfonyl)phenazine-1-carboxamide (30e) showed good activity against both MRSA (MIC = 32 μg/mL) and E. coli (MIC = 32 μg/mL). Molecule 18c also demonstrated significant biofilm dispersion and inhibition against S. aureus. Preliminary studies indicate the molecules do not disturb bacterial membranes and there activity is not directly linked to the generation of reactive oxygen species. Compound 18c displayed minor toxicity against mammalian cells. Metabolic stability studies of the most promising compounds indicate stability towards phase I and phase II metabolizing enzymes.

Original languageEnglish (US)
Pages (from-to)936-947
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume143
DOIs
Publication statusPublished - Jan 1 2018

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Keywords

  • Antibacterials
  • Biofilms
  • Medicinal chemistry
  • Phenazine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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