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1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
2
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
3
Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
4
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Therapeutic Chemistry Department, Pharmaceutical and Drug Industries, Research Division, National Research Centre, Giza, Egypt.
5
Group of Spectroscopy and Bioinformatics Applied to Biodiversity and Health, School of Medicine, Federal University of Mato Grosso Do Sul, Campo Grande, MS 79070900, Brazil.
6
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: martin.condasheridan@unmc.edu.
1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
2
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China.
3
Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
4
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA; Therapeutic Chemistry Department, Pharmaceutical and Drug Industries, Research Division, National Research Centre, Giza, Egypt.
5
Group of Spectroscopy and Bioinformatics Applied to Biodiversity and Health, School of Medicine, Federal University of Mato Grosso Do Sul, Campo Grande, MS 79070900, Brazil.
6
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: martin.condasheridan@unmc.edu.
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.
