TY - JOUR
T1 - Synthesis, biological evaluation, and metabolic stability of phenazine derivatives as antibacterial agents
AU - Krishnaiah, Maddeboina
AU - de Almeida, Nathalia Rodrigues
AU - Udumula, Venkatareddy
AU - Song, Zhongcheng
AU - Chhonker, Yashpal Singh
AU - Abdelmoaty, Mai M.
AU - do Nascimento, Valter Aragao
AU - Murry, Daryl J.
AU - Conda-Sheridan, Martin
N1 - Funding Information:
This work was support by the University of Nebraska Medical Center (UNMC, Start-up funds, MC-S). We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility at the University of Nebraska Medical Center for providing assistance with confocal microscopy. The ARLZEISS LSM is supported by the National Institutes of Health Shared Instrument Grant program: NIH S10-RR-027301 . The NMR Research Facility at UNMC (part of the Fred & Pamela Buffett Cancer Center) is supported by NIH grant number P30-CA036727 .
Funding Information:
This work was support by the University of Nebraska Medical Center (UNMC, Start-up funds, MC-S). We thank Janice A. Taylor and James R. Talaska of the Advanced Microscopy Core Facility at the University of Nebraska Medical Center for providing assistance with confocal microscopy. The ARLZEISS LSM is supported by the National Institutes of Health Shared Instrument Grant program: NIH S10-RR-027301. The NMR Research Facility at UNMC (part of the Fred & Pamela Buffett Cancer Center) is supported by NIH grant number P30-CA036727.
Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Antibacterials
KW - Biofilms
KW - Medicinal chemistry
KW - Phenazine
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U2 - 10.1016/j.ejmech.2017.11.026
DO - 10.1016/j.ejmech.2017.11.026
M3 - Article
C2 - 29227933
AN - SCOPUS:85037616630
SN - 0223-5234
VL - 143
SP - 936
EP - 947
JO - CHIM.THER.
JF - CHIM.THER.
ER -