Exploring 1,3-dihydroxyphenazine 5,10-dioxide as a new antimicrobial lead. Synthesis and in vitro evaluations

The development of multi-drug resistant (MDR) pathogens is a rapidly growing problem throughout the years which continues to threaten millions of lives and the global healthcare. Supply and development of new antibiotics has diminished and limited treatment options are left to manage infections caused by MDR pathogens. As recent events have shown, drug development against infectious pathogens is especially important to counteract this problem and screening for new drug leads is necessary. Iodinin and its O-methylated derivative; myxin are natural products belonging to the compound class of phenazine 5,10-dioxides which have been shown to possess potent antitumor and broad-spectrum antimicrobial activities in vitro. Some of their synthetic derivatives have also been shown to possess potent antimicrobial activities, such as 1,3-dihydroxyphenazine 5,10-dioxide, rendering them as valuable drug leads for potential chemotherapeutic agents. The aim of this study was to synthesize analogs from the lead compound 1,3-dihydroxyphenazine 5,10-dioxide and explore their antimicrobial activities in vitro. The synthesis was achieved by exposing 1,3-dihydroxyphenazine 5,10-dioxide to either commercially available carbamoyl chlorides or alkyl halides. Another aim of this study was to explore synthetic routes towards formyl substituted phenazine 5,10-dioxides. The chemical structure, mass and purity of all successfully synthesized analogs was confirmed with 1H-NMR, 13C-NMR, HRMS and HPLC analysis. Antimicrobial activities of eight characterized 1,3-O-functionalized phenazine 5,10-dioxides were evaluated in vitro against both S. aureus and E. coli and compared to the lead scaffold 1,3-dihydroxyphenazine 5,10-dioxide as well as the natural products iodinin and myxin. 1,3-Bis-substituted analogs showed potent activity against S. aureus with similar potency as myxin. 1-Hydroxy-3-methoxyphenazine 5,10-dioxide was further confirmed to be a highly potent compound and so did its close derivative, 3-ethoxy-1-hydroxyphenazine 5,10-dioxide, with both compounds containing an exploitable phenol moiety for further functionalization and drug development.

Author dc:creator

• Ísak Máni Stefánsson 1997-

Contributors dc:contributor

• Háskóli Íslands

• Lyfjafræði

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/1946/37756

OAI identifier oai:identifier

oai:skemman.is:1946/37756