Development of potential broad spectrum antimicrobials using C2-symmetric 9-fluorenone alkyl amine

Seoung-ryoung Choi; Marilynn A Larson; Steven H Hinrichs; Prabagaran Narayanasamy

doi:10.1016/j.bmcl.2016.02.087

Development of potential broad spectrum antimicrobials using C2-symmetric 9-fluorenone alkyl amine

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1997-9. doi: 10.1016/j.bmcl.2016.02.087. Epub 2016 Mar 2.

Authors

Seoung-ryoung Choi¹, Marilynn A Larson¹, Steven H Hinrichs¹, Prabagaran Narayanasamy²

Affiliations

¹ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900, United States.
² Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900, United States. Electronic address: p.narayanasamy@unmc.edu.

PMID: 26965856
DOI: 10.1016/j.bmcl.2016.02.087

Abstract

DNA-dependent RNA primase is essential for de novo primer synthesis during DNA replication in all living organisms. Bacterial DnaG primase is an attractive target for inhibition because it is essential, low in copy number and structurally distinct from eukaryotic and archaeal primases. DnaG primase is sensitive to known inhibitors including suramin and doxorubicin. Recently, tilorone was discovered by high throughput screening to be an inhibitor of Bacillus anthracis primase DnaG but it failed to reduce the growth of B. anthracis in vitro. In this study we determined that tilorone also inhibited DnaG primase from Staphylococcus aureus. C2-Symmetric fluorenone-based compounds, similar to tilorone chemical structure were synthesized and tested to identify potential lead compounds that inhibit bacterial growth in B. anthracis, MRSA and Burkholderia thailandensis. These compounds were evaluated by determining the minimum inhibitory concentration (MIC) against several different bacterial species which demonstrated 17.5 and 16 μg/ml MIC profiles. Importantly, some of the fluorenone-based compounds with a long carbon chain showed a relatively low MIC against B. anthracis, S. aureus, MRSA, Francisella tularensis, and B. thailandensis, suggesting it may be a promising lead compound.

Keywords: 9-Fluorenone; Bacillus anthracis; Bacterial primase; Staphylococcus aureus; Tilorone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacteria / drug effects*
Bacteria / enzymology
DNA Primase / antagonists & inhibitors
DNA Primase / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fluorenes / chemical synthesis
Fluorenes / chemistry
Fluorenes / pharmacology*
High-Throughput Screening Assays
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Enzyme Inhibitors
Fluorenes
DNA Primase