Novel bacterial topoisomerase inhibitors derived from isomannide

Antony Okumu; Yanran Lu; Sheri Dellos-Nolan; Jonathan L Papa; Bryan Koci; Nicholas T Cockroft; Judith Gallucci; Daniel J Wozniak; Jack C Yalowich; Mark J Mitton-Fry

doi:10.1016/j.ejmech.2020.112324

Novel bacterial topoisomerase inhibitors derived from isomannide

Eur J Med Chem. 2020 Aug 1:199:112324. doi: 10.1016/j.ejmech.2020.112324. Epub 2020 Apr 28.

Authors

Affiliations

¹ Division of Medicinal Chemistry and Pharmacognosy. The Ohio State University, Columbus, OH, 43210, USA.
² Microbial Infection and Immunity. The Ohio State University, Columbus, OH, 43210, USA.
³ Division of Pharmaceutics and Pharmacology. The Ohio State University, Columbus, OH, 43210, USA.
⁴ Eurofins Panlabs. St. Charles, MO, 63304, USA.
⁵ Department of Chemistry and Biochemistry. The Ohio State University, Columbus, OH, 43210, USA.
⁶ Microbial Infection and Immunity. The Ohio State University, Columbus, OH, 43210, USA; Department of Microbiology. The Ohio State University, Columbus, OH, 43210, USA.
⁷ Division of Medicinal Chemistry and Pharmacognosy. The Ohio State University, Columbus, OH, 43210, USA. Electronic address: mitton-fry.1@osu.edu.

PMID: 32402932
DOI: 10.1016/j.ejmech.2020.112324

Abstract

A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC₉₀ = 2 μg/mL) and other Gram-positive pathogens.

Keywords: Cystic fibrosis; DNA gyrase; MRSA; NBTI.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Dose-Response Relationship, Drug
Gram-Positive Bacteria / drug effects*
Microbial Sensitivity Tests
Molecular Structure
Structure-Activity Relationship
Topoisomerase Inhibitors / chemical synthesis
Topoisomerase Inhibitors / chemistry
Topoisomerase Inhibitors / pharmacology*

Substances

1,4-3,6-dianhydromannitol
Anti-Bacterial Agents
Bridged Bicyclo Compounds, Heterocyclic
Topoisomerase Inhibitors

Grants and funding

R01 AI061396/AI/NIAID NIH HHS/United States