Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety

Linsen Li; Antony Okumu; Sheri Dellos-Nolan; Zoe Li; Soumendrakrishna Karmahapatra; Anthony English; Jack C Yalowich; Daniel J Wozniak; Mark J Mitton-Fry

doi:10.1016/j.bmcl.2018.06.003

Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2477-2480. doi: 10.1016/j.bmcl.2018.06.003. Epub 2018 Jun 1.

Authors

Linsen Li¹, Antony Okumu¹, Sheri Dellos-Nolan², Zoe Li³, Soumendrakrishna Karmahapatra³, Anthony English³, Jack C Yalowich³, Daniel J Wozniak⁴, Mark J Mitton-Fry⁵

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 Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
⁴ Microbial Infection and Immunity, The Ohio State University, Columbus, OH 43210, USA; Department of Microbiology, The Ohio State University, Columbus, OH 43210, USA.
⁵ Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: mitton-fry.1@osu.edu.

PMID: 29871847
DOI: 10.1016/j.bmcl.2018.06.003

Abstract

Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1 μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.

Keywords: Antibacterial; Gyrase; MRSA; NBTI; TopoIV; Topoisomerase.

Publication types

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Crystallography, X-Ray
DNA Topoisomerases, Type II / metabolism*
Dioxanes / chemistry
Dioxanes / pharmacology*
Dose-Response Relationship, Drug
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Methicillin-Resistant Staphylococcus aureus / drug effects*
Methicillin-Resistant Staphylococcus aureus / enzymology
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Potassium Channel Blockers / chemical synthesis
Potassium Channel Blockers / chemistry
Potassium Channel Blockers / pharmacology*
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
Dioxanes
Ether-A-Go-Go Potassium Channels
GSK299423
Potassium Channel Blockers
Quinolines
Topoisomerase II Inhibitors
DNA Topoisomerases, Type II