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.
Linsen Li  1 ,  Antony Okumu  1 ,  Sheri Dellos-Nolan  2 ,  Zoe Li  3 ,  Soumendrakrishna Karmahapatra  3 ,  Anthony English  3 ,  Jack C Yalowich  3 ,  Daniel J Wozniak  4 ,  Mark J Mitton-Fry  5
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: [email protected].
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.