Novel bacterial topoisomerase inhibitors derived from isomannide

  • Eur J Med Chem. 2020 Aug 1;199:112324. doi: 10.1016/j.ejmech.2020.112324.
Antony Okumu  1 ,  Yanran Lu  1 ,  Sheri Dellos-Nolan  2 ,  Jonathan L Papa  3 ,  Bryan Koci  4 ,  Nicholas T Cockroft  1 ,  Judith Gallucci  5 ,  Daniel J Wozniak  6 ,  Jack C Yalowich  3 ,  Mark J Mitton-Fry  7
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: [email protected].
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.
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