2. Academic Validation
  3. Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA

Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with In Vivo Efficacy against MRSA

  • J Med Chem. 2021 Oct 28;64(20):15214-15249. doi: 10.1021/acs.jmedchem.1c01250.
Yanran Lu 1,  Sandip Vibhute 1,  Linsen Li 1,  Antony Okumu 1,  Steven C Ratigan 1,  Sheri Nolan 2,  Jonathan L Papa 3,  Chelsea A Mann 1,  Anthony English 3,  Anna Chen 2,  Justin T Seffernick 4,  Bryan Koci 5,  Leonard R Duncan 6,  Brieanna Roth 6,  Jason E Cummings 7,  Richard A Slayden 7,  Steffen Lindert 4,  Craig A McElroy 1,  Daniel J Wozniak 2 8,  Jack Yalowich 3,  Mark J Mitton-Fry 1
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 2 Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, Ohio 43210, United States.
  • 3 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 4 Department of Chemistry and Biochemistry, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, United States.
  • 5 Eurofins Panlabs, St. Charles, Missouri 63304, United States.
  • 6 JMI Laboratories, North Liberty, Iowa 52317, United States.
  • 7 Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, United States.
  • 8 Department of Microbiology, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, United States.
PMID: 34614347 DOI: 10.1021/acs.jmedchem.1c01250
Abstract

Novel bacterial Topoisomerase inhibitors (NBTIs) are among the most promising new Antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79. This molecule demonstrates potent Antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and Topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus Infection.

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