Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones

  • ACS Med Chem Lett. 2022 Mar 14;13(4):546-553. doi: 10.1021/acsmedchemlett.1c00539.
Michael C Ryan  1 ,  Eunjung Kim  2 ,  Xufeng Cao  1 ,  Walter Reichard  3 ,  Tyler J Ogorek  4 ,  Pronay Das  1 ,  Colleen B Jonsson  3  5 ,  Jerome Baudry  6 ,  Donghoon Chung  2 ,  Jennifer E Golden  1  4
Affiliations
  • 1. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
  • 2. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky 40202, United States.
  • 3. Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 4. Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
  • 5. College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 6. Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, Alabama 35899, United States.
PMID: 35450382 DOI: 10.1021/acsmedchemlett.1c00539
Abstract

Venezuelan and eastern equine encephalitis viruses are disease-causing, neuropathic pathogens with no approved treatment options in humans. While expanding the pharmacophoric model of antialphaviral amidines prepared via a quinazolinone rearrangement, we discovered that diamine-treated, 2-dihalomethylquinolinones unexpectedly afforded ring-expanded piperazine-fused benzodiazepinones. Notably, this new chemotype (19 examples) showed potent, submicromolar inhibition of virus-induced cell death, >7-log reduction of viral yield, and tractable structure-activity relationships across both viruses. Antiviral activity was confirmed in primary human neuronal cells. A mechanistic rationale for product formation is proposed, and key structural elements were comparatively modeled between a similarly substituted Antiviral amidine and piperazinobenzodiazepinone prototypes to guide future Antiviral development.

Products