2. Academic Validation
  3. Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones

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

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.

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