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ID: ALA5036385
Journal: ACS Med Chem Lett
Title: Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones.
Authors: Ryan MC, Kim E, Cao X, Reichard W, Ogorek TJ, Das P, Jonsson CB, Baudry J, Chung D, Golden JE.
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.
CiteXplore: 35450382