Alphaviruses are single-stranded, positive-sense RNA viruses which are transmitted primarily through arthropod vectors. Infection from Eastern (EEE), western (WEE), and Venezuelan equine encephalitis (VEE) alphaviruses can result in debilitating neurological symptoms, including potentially fatal encephalitis in humans, equines, and other vertebrates. No current FDA-approved antivirals or vaccines are available to treat any human alphavirus infection. The Golden laboratory has discovered multiple small molecule antiviral inhibitors of encephalitic alphaviruses that are in development, including benzamidines that resulted from an unexpected 2-chloroalkylquinazolinone rearrangement. Further study of this reaction as a function of substrate reactivity and structure recently revealed that 2-dihaloalkylquinazolinones, when treated with 1,2-disubstituted ethanediamines, undergo a ring expansion to form unique piperazine-fused benzodiazepinones. Using structure-activity relationship data from the benzamidine core, 19 piperazinobenzodiazepinones were designed, synthesized, and assessed for activity against VEEV and EEEV. Several analogs demonstrated submicromolar EC<sub>50</sub> values in a cytopathic assay, &gt; 7-log reduction in viral yield, and activity was confirmed in relevant human neuronal cells. Pharmacophoric insights from the SAR study and preliminary physiochemical and metabolic stability data will be shown, highlighting the piperazinobenzodiazepinones as a new scaffold for development against encephalitic alphaviruses. Further, this latest rearrangement chemistry will be discussed in terms of possible reaction mechanism as it relates to the body of quinazolinone-based rearrangement chemistry leading to new bioactive heterocycles.

Synthesis and antiviral activity of novel benzodiazepinones resulting from ring-expanded 2-dichloroalkylquinazolinones

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