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

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.

Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models

“…These constraints prompted us to seek an alternative scaffold with improved development potential. Hence, we have investigated several synthetic ( 40 , 53 , 54 ) and strategic options, including testing structurally related synthetic precursors to benzamidines. Hence, 2-pyrrolidinoquinazolinones have emerged as promising antiviral successors to the benzamidine architecture.…”

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses

“…The synthetic chemistry that led to the discovery and development of anti-VEEV benzamidines ML336 and BDGR-4 [ 163 , 166 ] was recently modified, leading to the formation of a new class of benzodiazepinones [ 169 ]. A structural model overlaying the benzodiazepinone framework with BDGR-4 showed remarkable alignment.…”

“…Aqueous solubility was modest for several compounds, and microsomal stability was marginal for compounds 7a and 7b (t 1/2 = 10 min) but was improved for 7o (t 1/2 = 45 min). The need for mechanism of action insights and structural modifications to improve microsomal stability were discussed to advance this new chemotype with potent antiviral cell activity against both VEEV and EEEV [ 169 ].…”

Mannich‐Type Condensation and Domino Quinazolinone‐Amidine Rearrangement Affords Ring‐Fused Mackinazolinones with Anti‐Amoebic Activity

“…For instance, guanidines result from C2‐chloroquinazolinones treated with an alkyldiamine [6] . Similar conditions with quinazolin‐4‐ones bearing halogenated C2 alkyl groups undergo predictable, yet divergent reaction pathways, yielding ring‐expanded benzodiazepinones [7] or ring‐opened benzamidines, [8] depending on the C2 substitution pattern. Alternatively, a hydrogen atom on a non‐halogenated, alkyl C2 substituent is abstractable with strong base, demonstrating that the core can serve as an enolizable carbonyl equivalent that reacts with electrophiles [9]…”