3 research outputs found
Recommended from our members
An assessment of the effectiveness of a kindergarten day care parent education program on the development of parents\u27 problem solving abilities.
Development of (<i>E</i>)‑2-((1,4-Dimethylpiperazin-2-ylidene)amino)-5-nitro‑<i>N</i>‑phenylbenzamide, ML336: Novel 2‑Amidinophenylbenzamides as Potent Inhibitors of Venezuelan Equine Encephalitis Virus
Venezuelan equine encephalitis virus
(VEEV) is an emerging pathogenic
alphavirus that can cause significant disease in humans. Given the
absence of therapeutic options available and the significance of VEEV
as a weaponized agent, an optimization effort was initiated around
a quinazolinone screening hit <b>1</b> with promising cellular
antiviral activity (EC<sub>50</sub> = 0.8 μM), limited cytotoxic
liability (CC<sub>50</sub> > 50 μM), and modest in vitro
efficacy
in reducing viral progeny (63-fold at 5 μM). Scaffold optimization
revealed a novel rearrangement affording amidines, specifically compound <b>45</b>, which was found to potently inhibit several VEEV strains
in the low nanomolar range without cytotoxicity (EC<sub>50</sub> =
0.02–0.04 μM, CC<sub>50</sub> > 50 μM) while
limiting
in vitro viral replication (EC<sub>90</sub> = 0.17 μM). Brain
exposure was observed in mice with <b>45</b>. Significant protection
was observed in VEEV-infected mice at 5 mg kg<sup>–1</sup> day<sup>–1</sup> and viral replication appeared to be inhibited through
interference of viral nonstructural proteins