Selenium-Electrocatalytic Cyclization of 2-Vinylanilides towards Indoles of Peptide Labeling.

A novel selenium-electrocatalytic intramolecular cyclization of 2-vinylanilides for synthesis of functionalized indoles and azaindoles has been developed. In contrast to the previous synthetic methods, this sustainable protocol enabled unparalleled broad substrates scope for viable indoles with highly functional and sensitive groups by employing recyclable selenium catalyst, under mild, metal- and external-oxidant-free conditions. The approach can be used to the late-stage modification of complex bioactive molecular system, thereby setting the stage for versatile syntheses of decorated indoles with peptide labeling. A plausible catalytic pathway was proposed.

Microglia-Based Phenotypic Screening Identifies a Novel Inhibitor of Neuroinflammation Effective in Alzheimer's Disease Models.

Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches. Herein, we employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines. The identified novel pharmacological inhibitor of neuroinflammation (named GIBH-130) was validated to alter phenotypes of neuroinflammation in AD brains. Notably, this molecule exhibited comparable in vivo efficacy of cognitive impairment relief to donepezil and memantine respectively in both ß amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models at a substantially lower dose (0.25 mg/kg). Therefore, GIBH-130 constitutes a unique chemical probe for pathogenesis research and drug development of AD, and it also suggests microglia-based phenotypic screenings that target neuroinflammation as an effective and feasible strategy to identify novel anti-AD agents.

Identification of hits as matrix-2 protein inhibitors through the focused screening of a small primary amine library.

Although amantadine derivatives are the only M2 drugs for influenza virus A, their use is limited in the U.S. because of drug resistance. Here we report the identification of multiple M2 inhibitors that were rapidly generated through focused screening of a small primary amine library that was designed using a scaffold-hopping strategy based on amantadine. These compounds are as active as amantadine and might be hits for further lead generation processes.