Discovery of Pyrazolo[1,5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity.

N-Methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM (R)-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, (R)-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases.

Crystalline-Sponge-Based Structural Analysis of Crude Natural Product Extracts.

Characterization of complex natural product mixtures to the absolute structural level of their components often requires significant amounts of starting materials and lengthy purification process, followed by arduous structure elucidation efforts. The crystalline sponge (CS) method has demonstrated utility in the absolute structure elucidation of isolated organic compounds at miniscule quantities compared to conventional methods. In this work, we developed a new CS-based workflow that greatly expedites the in-depth structural analysis of crude natural product extracts. Using a crude extract of the red alga Laurencia pacifica, we showed that CS affinity screening prior to compound isolation enables prioritization of analytes present in the extract, and we subsequently resolved the molecular structures of six sesquiterpenes with stereochemical clarity from around 10 mg crude extract. This study demonstrates a new chemotyping workflow that can greatly accelerate natural product discovery from complex samples.

X-ray Structure Analysis of N-Containing Nucleophilic Compounds by the Crystalline Sponge Method.

Crystalline sponges (CS) used under a set of standard conditions have often failed to give viable N-containing nucleophilic compounds. Despite the high affinity of these nucleophiles to the binding sites of the CS, N-containing compounds considerably harm the coordination framework of the CS during the guest-soaking step. Herein, it is disclosed that these compounds are efficiently absorbed into the CS, without harming the host, under mild conditions (<4 °C, <2 µg) that normally do not work for common organic guests. Moreover, the use of ZnCl2 as the metal component of CS significantly improved the tolerance and robustness of the host framework toward N-containing compounds. Out of 22 drug (or drug-like) N-containing compounds chosen from the WHO model list of essential medicines, we succeeded in analyzing 17 analytes with the modified protocols and/or by using the ZnCl2 -noded CS. This demonstrates that the CS method is now a practical tool for drug-discovery research in pharmaceutical industries.

Direct and Regioselective Monofluorination of N-Protected Pyridone Derivatives using N-Fluorobenzenesulfonimide (NFSI).

The direct monofluorination of N-protected pyridone derivatives has been developed using a stable electrophilic fluorinating reagent, N-fluorobenzenesulfonimide (NFSI). Interestingly, the fluorine atom is regioselectively introduced at the position opposite the carbonyl group in the pyridone substrate during the reaction. This method is applicable to a wide range of substrates and allows the regioselective late-stage monofluorination of pyridone scaffolds.

Collimonins A-D, Unstable Polyynes with Antifungal or Pigmentation Activities from the Fungus-Feeding Bacterium Collimonas fungivorans Ter331.

The isolation and structure elucidation of collimonins A-D (1-4) from the fungus-feeding bacterium Collimonas fungivorans Ter331 are reported. Collimonins are new derivatives of polyoxygenated hexadecanoic acid, including an ene-triyne moiety. Their absolute configurations were fully determined by combining spectroscopic, chemical, and crystalline sponge methods. Collimonins showed antifungal or pigmentation activities against the fungus Aspergillus niger ATCC 9029.

Development of an aquacatalytic system based on the formation of vesicles of an amphiphilic palladium NNC-pincer complex.

Two amphiphilic palladium NNC-pincer complexes bearing hydrophilic tri(ethylene glycol) chains and hydrophobic dodecyl chains were designed and prepared for the development of a new aquacatalytic system. In water, these amphiphilic complexes self-assembled to form vesicles, the structures which were established by means of a range of physical techniques. When the catalytic activities of the vesicles were investigated in the arylation of terminal alkynes in water, they were found to catalyze the reaction of aryl iodides with terminal alkynes to give good yields of the corresponding internal alkynes. The formation of a vesicular structure was shown to be essential for efficient promotion of this reaction in water.

A palladium NNC-pincer complex: an efficient catalyst for allylic arylation at parts per billion levels.

Allylic arylation of allylic acetates by sodium tetraarylborates in the presence of ppb to ppm (molar) loadings of a palladium NNC-pincer complex catalyst in methanol at 50 °C gave the corresponding arylated products in excellent yields. Total turnover numbers of up to 500,000,000 and turnover frequencies of up to 11,250,000 h(-1) were achieved.

Interesting nickel-catalyzed 1,2-addition to alpha,beta-unsaturated aldehydes with arylborates.

Ni-Et-Duphos-catalyzed 1,2-addition of potassium aryltrifluoroborates to alpha,beta-unsaturated aldehydes is described.