Fluorine-Activated and -Directed Allene Cycloadditions with Nitrile Oxides and Imine Oxides: Synthesis of Ring-Fluorinated Isoxazole Derivatives

Fuchibe, Kohei; Sakon, Kazuki; Suto, Kyosuke; Eto, Reo; Nakazono, Sho; Ichikawa, Junji

doi:10.1021/acs.orglett.3c02879

Cited by 4 publications

(1 citation statement)

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“…The direct functionalization of the isoxazole ring also has peculiar features and limitations. In general, the introduction of functional groups and substituents into the isoxazole fragment is carried out using transition metal catalysts, such as palladium and gold, in order to avoid highly acidic or basic conditions that destroy isoxazole derivatives [37][38][39][40][41].…”

Section: Introductionmentioning

confidence: 99%

5-Nitroisoxazoles in SNAr Reactions: A Novel Chemo- and Regioselective Approach to Isoxazole-Based Bivalent Ligands of AMPA Receptors

Vasilenko,

Temnyakova,

Dronov

et al. 2023

IJMS

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An efficient regioselective approach to novel functionalized bis(isoxazoles) with a variety of aromatic and aliphatic linkers was elaborated, based on the heterocyclization reaction of electrophilic alkenes under the treatment with tetranitromethane-triethylamine complex affording 3-EWG-5-nitroisoxazoles. The subsequent SNAr reactions of 5-nitroisoxazoles with various O,O-, N,N- and S,S-bis(nucleophiles) provide a wide range of bis(isoxazole) derivatives in good isolated yields. Employing an elaborated method, a series of novel bis(3-EWG-isoxazoles) as the promising allosteric modulators of AMPA receptors were designed and synthesized. The effect of the compounds on the kainate-induced currents was studied in the patch clamp experiments, revealing modulator properties for several of them. The best positive modulator potency was found for dimethyl 5,5′-(ethane-1,2-diylbis(sulfanediyl))bis(isoxazole-3-carboxylate), which potentiated the kainate-induced currents in a wide concentration range (10−12–10−6 M) with maximum potentiation of 77% at 10−10 M. The results were rationalized using molecular docking and molecular dynamics simulations of modulator complexes with the dimeric ligand-binding domain of the GluA2 AMPA receptor. The predicted physicochemical, ADMET, and PAINS properties confirmed that the AMPA receptor modulators based on the bis(isoxazole) scaffold may serve as potential lead compounds for the development of neuroprotective drugs.

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