Synthesis, Anticonvulsant Properties, and SAR Analysis of Differently Substituted Pyrrolidine‐2,5‐diones and Piperidine‐2,6‐diones

Abstract

Twenty-two differently substituted 1H-isoindole-1,3(2H)-diones (30-39), 8-azaspiro[4.5]decane-7,9-diones (40-45), and 3-azaspiro[5.5]undecane-2,4-diones (46-51) were synthesized and tested for anticonvulsant activity. These molecules were designed as analogs of previously obtained azaspirosuccinimides (1-24). Initial anticonvulsant screening was performed in mice using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined applying the minimal motor impairment rotorod test. The preliminary pharmacological results showed that 15 new compounds were effective in at least one animal model of epilepsy, from which nine molecules showed protection against both MES and scPTZ seizures. The structure-activity relationship analysis revealed that anticonvulsant activity was connected closely with the structure of the imide fragment; the most favorable one was the hexahydro-1H-isoindole-1,3(2H)-dione core. 2-(2-Chlorophenyl)hexahydro-1H-isoindole-1,3(2H)-dione (31) showed activity in the 6-Hz psychomotor seizure model, which identifies substances effective in partial and therapy-resistant epilepsy. 3-[(4-Chlorophenyl)amino]-3-azaspiro[5.5]undecane-2,4-dione (47) was active in the in vitro hippocampal slice culture neuroprotection assay.

C–H Bond Alkylation of Cyclic Amides with Maleimides via a Site-Selective-Determining Six-Membered Ruthenacycle

“…HRMS were recorded on a Waters Q-Tof 2 mass spectrometer at the corresponding facilities of the CRMPO, Centre Régional de Mesures Physiques de l’Ouest, Université de Rennes 1. Compounds 1 , 3 , 4 , 5 , and 7 have been synthesized according to literature protocols.…”

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

“…According to FDA Orange Book, piperidine ring falls among the top classified scaffolds in the list of 100 most exploited simple ring systems in drug design and synthesis [32]. Piperidine derivatives also demonstrate various biological functions such as antimalarial [33], anticonvulsant [34], anticancer [35], and antidepressant [36] activities. Crizotinib ® [37], Donepezil ® [38], Risperidone ® [39], and Methyl phenidate ® [40] are the well-known examples of piperidinebased drugs (Figure 1).…”

Site-Selective Ruthenium-Catalyzed C–H Bond Arylations with Boronic Acids: Exploiting Isoindolinones as a Weak Directing Group

“…The spectral data match those previously reported. 29 General Procedure for the Arylation Reactions, and Characterization of Products 2. [RuCl 2 (p-cymene)] 2 (9.2 mg, 0.015 mmol, 5 mol %), AgSbF 6 (20.6 mg, 0.06 mmol, 20 mol %), Ag 2 O (69.5 mg, 0.3 mmol, 1.0 equiv), Cu(OTf) 2 (21.7 mg, 0.06 mmol, 20 mol %), the corresponding N-arylisoindolinone derivative 1 (0.3 mmol, 1.0 equiv), and the corresponding phenylboronic acid derivative (0.75 mmol, 2.5 equiv) were taken in a 15 mL Schlenk tube, which was equipped with a magnetic stirrer bar.…”