Synthesis and anticonvulsant activity of imidooxy derivatives

Abstract

Previous results of anticonvulsant activity in several imidooxy carboxylates related to (aminooxy)acetic acid in young chicks, prompted an in-depth reinvestigation of these analogues in mice. A series of 22 succinimidooxy, phthalimidooxy, and naphthalimidooxy carboxylates were synthesized and evaluated for anticonvulsant activity by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS). Methyl (succinimidooxy)acetate (2d), ethyl (succinimidooxy)acetate (2e), methyl (phthalimidooxy)acetate (3d), ethyl (phthalimidooxy)acetate (3e), and ethyl 2-(phthalimidooxy)propionate (3g), which were initially found to be active as anticonvulsants in young chicks were uniformly inactive in the Phase I seizure tests involving maximal electroshock (MES), pentylenetetrazol (scMet), or neurologic toxicity toxicity (Tox). Several newer analogues, ethyl (succinimidooxy)formate (2c) and methyl 3-(phthalimidooxy)-2-methylacrylate (4h) were found to be active in the scMet (3a) or both (4h) evaluations. Most interesting was the anticonvulsant results of N-(benzyloxy)-2-azaspiro[4,4] nonane-1,3-dione (5b), which displayed anti-MES activity and a protective index (TD50/ED50) of greater than 4.5.

Catalytic mechanism of Escherichia coli ribonuclease III: kinetic and inhibitor evidence for the involvement of two magnesium ions in RNA phosphodiester hydrolysis

“…T7 RNA polymerase was purified in-house as described in (27). 2-hydroxy-4H-isoquinoline-1,3-dione was synthesized according to Edafiogho and coworkers (28) using homophthalic anhydride as starting material. 2-Methoxy-1,3(2H,4H)-isoquinolinedione was synthesized according to Bouzide (29) using 2-hydroxy-4H-isoquinoline-1,3-dione as starting material.…”

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

“…value of 0.72 is too low to be acceptable for clinical use. 204 The oxazine compounds (50, Fig. 17), which are moderately strong GABA-T inhibitors, are also potential anticonvulsant agents.…”

Anticonvulsant Potency of 10 Various P-Isopropoxyphenylsuccinimide Derivatives in the Maximal Electroshock-Induced Seizure Threshold Model in Mice

“…These attributes are, partially or fully, characteristic for a well-established antiepileptic drug -ethosuximide (3-ethyl-3-methyl-pyrrolidine-2,5-dione), which belongs to the succinimide class. However, this class of compounds is not exhausted as a source of new representatives with discussed activity [4][5][6][7][8][9].…”