Synthesis and Anticonvulsant and Neurotoxic Properties of SubstitutedN-Phenyl Derivatives of the Phthalimide Pharmacophore

Abstract

A series of compounds including 4-amino (1), 3-amino (2), 4-nitro (3), 2-methyl-3-amino (4), 2-methyl-3-nitro (5), 2-methyl-4-amino (6), 2-methyl-4-nitro (7), 2-methyl-5-amino (8), 2-methyl-5-nitro (9), 2-methyl-6-amino (10), 2-methyl-6-nitro (11), 2,6-dimethyl (12), 2-methyl-3-carboxy (13), 2-methoxycarbonyl (14), 2-methyl-4-methoxy (15), 2,4-dimethoxy (16), 2-chloro-4-amino (17), and 2-chloro-4-nitro (18) N-phenyl substituents of phthalimide were evaluated along with N-[3-methyl-(2-pyridinyl)]phthalimide (19), N-(3-amino-2-methylphenyl)succinimide (20), and phenytoin for anticonvulsant and neurotoxic properties. Initial screening in the intraperitoneal (ip) maximal electroshock-induced seizure (MES) test and the subcutaneous pentylenetetrazol-induced seizure (scPtz) test in mice led to the selection of 1, 2, 4, 10, 12, 17, and 19 for oral MES evaluation in rats. The resultant ED(50) values for 4, 10, 17, and phenytoin were 8.0, 28.3, 5.7 and 29.8 mg/kg, respectively. In the batrachotoxin affinity assay, IC(50) values for 17 and phenytoin were 0.15 and 0.93 microM, respectively, and in the recently validated magnesium deficiency-dependent audiogenic seizure test, ED(50) values of 5.2 and 23 mg/kg were obtained for 17 and phenytoin, respectively. Electrophysiology studies on compound 17 point out its ability to (i) potentiate GABA-evoked current responses with a failure to directly activate the GABAA receptor and (ii) to affect, at 100 microM excitatory non NMDA, but not NMDA, receptors with a 25% block of kainate-evoked response. Electrophysiology measurements on voltage-gated sodium channels in N1E-115 neuroblastoma cells confirm voltage-dependent block of these channels by compound 17. In view of its interaction with multiple ion channels, one would predict that compound 17 might be active in a wide range of seizure models.

Ligand-based design and synthesis of novel sodium channel blockers from a combined phenytoin–lidocaine pharmacophore

“…Using this information, a ligand-based molecular modeling study was successful in the design of a new small molecule which binds potently (IC 50 = 9 μM) to the NVSC4–6 and a relationship between [ 3 H]-BTX-B inhibition and anticonvulsant activity in mice has been established 7…”

The Synthesis and Anticonvulsant Activity of some ω‐Phthalimido‐N‐phenylacetamide and Propionamide Derivatives

“…Two additional bands appeared at around 1770 and 1720 cm Ϫ1 in spectra indicating the presence of phthalimide carbonyl groups. 13 C NMR spectra, the resonance signals did not account for the total number of carbon atoms in individual compounds, since as expected certain signals represent more than one carbon atom ( Table 2). …”

“…Anilide is the other pharmacophore moiety known to produce potent anticonvulsant drugs such as ameltolide [4- [11] and certain N-phenylphthalimides [12,13]. Anti-MES activity of anilides is directly influenced by the nature and pattern of substitution on the N-phenyl ring.…”

Synthesis and anticonvulsant activity ofN,N-phthaloyl derivatives of central nervous system inhibitory amino acids

“…N-Phenylphthalimides represent another group of anticonvulsant compounds containing the phthalimide moiety [29][30][31] . As the present phthalimides of amino acid amides, these compounds displayed a similar seizure-antagonizing profile in the MES and ScMet tests as phenytoin.…”