Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones.

The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a-d), 3-(2-chlorophenyl)- (10a-d), 3-(3-chlorophenyl)- (11a-d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a-d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5-8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a-d, 10a-d, 11a-d and 12a-d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl)methyl]-3-(2-chlorophenyl)pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro.

Evaluation of mutagenic and antimutagenic properties of new derivatives of pyrrolidine-2,5-dione with anti-epileptic activity, by use of the Vibrio harveyi mutagenicity test.

The Vibrio harveyi test was used to evaluate mutagenic and antimutagenic properties of nineteen new derivatives of pyrrolidine-2,5-dione (compounds 1-19) with antiepileptic activity. Four V. harveyi strains were used: BB7 (wild type) and the genetically modified strains BB7M, BB7X and BB7XM (i.e. strains with additional mucA and mucB genes, UV hypersensitivity, and UV hypersensitivity with plasmid pAB91273, respectively). None of the derivatives of 2-ethyl-2-methylsuccinic acid (compounds 1-7) had mutagenic activity against the tester strains of V. harveyi, but this set had strong or moderate antimutagenic activity against 4-nitroquinoline-N-oxide (NQNO) in the tester strains BB7, BB7X, and BB7M. This antimutagenic activity ranged from 51% to 67%, through 51-66% to 71-83% for V. harveyi BB7, BB7X and BB7M strains, respectively. Mutagenic activities in the group of 2,2-diphenyl-succinic acid derivatives (compounds 8-19) were variable and depended on the tester strain used. Compounds 8-19 were devoid of mutagenic properties against BB7 (wild-type strain). Among this group only compound 9, with the fluorine substituent in position 2 of the aromatic system, was devoid of mutagenic potential against all tester strains. The compounds in this group (8-19) demonstrated strong antimutagenic activity only against strain BB7 (inhibition ranging from 51% to 71%). We conclude that there are various mutagenic and antimutagenic activities of derivatives of pyrrolidine-2,5-dione. Moreover, our studies have proven that the V. harveyi test can be applied for primary mutagenicity and antimutagenicity assessment of these new compounds.

Synthesis and biological properties of new N-Mannich bases derived from 3-methyl-3-phenyl- and 3,3-dimethyl-succinimides. Part V.

Twenty four new 1-[(4-phenylpiperazin-1-yl)-methyl]- derivatives of 3-phenyl-3-methyl- (6-17) and 3,3-dimethyl-pyrrolidine-2,5-diones (18-29) have been synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection in mice. The acute neurological toxicity was determined using the rotorod screen. Although no anti-seizure properties were found in the scPTZ screen, fourteen compounds revealed protection in electrically induced seizures. From these molecules seven compounds were tested in rats after oral administration (MES test). In the whole series the most effective in rats were 1-[{4-(4-fluorophenyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8) with ED50 value of 7.78 mg/kg, it's 3-chlorophenyl- (10) and 3,4-dichlorophenyl- (12) analogs with ED50 values of 27.93 mg/kg and 15.11 mg/kg, respectively. To explain the possible mechanism of action for the most active derivatives 8, 10 and 12 the influence on NaV1.2 sodium channel currents were evaluated in vitro. The results of electrophysiological studies showed higher inhibition of NaV1.2 currents in comparison with phenytoin used as a model antiepileptic drug active in electrically induces seizures. Additionally, eleven 3-phenyl-3-methyl-pyrrolidine-2,5-diones as more promising in the anticonvulsant screening were evaluated in the Vibrio harveyi test to estimate their anti/mutagenic activity.

Synthesis and anticonvulsant properties of new N-Mannich bases derived from 3,3-diphenyl- and 3-ethyl-3-methyl-pyrrolidine-2,5-diones. Part III.

Twenty-four new N-[(4-phenylpiperazin-1-yl)-methyl] derivatives of 3,3-diphenyl- (7-18) and 3-ethyl-3-methyl-pyrrolidine-2,5-dione (19-30) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES). In the whole series the most effective compound was N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3,3-diphenyl-pyrrolidine-2,5-dione (14) with an ED(50) value of 30.3 mg/kg (p.o. rats) in the MES test. To explain the possible mechanism of action, for chosen active derivatives 7, 8, 9, 11, 14, 23, and 26, their influence on Na(V) 1.2 sodium channel currents was evaluated in vitro. The crystallographic structures for several molecules (8, 10, and 11) were solved.

Synthesis, anticonvulsant activity and 5-HT1A/5-HT7 receptors affinity of 1-[(4-arylpiperazin-1-yl)-propyl]-succinimides.

BACKGROUND: Epilepsy is the most prevalent neurological disorder, affecting approximately 50 million people worldwide. Even though significant advances have been made in epilepsy research, convulsions in about 30% of epileptics are still inadequately controlled by standard drug therapy. For this reason, constant attempts are made to investigate new chemical agents and mechanisms through which epilepsy can be effectively controlled. Therefore, in the present studies, a series of sixteen new 1-[(4-arylpiperazin-1-yl)-propyl]-3-methyl-3-phenyl- and 3-ethyl-3-methylpyrrolidine-2,5-dione derivatives as potential anticonvulsant agents was synthesized. METHODS: Anticonvulsant properties were evaluated in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and psychomotor seizure (6-Hz) tests after intraperitoneal injection in mice. The acute neurological toxicity was determined in the motor impairment rotorod screen. RESULTS: The compounds showed activity at a dose of 30 mg/kg (4, 8, 16) or 100 mg/kg (6, 9, 10, 12, 17, 18) in the MES model in mice. Four or them (8, 10, 16, 17) were also evaluated after po administration in rats. In this series, the most active was 1-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propyl}-3-methyl-3-phenyl-pyrrolidine-2,5-dione (8) with the ED(50) value of 28.2 mg/kg, TD(50) value of 268.5 mg/kg and protective index of 9.52 after po administration in rats. CONCLUSIONS: Taking into consideration the role of 5-HT(1A) and 5-HT(7) receptor subtypes in relation to the control of seizures as well as the fact that all compounds obtained belong to the class of long-chain arylpiperazines, their serotonin 5-HT(1A) and 5-HT(7) receptor affinity was determined. The most potent 5-HT(1A) receptor ligands are 2-OCH(3) (11, 19) and 3-Cl (8, 16) derivatives with K(i) = 72, 14 nM, and 109, 44 nM, respectively. With respect to the 5-HT(7) receptors, the best K(i) values were obtained for derivatives 8 and 11 (K(i) = 76 nM and 63 nM, respectively).

Synthesis and anticonvulsant properties of new mannich bases derived from 3,3-disubstituted pyrrolidine-2,5-diones. Part IV.

A library of 21 new N-Mannich bases of 3,3-diphenyl- (5a-g), 3-methyl-3-phenyl- (6a-g), and 3-ethyl-3-methylpyrrolidine-2,5-diones (7a-g) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The acute neurological toxicity was determined applying the rotarod screen. The results in mice showed that 13 compounds were effective in the MES or/and scPTZ screen. From these, seven molecules were tested in the MES seizures after oral administration in rats. The quantitative studies showed that N-[{4-(2-hydroxyethyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6c) and N-[(4-benzylpiperidin-1-yl)-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6f) revealed higher protection in the MES and scPTZ tests than valproic acid or ethosuximide which were used as reference antiepileptic drugs. Four compounds (5c, 6c, 6e, 6f) showed high effectiveness in the 6-Hz psychomotor seizure model of partial and therapy resistant epilepsy.

Synthesis and anticonvulsant properties of new Mannich bases derived from 3-aryl-pyrrolidine-2,5-diones. Part 1.

A series of new Mannich bases of N-[(4-arylpiperazin-1-yl)-methyl]-3-(chlorophenyl)-pyrrolidine-2,5-diones 10-23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES-test. In this model of seizures, the most active were N-[{4-(4-chlorophenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 16 and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-(3-chlorophenyl)-pyrrolidine-2,5-dione 17 with ED(50) values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10, 14, and 16 were tested in the psychomotor seizure 6-Hz test from which N-[{4-(2-chlorophenyl)-piperazin-1-yl}-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione 10 revealed the highest protection with an ED(50) of 78 mg/kg. Compounds 10, 12, and 17 were also tested in the pilocarpine-induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.

Synthesis, physicochemical and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)alkyl]-3-phenyl- and 3-(3-methyl-phenyl)-pyrrolidine-2,5-diones.

The series of N-[(4-arylpiperazin-1-yl)-alkyl]-3-phenyl- and 3-(3-methylphenyl)-pyrrolidine-2,5-diones [VIII-XXV] were synthesized and evaluated for anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed in mice, using intraperitoneal (ip) maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole-induced (scPTZ) seizure threshold tests. The neurotoxicity was determined applying the rotorod screen. Compounds VIII-XXV revealed protection only in the electrically induced seizures or were inactive. The most active were Mannich bases of 3-(3-methylphenyl)-pyrrolidine-2,5-dione with electron-withdrawing substituents at position-3 of 4-arylpiperazine fragment [XVII, XVIII], as well as compounds with ethylene or propylene spacer between imide and 4-arylpiperazine nitrogen atoms [XX-XXII, XXV]. All these compounds showed anti-MES protection in mice at doses of 100 mg/kg. Additionally, when given orally, compound XVIII was also active in rats MES screen at a dose of 30 mg/kg.

Synthesis and anticonvulsant activity of new spirosuccinimides differently substituted at the imide nitrogen atom.

In the present study the series of spirosuccinimides with the aromatic ring at the imide nitrogen atom was synthesized. All the compounds were tested for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. The neurotoxic properties were determined applying the rotorod test (TOX). The most active were N-(2-methoxyphenyl)- [V] and N-(4-chlorophenyl-amino)-2-azaspiro[4.5]decane-1,3-dione [XI] that inhibited seizures at a dose of 100 mg/kg in the scPTZ and MES tests, respectively. The other derivatives, namely N-(3-methoxyphenyl)- [VI], N-(1-phenylethyl)- [VIII], N-(diphenylmethyl)- [IX], N-(6-aminopyridin-2-yl)- [XII] 2-azaspiro[4.5]decane-1,3-diones, and the compounds with the methyl group at position-3 [XIV, XVII] or at position-4 [XVIII] of the cyclohexane ring showed anti-MES and/or anti-scPTZ protections at doses of 300 mg/kg. The results obtained revealed that anticonvulsant activity depended on the substitution mode of the aromatic ring as well as the kind of spacer between imide nitrogen atom and aromatic system.