mannich-bases and Seizures

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Imidazolidines; Mannich Bases; Mice; Molecular Structure; Oxaliplatin; Pain; Rats; Seizures; Structure-Activity Relationship

Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5-benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity.. Synthesis, characterization, structure activity relationship and anticonvulsant activity of the Mannich bases of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives.. All the derivatives were synthesized in three steps. In the first step, substituted 4-hydroxy chalconylbenzene was synthesized by the reaction of 4-hydroxyacetophenone and substituted benzaldehyde, in the presence of potassium hydroxide. In the second step, 2,3-dihydro- 1,5- benzothiazepines and 2,3-dihydro-1,5-benzoxazepines were synthesized by the reaction of 2- thio/aminophenol with chalcones in the presence of glacial acetic acid. In the third step, these compounds finally underwent Mannich reaction with different secondary amines to the respective title compounds. All the synthesized derivatives were characterised and evaluated for anticonvulsant activity using MES (Maximal Electroshock Induced Seizure) and INH (Isoniazide Induced Convulsion) models.. The synthesized derivatives were found to be more active in the MES model than INH model, with phenytoin and diazepam being the standards respectively. Accordingly, the mode of action of the synthesized compounds may be similar to phenytoin. The methyl piperazine containing compound, at a dose of 30 mg/kg., was found to be the most active and promising compound in the series.. The benzothiazepine derivatives showed better anticonvulsant activity than the benzoxazepines derivatives.

Topics: Animals; Anticonvulsants; Drug Evaluation, Preclinical; Electroshock; Male; Mannich Bases; Mice; Seizures; Structure-Activity Relationship

The aim of this study was to synthesize a series of new N-Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties.. The target compounds 8-12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one (7) by a Mannich-type reaction. The obtained compounds were assessed and tested for their anticonvulsant activity in two screening mouse models of seizures, i.e., the maximal electroshock (MES) test and in the subcutaneous pentylenetetrazole (scPTZ) test. The effect of these compounds on animals' motor coordination was measured in the rotarod test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals' locomotor activity was also evaluated.. Compound 8 showed protection (25%) in the MES and in the scPTZ tests at the dose of 100mg/kg and was not neurotoxic. In the four-plate test, compound 8 at the dose of 30mg/kg showed a statistically significant (p<0.05) anxiolytic-like activity. In the forced swim test, it reduced the immobility time by 24.3% (significant at p<0.05), which indicates its potential antidepressant-like properties. In the locomotor activity test, compound 8 significantly reduced animals' locomotor activity by 79.9%.. The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) a promising lead structure for further development.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Dose-Response Relationship, Drug; Electroshock; Male; Mannich Bases; Mice; Pentylenetetrazole; Piperazines; Seizures; Structure-Activity Relationship

The aim of this paper was to describe the synthesis of a library of 28 new 1,3-substituted pyrrolidine-2,5-dione as potential anticonvulsant agents. The anticonvulsant activity was evaluated using three acute models of seizures in mice (MES-maximal electroshock, scPTZ-subcutaneous pentylenetetrazole, and 6Hz-psychomotor seizure tests). The neurotoxicity was determined by rotarod test. The most promising compound was found to be N-[{morpholin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (15), as it was active in the MES (ED

Topics: Animals; Anticonvulsants; Mannich Bases; Mice; Pyrrolidines; Seizures

The aim of the present experiments was to examine anticonvulsant activity of new pyrrolidine-2,5-dione and 3-methylpyrrolidine-2,5-dione derivatives in animal models of epilepsy. In addition, the possible collateral antinociceptive activity was assessed. Anticonvulsant activity was investigated in the electroconvulsive threshold (MEST) test and the pilocarpine-induced seizure models in mice. Antinociceptive activity was examined in the hot plate and the formalin tests in mice. Considering the drug safety evaluation, the Vibrio harveyi test was used to estimate anti/mutagenic activity. To determine the plausible mechanism of anticonvulsant action, for two chosen compounds (12 and 23), in vitro binding assays were carried out. All of the tested compounds revealed significant anticonvulsant activity in the MEST test. Compounds 12 and 23 displayed anticonvulsant effect also in pilocarpine-induced seizures. Four of the tested compounds (12, 13, 15, and 24) revealed analgesic activity in the hot plate test as well as in the first phase of the formalin test, and all of them were active in the second phase of the formalin test. The possible mechanism of action of compounds 12 and 23 is the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. The obtained results indicate that in the group of pyrrolidine-2,5-diones, new anticonvulsants with collateral analgesic properties can be found.

Topics: Analgesics; Animals; Anticonvulsants; Calcium Channels, L-Type; Formaldehyde; Hot Temperature; Male; Mannich Bases; Mice; Motor Activity; Mutagenicity Tests; Pain; Pilocarpine; Seizures; Sodium Channels; Succinimides; Vibrio

5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, two small series of amine derivatives (Mannich bases) and amide ones were designed containing β-tetralinohydantoin system. In preliminary studies, some of arylpiperazinylmethyl derivatives with a β-tetralinohydantoin moiety were effective in screening anticonvulsant tests in mice.. These new amine and amide derivatives of β-tetralinohydantoin were evaluated in standard anticonvulsant screens (maximal electroshock (MES) or pentylenetetrazole (scPTZ) seizure tests) and their neurotoxicity was assessed in standardized rotarod tests. Additionally, due to structural features (a hydantoin ring), influence on antiarrhythmic activity, electrocardiogram components and blood pressure was tested in rats.. The new N-Mannich bases were effective in maximal electroshock or pentylenetetrazole seizures screens; and the most interesting compound 4 (1-{[4-(1-phenyethyl)-piperazin-1-yl]methyl}-3',4'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,2'-naphthalene]-2,5-dione) displayed anticonvulsant activity in both the aforementioned tests. Furthermore, compound 6, an amide derivative of β-tetralinohydantoin, displayed significant antiarrhythmic activity in a barium chloride-induced arrhythmia model (ED50 16.3mg/kg), but it was devoid of anticonvulsant protection. None of the tested compounds affected the electrocardiogram components or blood pressure in normotensive rats.. All new N-Mannich bases containing the β-tetralinohydantoin system and 1-phenylalkylpiperazine were classified to Anticonvulsant Screening Program 1st class. In contrast, our results suggested that the introduction of an amide bond in the alkyl side chain of the β-tetralinohydantoin system abolished the anticonvulsant activity, but not the antiarrhythmic one. However, further studies are required for a definitive conclusion.

Topics: Amides; Animals; Anti-Arrhythmia Agents; Anticonvulsants; Disease Models, Animal; Drug Design; Electroshock; Male; Mannich Bases; Neurotoxicity Syndromes; Pentylenetetrazole; Phenytoin; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Seizures; Structure-Activity Relationship

A series of 22 new N-[(4-phenylpiperazin-1-yl)-methyl]-3-methyl-pyrrolidine-2,5-dione and pyrrolidine-2,5-dione derivatives were synthesized and evaluated for their anticonvulsant activities in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that seven compounds were effective in the MES or/and scPTZ seizure tests. The quantitative evaluation in both tests after i.p. administration into mice revealed that the most active compounds were N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-methyl]-3-methylpyrrolidine-2,5-dione (12) with ED50  = 16.13 mg/kg (MES), ED50  = 133.99 mg/kg (scPTZ) and N-[{4-(3,4-dichlorophenyl)-piperazin-1-yl}-methyl]-pyrrolidine-2,5-dione (23) with ED50  = 37.79 mg/kg (MES), ED50  = 128.82 mg/kg (scPTZ), whereas N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-pyrrolidine-2,5-dione (24) was effective only in the MES test with ED50  = 16.37 mg/kg. These molecules showed higher potency and also lower neurotoxicity than the reference antiepileptic drugs such as ethosuximide and valproic acid.

Topics: Animals; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Electroshock; Ethosuximide; Male; Mannich Bases; Mice; Molecular Structure; Motor Activity; Neurotoxicity Syndromes; Pentylenetetrazole; Pyrrolidines; Rotarod Performance Test; Seizures; Structure-Activity Relationship; Valproic Acid

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.

Topics: Administration, Oral; Animals; Anticonvulsants; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Disease Models, Animal; Drug Design; Electroshock; Humans; Male; Mannich Bases; Mice; Microsomes, Liver; Motor Activity; Pentylenetetrazole; Protein Binding; Pyrrolidines; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

A series of novel Mannich bases of chlorokojic acid (2-chloromethyl-5-hydroxy-4H-pyran-4-one) were synthesized and their biological activities were investigated. Anticonvulsant activity results according to phase-I tests of Antiepileptic Drug Development (ADD) Program revealed that compound 13 was the most effective one at 4 h against subcutaneous pentylenetetrazole (scPTZ)-induced seizure test. Antimicrobial activities were evaluated in vitro against bacteria and fungi by using broth microdilution method. The antitubercular activities against Mycobacterium tuberculosis and M. avium were discussed with Resazurin microplate assay (REMA). The antimicrobial activity results indicated that compounds 1 and 12 (MIC: 8-16 µg/mL) showed higher activity against Gram negative bacteria while compound 12 had MIC: 4-16 µg/mL against Gram positive bacteria. Compound 1 was the most active one with MIC values of 8-32 µg/mL against fungi. Mannich bases also exhibit significant antitubercular activity in a MIC range of 4 to 32 µg/mL, especially compound 18 against M. avium.

Topics: Animals; Anti-Infective Agents; Anticonvulsants; Antitubercular Agents; Chemistry Techniques, Synthetic; Drug Design; Drug Evaluation, Preclinical; Gram-Negative Bacteria; Gram-Positive Bacteria; Male; Mannich Bases; Mice; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Pentylenetetrazole; Pyrones; Seizures

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.

Topics: Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Male; Mannich Bases; Mice; NAV1.2 Voltage-Gated Sodium Channel; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship; Succinimides; Toxicity Tests, Acute

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.

Topics: Administration, Oral; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Drug Design; Electroshock; Injections, Intraperitoneal; Male; Mannich Bases; Mice; Molecular Structure; Motor Activity; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Succinimides

Synthesis and anticonvulsant activity of new N-Mannich bases of 3-(2-fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones have been described. Initial anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetrazole seizures test (scPTZ). The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that majority of compounds were effective in the MES test. Only seven molecules showed protection in the scPTZ test. The quantitative evaluation in the MES seizures after oral administration into rats showed that the most active were 1-[{4-(4-fluorophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (14) with ED(50) of 7.4mg/kg and 1-[{4-(3-bromophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (16) with ED(50) of 26.4mg/kg. These molecules were more potent and also less neurotoxic than phenytoin which was used as reference antiepileptic drug.

Topics: Administration, Oral; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Electroshock; Male; Mannich Bases; Mice; Mice, Inbred Strains; Molecular Structure; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Succinimides

Synthesis, physicochemical and anticonvulsant properties of new N-Mannich bases 3-24 derived from 5-cyclopropyl-5-phenyl- and 5-cyclopropyl-5-(4-chlorophenyl)-hydantoins were described here. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. Selected derivatives were also screened in the 6-Hz test. The neurotoxicity was determined applying the rotorod test. The pharmacological results revealed that the majority of compounds were effective in MES and/or scPTZ tests. The quantitative studies after oral administration into rats showed that several molecules were more potent than phenytoin and ethosuximide which were used as reference antiepileptic drugs. From the whole series the most active was 3-[(4-phenylpiperazin-1-yl)-methyl]-5-cyclopropyl-5-phenyl-imidazolidine-2,4-dione (3) with the ED(50) value of 5.29 mg/kg in the MES test.

Topics: Administration, Oral; Animals; Anticonvulsants; Disease Models, Animal; Hydantoins; Male; Mannich Bases; Mice; Molecular Structure; Neurotoxicity Syndromes; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

A series of new 3-hydroxy-6-hydroxymethyl-2-substituted 4H-pyran-4-one derivatives were synthesized as potential anticonvulsant compounds. Mannich compounds were prepared by the reaction of appropriate substituted piperazine derivatives with kojic acid and formaline. The structure of the synthesized compounds was confirmed using the elementary analysis results and spectroscopic techniques such as IR, 1H-NMR and ESI-MS. Anticonvulsant activities of the synthesized compounds were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet) induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed according to procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies, 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 11) against MES seizures and 3-hydroxy-6-hydroxymethyl-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4H-pyran-4-one (compound 7) against scMet seizures were determined to be the most active compounds at all doses without neurotoxicity.

Topics: Animals; Anticonvulsants; Convulsants; Electroshock; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mannich Bases; Mice; Neurotoxicity Syndromes; Pentylenetetrazole; Postural Balance; Pyrones; Seizures; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship

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.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Male; Mannich Bases; Mice; Mice, Inbred Strains; Molecular Structure; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship; Succinimides

The synthesis and anticonvulsant properties of new N-Mannich bases of [7,8-f]benzo-2-aza-spiro[4.5]decane-1,3-diones (5a-h) and [7,8-f]benzo-1,3-diaza-spiro[4.5]decane-2,4-diones (7a-h) were described. Initial anticonvulsant screening was performed using intraperitoneal (ip) maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the rotarod test. The majority of compounds were effective in the MES or/and scPTZ screen. The quantitative studies showed that several molecules were more potent than phenytoin, used as reference drug. Selected derivatives were screened in the 6-Hz test and also assessed for potential activity against nerve agents using the Pilocarpine Induced Status Prevention model. To explain the possible mechanism of anticonvulsant action, for chosen active derivatives, their influence on voltage-dependent Na(+) channel were tested in vitro.

Topics: Animals; Anticonvulsants; Electroshock; Hydantoins; Male; Mannich Bases; Mice; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Sodium Channels; Spiro Compounds; Succinimides

Bis-Mannich bases, bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 1-4, and their corresponding structural and non-classical isomers, 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinol hydrochlorides 5-8, were synthesized. The aryl part was phenyl in 1 and 5, p-methylphenyl in 2 and 6, p-chlorophenyl in 3 and 7, and 2-thienyl in 4 and 8. The chemical stuructures of the compounds were confirmed by 1H-NMR, 13C-NMR, UV, IR and elemental analyses. Anticonvulsant activities of the compounds were evaluated by the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scMet) tests in the dose range of 30-300 mg/kg. Alterations in biological activity depending on modifications in chemical structure were also followed. Compounds 1-4, 6, and 8 were toxic and caused death of the animals 20 min after the injection. Compounds 2, 3 and 6 were also neurotoxic at the 100 mg/kg dose level. While only compound 7 was active in the scMet test at 300 mg/kg within 4 h, all the compounds showed activity in the MES test at different dose levels and time periods. In conclusion, compounds 5 and 7, which were not toxic and did not show neurotoxicity, seemed to be candidate compounds to develop new anticonvulsant compounds useful in the treatment of the grand mal (compounds 5, 7) and petit mal (compound 7) epilepsies.

Topics: Animals; Anticonvulsants; Convulsants; Electroshock; Elements; Ethylamines; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mannich Bases; Mice; Neurotoxicity Syndromes; Pentylenetetrazole; Piperidines; Postural Balance; Seizures; Spectrophotometry, Infrared

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.

Topics: Animals; Anticonvulsants; Antifungal Agents; Candida albicans; Dose-Response Relationship, Drug; Electroshock; Male; Mannich Bases; Mice; Microbial Sensitivity Tests; Pentylenetetrazole; Pyrans; Seizures

Mono-Mannich bases, 3-amino-1-aryl-1-propanone hydrochlorides (Ig1-Ig4), and their corresponding azine derivatives, N,N'-bis(3- amino-1-aryl-propylidene) hydrazine dihydrochlorides (D1-D4), were synthesized and their anticonvulsant activities were evaluated. Alterations in biological activity depending on modifications in chemical structure were also followed. The aryl part was phenyl in Ig1, D1, Ig2, D2, Ig3, D3, or p-hydroxyphenyl in Ig4, and D4. The amine part was dimethylamine in Ig1, D1, Ig4, and D4, piperidine in Ig2, D2 or morpholine in Ig3, D3. Compounds D2, D3, and D4 are new. The anticonvulsant activity was determined by maximal electroshock (MES) and subcutaneous metrazole (pentetrazol; scMet) tests. The rotorod toxicity test was used for determining neurological deficits. While the compounds were not effective in scMet, they were found to exert protective effect in MES. The results of MES are as follows: Compound [dose level (mg/kg), time (h)]: Ig1 [30 (0.5 h), 100 (0.5 h)]; Ig2 [30 (0.5 h, 4 h)]; Ig3 [30 (0.5 h), 100 (0.5 h), 300 (0.5 h, 4 h)]; Ig4 [300 (0.5 h, 4 h), 100 (4 h)]; D1 [30 (0.5 h)]; D3 [100 (0.5 h,4 h), 300 (0.5 h), 30 (4 h)]]; D4 [300 (0.5 h, 4 h)]. D2 did not show any anticonvulsant activity in both tests. Ig1, Ig2, D1, D2, and D3 exhibited neurotoxicity. Compounds Ig2, D1, and D2 were neurotoxic at 100 mg/kg dose level at 0.5 h. Ig1 was neurotoxic at 300 mg at 0.5 h, D3 was neurotoxic at 300 mg at 4 h. Conversion of mono-Mannich bases to their corresponding azine derivatives generally decreased the anticonvulsant activity. Ig3, Ig4 and D4 seem to be promising candidates to develop new anticonvulsant compounds for grand mal epilepsy for further synthesis and in vivo studies, since they were effective in MES screening and no neurotoxicity was observed with them.

Topics: Animals; Anticonvulsants; Aza Compounds; Convulsants; Electroshock; Indicators and Reagents; Mannich Bases; Pentylenetetrazole; Postural Balance; Quinolines; Rats; Seizures