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Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N 3 can be more easily alkylated than N 1 under basic conditions. In this study, we explored methods for direct N 1 -selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide ( t BuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N 1 -monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

In this work a set of novel derivatives of parabanic acid 9a-d, 12a-d and 13a-d was synthesized and their anticonvulsant potential was evaluated. All the compounds under investigation exhibited anticonvulsant activity in both scPTZ and MES tests. In phase II anticonvulsant study, the trimethoxy phenyl derivative 9a evoked the highest potency among the tested compounds in scPTZ test. It displayed 1.72- and 17.05-folds activity more than the standard drugs phenobarbital and ethosuximide, respectively. In addition, the margin of safety for compound 9a is better than that of the reference antiepileptic drug ethosuximide. Also, compound 9a was devoid of hepatotoxicity indicated by measurements of serum level of ALT, AST, ALP, albumin and total protein. Furthermore, treatment with compound 9a significantly increased the GABA brain level by 2.56-folds compared to the control value. Additionally, molecular docking was performed on the active site of GABA-AT to clarify the interactions of the most potent compound 9a with the enzyme. In MES test, compound 12a exhibited the most potent activity against electric stimuli-induced seizures with the lowest ED 50  = 13.7 mg/kg and protective index >36.5. Both candidates 9a and 12a could be a good starting point to develop new molecules as novel antiepileptic drugs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Epilepsy, one of the most frequent neurological afflictions in man characterized by excessive temporary neuronal discharges resulting in uncontrolled convulsion, requires special medical attention. Though several new anticonvulsants are introduced, some types of seizures are still not adequately treated with current therapy. Toxicity, intolerance, and lack of efficacy for certain types of seizure are some of the limitations of the current medications., Methods: Maximal electroshock (MES) seizure model was used in the present study to evaluate the anticonvulsant activity of the drugs. Seizures were induced in ten weeks old male Wistar rats (200-220 g) by delivering electro shock of 150 mA for 0.2 sec by means of a convulsiometer through a pair of ear clip electrodes. The test compounds (1-10, 100 mg/kg) were administered by oral route 30 mins before the maximal electroshock seizure test by suspending in carboxymethylcellulose (1%). The animals were observed closely for 2 mins. The percentage of inhibition of seizure relative to control was recorded and calculated. Phenytoin (100 mg/kg, p.o) was used as a standard drug. The data was analysed by using one way ANOVA followed by dunnett's test., Results: In our present series of compounds the active compounds possess all the requirements essential for anticonvulsant activity as proposed by Dimmock and others. In this study, it reveals that, compounds showing anticonvulsant activity with more lipophilic N-substitution group are more active than hydrophobic substitution in the hydantoin ring. The rapid onset of action is believed to be due to the substitution of more lipophilic propyl group in the N-substitution in the hydantoin moiety. Evidently, this distal hydrophobic centre alters the bioavailability of the molecules., Conclusion: The results are encouraging and show that, the hydantoins are more potential molecules for the treatment of anticonvulsant. Anticonvulsants have greatly improved the lives of people with epilepsy. Approximately 70% of patients can achieve complete freedom from seizures with appropriate treatment. Lipophilicity appears to govern the MES activity. If there is lipophilic moiety, then MES activity is favoured. All the compounds have shown promising and significant protective effect on maximal electroshock induced seizures when compared to vehicle treated control rats., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Highly substituted chiral hydantoins were readily synthesized from simple dipeptides in a single step under mild conditions. This reaction proceeded through the dual activation of an amide and a tert-butyloxycarbonyl (Boc) protecting group by Tf2O-pyridine. This method was successfully applied in the preparation of a variety of biologically active compounds, including drug analogs and natural products.

The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

In the present study on the development of new anticonvulsants, twenty new N-3-arylamide substituted 5,5-cyclopropanespirohydantoin derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Three compounds 5d, 5j and 5t showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 5j showed the MES-induced seizures with ED50 value of 9.2 mg/kg and TD50 value of 421.6 mg/kg after intraperitoneally injection to mice, which provided compound 5j with a protective index (TD50/ED50) of 45.8 in the MES test., (Crown Copyright © 2010. Published by Elsevier Masson SAS. All rights reserved.)

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., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Thirteen new 5-cyclopropanespirohydantoins with various N-3 substituents were synthesized and their pharmacological activity was determined with the objective to better understand their structure-activity relationship (SAR) for anticonvulsant activity. The anticonvulsant effects of these compounds were evaluated by maximal electroshock seizure (MES) test and subcutaneous pentylenetetrazole (scPTZ) test models in mice. All compounds substituted with cyclopropyl group at fifth position of hydantoin ring showed better protection against MES test. Compounds 5b, 5d, 5e, 5g and 5j were found to be the most potent compounds of this series and compared with the reference drug phenytoin sodium in MES test. Compound 5j also showed equipotent activity with the standard drug sodium valproate at the doses of 20 and 40 mg kg(-1) in scPTZ test.

Phenylmethylenehydantoins (PMHs) and their des-phenyl analogues were synthesized and evaluated for anticonvulsant activity using the maximal electroshock seizure (MES) assay. The phenyl rings of PMHs were substituted with a wide spectrum of groups, and the selection of substituents was guided by Craig's plot. Phenylmethylenehydantoins substituted with alkyl (2, 3, 5, 6, 12, 14), halogeno (35, 38, 41), trifluoromethyl (11), and alkoxyl (23) groups at the phenyl ring were found to exhibit good anticonvulsant activity with ED(MES(2.5)) ranging from 28 to 90 mg/kg. Substitution of polar groups such as -NO(2), -CN, and -OH was found to be less active or inactive on PMHs. Replacement of the phenyl ring with heteroaromatic rings reduced or caused the loss of anticonvulsant activity. The study identified two PMHs, 14 (ED(MES(2.5)) = 28 +/- 2 mg/kg) and 12 (ED(MES(2.5)) = 39 +/- 4 mg/kg), to be the most active candidates of the series, which are comparable to phenytoin (55, ED(MES(2.5)) = 30 +/- 2 mg/kg) in their protection against seizure. Multivariate analysis performed on the whole series of 54 PMHs further supported the finding that the alkylated phenylmethylenehydantoins are the best acting compounds. The SAR model derived on the basis of 12 of the most active phenylmethylenehydantoins demonstrated good predicting ability (root-mean-square error of prediction (RMSEP) = 0.134; RMSEE = 0.057) and identified LUMO energy and the log P as critical parameters for their anticonvulsant activity.

Proven conformationally restricted analogues of anticonvulsant functionalized amino acids (FAAs) were prepared using short-range cyclizations and evaluated in pharmacological assays providing new information concerning the structural requirements for FAA function.

Iminohydantoins selectively substituted at position C-5 and their 1-carbobenzoxy derivatives have been synthesized, and their anticonvulsant activity was evaluated in mice. In general, the more lipophilic 1-carbobenzoxy iminohydantoins were more potent than the unsubstituted counterparts. Evaluation of the individual enantiomers of the chiral iminohydantoins showed that the anticonvulsant activity resided primarily in the S isomers. In this study, (S)-(+)-1-carbobenzoxy-5-isobutyl-2-iminohydantoin (9a) was the most active member. This compound was not nearly as active as phenytoin against electrically induced convulsions, but was also active against pentylenetetrazole-induced seizures, suggesting a broader clinical potential. The closest analogue of phenytoin, viz., 5,5-diphenyl-2-iminohydantoin (1), failed to show any significant activity. Methylation on N-3 or the imino nitrogen of 1 also did not provide a compound with substantial activity. 2-Thiophenytoin was not active against electroshock seizures and showed only a weak activity against pentylenetetrazole. This study suggested that the structure-activity relationship of 2-iminohydantoins was quite different from that of 2-hydantoins.

A selected group of alkoxy- and halogen-substituted 5-benzylidino- and 5-benzylhydantoins was prepared and screened for anticonvulsant activity as measured by the ability of the compound to prevent maximal electroshock and metrazol-induced threshold clonic seizures in rats. The structure-activity studies revealed 5-[3-(trifluoromethyl)benzyl]hydantoin (14) to be the most potent member of the series.

A simple one-step method for the N-alkoxymethylation of barbituric acids and hydantoins is presented. The compounds are N-methoxymethylated or N-ethoxymethylated using phosphorus pentoxide and dimethoxymethane or diethoxymethane, respectively, in a chlorinated solvent. 1-Methoxymethyl-3-ethyl-5-phenylhydantoin showed significant anticonvulsant activity in the subcutaneous pentylenetetrazol test, while 1,3-bis(methoxymethyl)-5-ethyl-5-(p-tolyl) barbituric acid was inactive.

Alkoxymethyl, acyloxymethyl, and mixed alkylalkoxymethyl or alkylacyloxymethyl derivatives of 5-ethyl-5-phenylhydantoin exhibit anticonvulsant activity. Also effective are bis(alkoxymethyl) and mixed alkylalkoxymethyl derivatives of 5,5-diphenylhydantoin. Of particular interest are 1,3-bis(methoxymethyl)-5,5-diphenylhydantoin and 3-acetoxymethyl-5-ethyl-5-phenylhydantoin, which show good activity against maximal electroshock seizures, and 3-methoxymethyl-5-ethyl-5-phenylhydantoin, which is effective against both maximal electroshock and pentylenetetrazole. None of the above compounds show greater activity against maximal electroshock seizures than the parent compounds, however.

Selectively substituted hydantoins 1 (15 examples), 4-hydroxy-2-imidazolidinones 2 (13 examples), 2-imidazolones 3 (10 examples), 2-imidazolidinones 4 (four examples), vicinal diamines 5 (two examples), and simple amino acid derivatives 6 (four examples) have been prepared and evaluated in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole seizure threshold (sc Met), and rotorod (Tox) tests. The medium effective doses (ED50) and the medium toxic dose (TD50) for the most active compounds are reported. In general, the most pronounced activity was observed for hydantoins 1 and protected amino acids 6. Within each series of compounds, enhanced anticonvulsant activity was often noted for compounds containing an aromatic group one carbon removed from a nitrogen atom. Among the most active compounds observed were the amino acid derivative N-acetyl-D,L-alanine benzylamide (6d) and the two 2-imidazolones 4-methyl-1-(phenylmethyl)-1,3-dihydro-2H-imidazol-2-one (3e) and 1-phenyl-1,3-dihydro-2H-imidazol-2-one (3g). Compound 6d proved to be slightly more potent in the MES test than phenacemide.

We have synthesized a novel derivative of oxymorphone, oxymorphone-6 alpha-spirohydantoin. The derivative was less toxic in mice than the parent compound and it showed a significant anticonvulsive activity. It exerted agonist effects in doses lower than those of morphine and its agonist effects were longer lasting. Furthermore, both oxymorphone and the 6-spirohydantoin showed definite antagonist properties 48 hr later: they prevented analgesic effects of morphine. The antagonist effects of the derivative persisted for a week.

A 2-spirohydantoin of 6,7-dimethoxytetrahydronaphthalene was synthesized and purified. The compound, showing structural similarities to both phenytoin and dopamine, was found to decrease spontaneous motor activity of mice and to exert a pronounced protective effect against convulsive seizures induced by pentylenetetrazol (Metrazol).