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In the present investigation, we described herein the molecular properties prediction by Molinspiration (2008) and synthesized a series of 17 2-(substituted benzylidene/ethylidene)-N-(substituted phenyl)hydrazinecarboxamide analogues. All the title compounds (4a–q) followed the Lipinski “Rule of Five.” The synthesized compounds were characterised by elemental analyses and spectral data followed by anticonvulsant activity according to the Antiepileptic Drug Development Programme Protocol. 2-(4-Hydroxybenzylidene)-N-(2-chlorophenyl)hydrazinecarboxamide (4j) was found to be the most active compound of the series showing protection at 4.0 h at a dose of 100 mg/kg against maximal electroshock seizure test and 50 % (2/4, 0.25, 1–2 h) and 100 % (4/4, 0.5 h) protection in 6 Hz psychomotor seizure test without showing any neurotoxicity. N-(2-chlorophenyl)hydrazine carboxamide (3b) showed 100 % (4/4, 0.25–2 h) and 66.6 % (2/3, 4 h) protection in 6 Hz psychomotor seizure test.

A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25-2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg.

Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities.

Purpose sec-Butyl-propylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a CNS-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The current study evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death.

Recently, we reported that select N′-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N′-benzyl 2-amino acetamides (MES ED50 = 13–21 mg/kg) exceeded those of phenobarbital (ED50 = 22 mg/kg). Two additional studies defining the structure–activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N′-benzyl 2-amino-3-methylbutanamide and (R)-N′-benzyl 2-amino-3,3-dimethylbutanamide were sensitive to substituents at the 4′-N′-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved acti...

Primary amino acid derivatives (PAADs) (N'-benzyl 2-substituted 2-amino acetamides) are structurally related to functionalized amino acids (FAAs) (N'-benzyl 2-substituted 2-acetamido acetamides) but differ by the absence of the terminal N-acetyl group. Both classes exhibit potent anticonvulsant activities in the maximal electroshock seizure animal model, and the reported structure-activity relationships (SARs) of PAADs and FAAs differ in significant ways. Recently, we documented that PAAD efficacy was associated with a hydrocarbon moiety at the C(2)-carbon, while in the FAAs, a substituted heteroatom one atom removed from the C(2)-center was optimal. Previously in this issue, we showed that PAAD activity was dependent upon the electronic properties of the 4'-N'-benzylamide substituent, while FAA activity was insensitive to electronic changes at this site. In this study, we prepared analogues of (R)-N'-benzyl 2-amino-3-methylbutanamide to identify the structural components for maximal anticonvulsant activity. We demonstrated that the SAR of PAADs and FAAs diverged at the terminal amide site and that PAADs had considerably more structural latitude in the types of units that could be incorporated at this position, suggesting that these compounds function according to different mechanism(s).

A series of 2-[2-(substituted)hydrazinyl]-1,3-benzothiazole and 2-(1,3-benzothiazol-2-ylsulfanyl)-N′-(substituted)acetohydrazide were designed and synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The most active compound of the series was 2-(1,3-benzothiazol-2-ylsulfanyl)-N′-[4-(4-bromophenoxy)benzylidene]acetohydrazide BT 15, which showed 75% protection (3/4, 1.0 h) and 50% protection (2/4, 0.5 h) at a dose of 100 mg/kg in mice. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as GABA (A) alpha-1, glutamate, GABA (A) delta receptors and Na/H exchanger, in Lamarckian genetic algorithm-based flexible docking studies.

A series of (E)-N′-(substituted-benzylidene)isonicotinohydrazide derivatives were synthesized by coupling it with different substituted aldehydes, acetophenone, and benzophenones in presence of absolute ethanol along with catalytic amount of glacial acetic acid. All the synthesized compound were confirmed and characterized by using various spectral technique like IR, 1H NMR, 13C NMR, and mass spectroscopy studies. Anticonvulsant evaluations of all the synthesized compounds were done using various seizures models like maximal electroshock-induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) at a dose of 30, 100, and 300 mg/kg body weight and anticonvulsant activity was noted at 0.5 h and 4 h time intervals after the drug administration. Compound 1a (E)-N′-2-benzylidene isonicotinohydrazide, 1g (E)-N′-2-ethoxybenzylidene isonicotinohydrazide, 1k (E)-N′-3-flourobenzylidene isonicotinohydrazide and 3a (E)-N′-diphenylmethylene isonicotinohydrazide showed protection in MES model, which indicates that these compounds have the ability to prevent the spread of seizure at 300 mg/kg dose and showed protection at 0.5 h duration. Compound 3a was also found to be active in scPTZ screen at a dose of 300 mg/kg. In neurotoxicity screen, all the synthesized compounds were found non-toxic except compounds 1n, 2a, and 3b. Further compounds 1a, 1g, 1k, and 3a were also evaluated in the minimal clonic seizure model and exhibited potent anticonvulsant activity with lower neurotoxicity. Among all synthesized derivatives, analogue 3a was found to exhibit protection in MES and scPTZ seizure models. This study proved that isonicotinoyl hydrazides synthesized by condensing isoniazid with various aldehydes and ketones displayed moderate to potent anticonvulsant activity.

Various 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea (5a–p) were designed keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity. Their in vivo anticonvulsant screenings were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Compound 5f was found active in MES screening while compounds 5h, 5i, 5k and 5l showed significant anticonvulsant activity in both the screenings and were devoid of any neurotoxicity. Compound 5h and 5i showed marked protection at 300 mg/kg against MES and scPTZ screening. Compound 5i also showed protection against MES screening at the dose of 100 mg/kg. In 6 Hz screening these two compounds showed significant protection and emerged as lead compounds for future investigations., Graphical abstract Various 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea (5a–p) were synthesized and evaluated. Anticonvulsant screening revealed some potential compounds that were active in both MES and scPTZ screenings. Highlights ► Various 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea (5a–p) were synthesized and evaluated. ► Compound 5f was found active in MES screening while compounds 5h, 5i, 5k and 5l showed significant anticonvulsant activity in both the screenings and were devoid of any neurotoxicity. ► Compound 5h and 5i showed marked protection at 300 mg/kg against MES and scPTZ screening. ► In 6 Hz screening compounds 5h and 5i showed significant protection.

A series of ten compounds (Compounds J(1)-J(10)) of (±) 3-menthone aryl acid hydrazone was synthesized and characterized by thin layer chromatography and spectral analysis. Synthesized compounds were evaluated for anticonvulsant activity after intraperitoneal (i.p) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure method and minimal clonic seizure test. Minimal motor impairment was also determined for these compounds. Results obtained showed that four compounds out of ten afforded significant protection in the minimal clonic seizure screen at 6 Hz. Compound J(6), 4-Chloro-N-(2-isopropyl-5-methylcyclohexylidene) benzohydrazide was found to be the most active compound with MES ED(50) of 16.1 mg/kg and protective index (pI) of greater than 20, indicating that (±) 3-menthone aryl acid hydrazone possesses better and safer anticonvulsant properties than other reported menthone derivatives viz. menthone Schiff bases, menthone semicarbazides and thiosemicarbazides.

Five new series of 3,4-ethylenedioxythiophene derivatives carrying important pharamacophores, viz., amide, ester, ether and active secondary aryl moieties have been designed and synthesized through multistep reactions starting from thiodiglycolic ester and diethyl oxalate. They have been characterized by elemental and spectral data. All the target compounds have been screened for their anticonvulsant activity at three different models viz. maximal electroshock (MES), subcutaneous metrazole (scMET), and 6 Hz screen and evaluated for their neurotoxicity in rotorod model. Compound 6a emerged as lead with no neurotoxicity. All the five series of compounds are safe in the toxicity studies at the maximum dose of 300 mg/kg of body weight. Amongst the tested compounds, the ester pharmacophore with thioamide fragment has showed better activity than the other analogs.

2,4(1H)-Diarylimidazoles have been previously shown to inhibit hNa(V)1.2 sodium (Na) channel currents. Since many of the clinically used anticonvulsants are known to inhibit Na channels as an important mechanism of their action, these compounds were tested in two acute rodent seizure models for anticonvulsant activity (MES and scMet) and for sedative and ataxic side effects. Compounds exhibiting antiepileptic activity were further tested to establish a dose response curve (ED(50)). The experimental data identified four compounds with anticonvulsant activity in the MES acute seizure rodent model (compound 10, ED(50)=61.7mg/kg; compound 13, ED(50)=46.8mg/kg, compound 17, ED(50)=129.5mg/kg and compound 20, ED(50)=136.7mg/kg). Protective indexes (PI=TD(50)/ED(50)) ranged from 2.1 (compound 10) to greater than 3.6 (compounds 13, 17 and 20). All four compounds were shown to inhibit hNa(V)1.2 in a dose dependant manner. Even if a correlation between sodium channel inhibition and anticonvulsant activity was unclear, these studies identify four Na channel antagonists with anticonvulsant activity, providing evidence that these derivatives could be potential drug candidates for development as safe, new and effective antiepileptic drugs (AEDs).

A series of aryl acid hydrazones of substituted aromatic acid hydrazides (D 1 to D 20) were synthesised and evaluated for anticonvulsant activity. Aryl acid hydrazones of Nicotinic acid hydrazide (D 8, D 9, and D 10) have displayed excellent protection in maximal electroshock screen. These compounds have also exhibited excellent binding properties with Lys 329 residue of gamma amino butyrate amino transferase (GABA-AT) in Lamarckian genetic algorithm based flexible docking studies. Compound D 8, N 1-(4-chlorobenzylidene) nicotinohydrazide was found to be the most potent analog with ED50 value of 16.1 mg/kg and protective index (PI = TD50/ED50) value of >20, which was much greater than that of the prototype drug phenytoin (PI = 6.9). It has shown free binding energy value of −10.20 kcal/mol and inhibition constant (Ki) value of 33.30 nM for GABA-AT, indicating that aryl acid hydrazones of nicotinic acid hydrazide could be considered as a new pharmacophore in the design of novel anticonvulsant drugs.

Five bis-benzamidines were screened towards murine magnesium deficiency-dependent audiogenic seizures, unravelling two compounds with efficacious doses 50 (ED(50)) less than 10mg/kg. They were also screened against maximal electroshock and subcutaneous pentylenetetrazole-induced seizures, and explored for superoxide -scavenging activity. 1,2-Ethane bis-1-amino-4-benzamidine (EBAB) was selected and evaluated in 6 Hz seizure test (ED(50)=49 mg/kg) and at 4 microg/kg in focal cerebral ibotenate poisoning in pups (sizes of both white and grey matter wounds were halved). EBAB was further tested on NMDA-induced seizures in mice (ED(50)=6 mg/kg) and on (3)H-TC -binding to a rodent cerebral preparation (IC(50)=1.4 microM). Taken as a whole, present data emphasise the suitability of bis-benzamidines as templates for designing brain protective compounds.

WOS: 000276528700010 PubMed: 20363141 In this study, as a continuation of our research for new (arylalkyl) imidazole anticonvulsant compounds, the design, synthesis and anticonvulsant/antimicrobial activity evaluation of a series of 2-acetylnaphthalene derivatives have been described. Molecular design of the compounds has been based on the modification of nafimidone [1-(2-naphthyl)-2-(imidazol-1-yl)ethanone], which is a representative of the (arylalkyl) imidazole anticonvulsant compounds as well as its active metabolite, nafimidone alcohol (3, 4). In general, these compounds were variously substituted at the alkyl chain between naphthalene and imidazole rings and subjected to some other modifications to evaluate additional structure-activity relationships. The anticonvulsant activity profile of those compounds was determined by maximal electroshock seizure (MES) and subcutaneous metrazol (scM) seizure tests, whereas their neurotoxicity was examined using rotarod test. All the ester derivatives of nafimidone alcohol (5a-h), which were designed as prodrugs, showed anticonvulsant activity against MES-induced seizure model. Four of the most active compounds were chosen for further anticonvulsant evaluations. Quantification of anticonvulsant protection was calculated via the ip route (ED(50) and TD(50)) for the most active candidate (5d). Observed protection in the MES model was 38.46 mg kg (1) and 123.83 mg kg (1) in mice and 20.44 mg kg (1), 56.36 mg kg (1) in rats, respectively. Most of the compounds with imidazole ring also showed antibacterial and/ or antifungal activities to a certain extent in addition to their anticonvulsant activity. (C) 2010 Elsevier Ltd. All rights reserved. Hacettepe UniversityHacettepe University [HUBAB 02 02 301 002] This project was supported by Hacettepe University Scientific Research Fund (HUBAB 02 02 301 002).

Several series of compounds containing the 1,4-dioxo-2-butenyl moiety have been prepared as candidate cytotoxins, including the methyl N-arylmaleamates, methyl N-arylfumaramates, and N-arylmaleimides. In addition, the N-arylisomaleimides were synthesized which are the structural isomers of N-arylmaleimides. These compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. Methyl N-arylfumaramates showed the highest cytotoxic potencies and, in particular, methyl N-(3,4-dichlorophenyl)fumaramate is six times more potent than melphalan towards L1210 cells and is equipotent with this drug in the Molt 4/C8 assay. Electrophilicity of compounds under investigation was demonstrated by carrying out thiolation using model benzyl mercaptan on representative compounds. Methyl N-(3,4-dichlorophenyl)fumaramate and methyl N-(4-chlorophenyl)maleamate inhibited human N-myristoyltransferase, a possible molecular target, in high micromolar range. QSAR and molecular modeling revealed some correlations between different structural features of a number of the molecules and cytotoxic potencies. Methyl N-arylfumaramates were well tolerated in mice in comparison to the analogs in other series of compounds tested. The data obtained in this investigation affords guidelines for preparing new series of molecules with greater potencies. ispartof: Bioorganic & Medicinal Chemistry Letters vol:20 issue:5 pages:1510-5 ispartof: location:England status: published

Various 2-benzylidene-6-(nitrobenzylidene)cyclohexanones were prepared as candidate cytotoxins in which the nitro group was located in the ortho, meta and para positions leading to series 1-3, respectively. The CC50 values towards human HSC-2 and HSC-4 oral squamous cell carcinomas as well as human HL-60 promyelocytic leukemic cells are in the low micromolar range in general. On the other hand, most of the compounds afforded clear evidence of being far less toxic towards human HGF gingival fibroblasts, HPC pulp cells and HPLF periodontal ligament. broblasts which are non-malignant cells. Selectivity index (SI) figures were generated which are the ratios of the average CC50 values towards normal cells and the CC50 figure towards a malignant cell line. Huge SI values were obtained for many of the compounds. In particular 1c, 2f, 3c and 3g which have average SI values of >76, >38, 124 and 341, respectively, are clearly lead molecules affording direction for amplification of this area of study. A lead compound 1c caused internucleosomal DNA fragmentation and activation of caspase-3 in HL-60 cells but not in HSC-2 carcinomas. In a short-term toxicity study, doses up to and including 300 mg/kg of the majority of the compounds prepared in this study did not cause any mortalities to mice. Some guidelines for development of these tumor-selective cytotoxins are presented. (C) 2010 Elsevier Ltd. All rights reserved.

A series of novel (+/-) 3-menthone semi carbazides (1-7) and thiosemicarbazides synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established after intraperitoneal administration in three seizure models in mice which include maximal electroshock seizure (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Seven compounds exhibited protection in both models and N(1) - (4-fluorophenyl) - N(4)- (menth-3-one) semicarbazide (4) emerged as the most active compound with MES ED(50) of 44.15mg/kg and scPTZ ED(50) of 38.68mg/kg at 0.25h duration. These compounds were found to elevate gamma-amino butyric acid (GABA) levels in the midbrain region, thus indicating that (+/-) 3-menthone semicarbazides could be considered as a lead molecule in designing of a potent anticonvulsant drug.

The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3) has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2′, 3′, 4′) showed that 4′-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4′-site. The SAR indicated that non-bulky 4′-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were either comparable with or exceeded that of (R)-3, and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.

Thirty nine new 3,4-di(substituted)oxy-N(2),N(5)-bis(substituted)thiophene-2,5-dicarbohydrazides were synthesized starting from ethyl thiodiglycolate through multi-step reactions. In the synthetic sequence, 3,4-dihydroxythiophene-2,5-diester (1) was obtained by condensing the ethyl thiodiglycolate with diethyl oxalate. It was derivatized using different alkyl halides to give disubstituted thiophene esters (2-5), which were then converted to corresponding hydrazides (6-9) following usual methods. Finally, these hydrazides, on treatment with various substituted carbonyl compounds underwent smooth condensation to yield target hydrazones (10-13). The new compounds were characterized using FT-IR, (1)H NMR and (13)C NMR, mass spectral and elemental analyses. The anticonvulsant activity of the title compounds was established after intraperitoneal (ip) administration in three seizure models, which include maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and 6 Hz screens and their neurotoxicity was also evaluated. Compound 11f has emerged as an active compound with no neurotoxicity in this series. Also, the structure-activity relationship of the tested compounds was discussed.

Several diaminodiphenyl analogs were assessed in vivo for their capacity to inhibit seizure induction and propagation in rodents. Both 3,4′- and 4,4′-diaminodiphenyl compounds prevented seizures for as long as 4 h after maximal electric shock induction. 4,4′-Diphenyl compounds bridged by a methylene, sulfide, or carbonyl linker also attenuated focal seizure acquisition in a kindling model. Of these analogs, based upon data generated in two rodent species, 4,4′-thiodianiline ( 1 ) was identified as the most active compound, significantly reducing seizure staging scores and after-discharge duration for several hours after systemic administration. All compounds were devoid of acute in vivo neurotoxicity at doses well above those required for anticonvulsant activity.

A series of new substituted 1,2,4-thiadiazoles were synthesized by appropriate route and screened for anticonvulsant, neurotoxic and sedative-hypnotic activity. The structures of the synthesized compounds were confirmed by IR spectroscopy, (13)C NMR and elemental (nitrogen and sulphur) analysis. After i.p. injection of the compounds to mice or rate at doses of 30, 100, and 300 mg/kg, body weights were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models after 0.5 and 4 h. Rotorod method and phenobarbitone-induced hypnosis potentiation study were employed to examine neurotoxicity and sedative-hypnotic activity, respectively. All the compounds except 4g showed protection against MES screen after 0.5 h. Compounds 3a-c, 4a-c were active at 100 mg/kg dose i.p., whereas remaining compounds showed activity at 300 mg/kg. All 14 compounds except 3g showed neurotoxicity at 100 and 300 mg/kg after 0.5 h. Compounds 3b and 4b showed NT after 4 h. Two compounds 3b and 4g showed significant (p0.05) percentage increase in sleeping time i.e. 67% and 59%, respectively. It may be concluded that the synthesized compounds were potent against MES-induced seizures than ScPTZ induced and showed low potency as sedative-hypnotic agent which is advantageous.

This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a–c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC50 values in the two series of compounds are presented based on molecular modeling, log P values and respiration in rat liver mitochondria.

Summary Purpose: To evaluate the anticonvulsant profile and behavioral toxicity of rufinamide in animal seizure models compared to the established antiepileptic drugs (AEDs): phenytoin, phenobarbital, valproate, and ethosuximide, or vehicle. Methods: In acute studies of anticonvulsant efficacy, the AEDs were administered via oral (CF1 mice and Sprague–Dawley rats) and intraperitoneal (CF1 mice) routes. The AEDs were assessed for their ability to inhibit seizures induced by maximal electroshock (MES) or subcutaneous pentylenetetrazol, and ability to block seizures induced by subcutaneous strychnine, bicuculline, or picrotoxin. Tolerance of oral rufinamide was assessed in rats following 5-day (versus single-dose) treatment with oral rufinamide using the dose equivalent necessary to achieve a 50% decrease in seizure frequency (ED50). Metabolic tolerance was also evaluated using an in vitro liver microsomal assay. Results: Oral rufinamide suppressed pentylenetetrazol-induced seizures in mice (ED50 45.8 mg/kg) but not rats, and was active against MES-induced tonic seizures in mice (ED50 23.9 mg/kg) and rats (ED50 6.1 mg/kg). Intraperitoneal rufinamide suppressed pentylenetetrazol-, bicuculline-, and picrotoxin-induced clonus in mice (ED50 54.0, 50.5, and 76.3 mg/kg, respectively). Rufinamide was partially effective in the mouse strychnine test. The behavioral toxicity of rufinamide was similar to or better than established AEDs tested in this study. In general, the protective index of rufinamide was greater than that of the other AEDs. Conclusions: The efficacy and behavioral toxicity profiles in these animal models suggest that rufinamide may be effective in the treatment of generalized and partial seizures.

JZP-4 is a potent calcium and sodium channel blocker, which is currently being evaluated in patients as an anticonvulsant and mood stabilizer. In the current studies, JZP-4 was evaluated in a variety of animal models for anticonvulsant, antimania and antidepressant activity. In the mouse and rat maximal electroshock models, JZP-4 was slightly more potent than LTG. In the mouse pentylenetetrazole induced seizures model, JZP-4 was approximately twice as potent as lamotrigine in prolonging the time to clonus. In the mouse 6-Hz model for drug resistant or refractory epilepsy, JZP-4 had potent anticonvulsant activity at all current intensities, whereas LTG was active at only the lowest current intensity. In the mouse amphetamine-chlordiazepoxide model for antimanic effects, JZP-4, but not LTG, produced dose-related and significant effects at 3 and 10 mg/kg i.p. In the rat forced swim model of antidepressant activity, JZP-4 (30 mg/kg i.p.) produced a significant reduction in immobility and an increase in climbing behavior. LTG (30 mg/kg i.p.) produced similar effects but these effects did not achieve statistical significance. The specificity of this antidepressant response was confirmed in the rat locomotor test. In this test, JZP-4 produced dose-related and significant reductions in locomotor activity, indicating that it was not a CNS stimulant. LTG produced no significant effects in the rat locomotor test. The studies have demonstrated that JZP-4 has greater potency and efficacy than LTG in models of refractory epilepsy, antidepressant activity and antimania activity. The variance between the effects of LTG and JZP-4 may be related to the greater potency at sodium channels or the additional pharmacological actions of JZP-4 on calcium channels.

A series of 3-aryl amino/amino-4-aryl-5-imino-Δ2-1,2,4-thiadiazoline have been synthesized using an appropriate synthetic route and characterized by elemental analyses and spectral data. The anticonvulsant activity of all the synthesized compounds was evaluated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (ScPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. All the test compounds were administered at doses of 30, 100, and 300 mg/kg body weight and the anticonvulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. Some of the compounds were evaluated for the Phenobarbitone induced hypnosis potentiation test. Among the compounds tested, all except 2h showed protection from MES seizures, whereas only 3b was found to be active in the ScPTZ test.

A series of 3-benzylidene-4-chromanones 1a – l were prepared and their cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 lymphoid leukemia cells were compared to the previously generated biodata in these three assays for the isosteric 2-benzylidene-1-tetralones 2a – l . Over 40% of the compounds in series 1 were more potent than their counterparts in series 2 , while equipotency was noted in one-third of the comparisons made. In general the IC 50 values of 1a – l towards the human T-lymphocytes were in the low micromolar range. Molecular modelling revealed differences in shapes of representative molecules in series 1 and 2 which may contribute to the variation in cytotoxic potencies. Most of the compounds in series 1 displayed greater potencies towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC, and HPLF normal cells and were well tolerated in mice.

A series of N-methyl/acetyl 5-(un)-substituted isatin-3-semicarbazones were screened for anticonvulsant and sedative-hypnotic activities. The results revealed that protection was obtained in all the screens i.e., Maximal electroshock, (MES) subcutaneous pentylene tetrazole (scPTZ) and subcutaneous strychnine (scSTY) screens. Three compounds (5a, 5e and 5i) possessed anti-MES activity and all the compounds were less neurotoxic than phenytoin, carbamazepine and phenobarbital. All the compounds were completely non-toxic at 4h when compared to phenytoin, carbamazepine and phenobarbital, which were toxic at 100 and 300 mg/kg respectively. Compounds 5a, 5b, 5e, 5g and 5i emerged as the active compounds in oral MES screen. Selected compounds were evaluated for quantification studies in MES, scPTZ and neurotoxicity screens after i. p (5b, 5i) and oral administration (5a, 5g) in rats. Among all the compounds 5a, 5b and 5g emerged as broad-spectrum compounds as indicated by their protection in MES, scSTY and scPTZ screens. All the compounds except compound 5b showed significant sedative-hypnotic activity.

A series of nine 1-(4-((E)-3-arylacryloyl)phenyl)-1H-pyrrole-2,5-diones 3a–i (4′-aminochalcone-based maleimides) was synthesized as candidate cytotoxic agents. The efficacy of these potential cytotoxics were evaluated against three representative cell lines and more than half of the drug candidates proved to exhibit significant cytostatic activity in vitro. QSAR studies using statistical analyses on several physicochemical parameters and IC50 values resulted in a few very important correlations which will aid in later the amplification of the project. Representative test compounds were well tolerated by mice in in vivo survival and toxicity studies.

Several semicarbazones of acetophenone and p-chloroacetophenone Mannich bases were designed and synthesized to meet the pharmacophore requirements essential for anticonvulsant activity. Mannich bases of acetophenone and p-chloroacetophenone were prepared by reacting formaldehyde with various secondary amines and then condensed with several aryl semicarbazides to yield the corresponding semicarbazones. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES) and by subcutaneous metrazole (ScMet) and strychnine (ScSty) induced seizure methods, and their neurotoxic effects were determined using the rotorod test. The title compounds were also investigated for antidepressant and sedative-hypnotic potentiation properties. It is established that 3-[3-chlorophenyl(β-dimethylaminopropiophenone)semicarbazone] has excellent anticonvulsant activity in MES, ScSty, and ScMet tests and exhibits a potent antidepressant effect in the absence of sedative-hypnotic potentiation. The present study has proved our earlier hypothesis concerning the pharmacophore model with essential binding sites for semicarbazones. The inclusion of an additional moiety (CH2-CH2-N

Two series of pharmacophoric hybrids of phthalimide-GABA-anilides/hydrazones were designed and synthesized and evaluated for their anticonvulsant and neurotoxic properties. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests. All of the compounds were ineffective in the MES test. Most of the compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model.

A series of sulphonamide derivatives (1-11) were synthesized in good yield and evaluated for their possible anticonvulsant activity and neurotoxic study. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Majority of the compounds were active in MES and scPTZ tests. All the compounds were less toxic than the standard drug phenytoin.

Background/Aims: GBR12909 has been reported to possess anticonvulsant activity with focal brain perfusion to the hippocampus of pilocarpine, although an earlier publication suggested any anticonvulsant effects were only mild. Here we further explored the anticonvulsant potential of GBR12909 with a suite of anticonvulsant assays in both zebrafish and mammals and then explored whether it possessed any QT effects which might limit clinical utility. Methods: We assessed the anticonvulsant effects of GBR12909 in zebrafish pentylenetetrazole (PTZ), mammalian maximal electroshock and PTZ models of generalized epilepsy and a rodent hippocampal kindling model. Cardiac effects were assessed in zebrafish and man. Results: GBR12909 possesses anticonvulsant activity in zebrafish and rodent models of generalized epilepsy. However, phase 1 human data indicated potential QT effects. Subsequent testing in a zebrafish QT assay confirmed marked arrhythmogenic potential. Conclusion: Further clinical development of GBR12909 in epilepsy was considered inappropriate because of insufficient window between the therapeutic effects and the cardiac arrhythmia problems identified in zebrafish assays. Any further development based on this mechanism of action should avoid the GBR12909 chemical scaffold, or involve structure-activity dissociation of its neurological and cardiac effects.

A series of substituted N-(3-methylpyridin-2-yl) semicarbazones was designed and synthesized to meet the structural requirements essential for anticonvulsant activity. The structures of all the synthesized compounds were confirmed by means of spectral and elemental analysis. All the compounds were evaluated for their anticonvulsant activity by maximal electroshock seizures (MES) test, subcutaneous pentylenetetrazole (scPTZ) screen, subcutaneous strychnine (scSTY) pattern test and subcutaneous picrotoxin (scPIC) seizure threshold test along with the behavioral, and neurotoxicity evaluation. A number of N-(3-methylpyridin-2-yl) semicarbazone derivatives exhibited significant protection after intraperitoneal administration at the dose of 100 and 300 mg/kg. Compound N1-(3-methylpyridin-2-yl)-N4-(isatin) semicarbazone (19) emerged as the most active analogue of the series, being more effective in most of the test models than ethosuximide and sodium valporate.

Various 2,4-dimethoxyphenylsemicarbazones were synthesized starting from 2,4-dimethoxyaniline via a phenylcarbamate intermediate. The structures were confirmed by spectral and elemental analyses. The anticonvulsant activity of the synthesized compounds was established after intraperitoneal administration in three seizure models in mice which include maximal electroshock seizure, subcutaneous pentylenetetrazole, and subcutaneous strychnine-induced seizure screens. Nine compounds exhibited protection in all the three seizure models, and N1-(2,4-dimethoxyphenyl)-N4-(propan-2-one)semicarbazone (17) emerged as the most active compound with no neurotoxicity. These compounds were found to elevate gamma-aminobutyric acid (GABA) levels in the midbrain and medulla oblongata regions equipotent to clobazam.

A library of 35 benzylacetamide derivatives was evaluated for anticonvulsant activity as reflected in the ED50 (mg/kg) required to suppress seizure activity in the maximal electroshock seizure (MES) test. Using the method of partial least-squares regression in conjunction with cross-validation, the influence of 31 topological, electronic, physico chemical, and structural properties on anticonvulsant activity was investigated. A QSAR model of the logED50 in the MES test was established (R2adj = 0.77) as a function of the following seven properties: the Wiener index on distance code (Wmean), the mean information index on atomic composition (rIac), the partial charge at the C-terminal carbonyl carbon (qCC), the sum of partial charges in the α substituent (qαtotal), the number of hydrogen bond donors and acceptors in the α substituent (Hdα and Haα), and the calculated value of the squared n-octanol/water partition coefficient. Based on this model, two new amido ketone compounds — (R,S)-2-acetamido-5-phenyl-3-pentanone and cis/trans-(R,S)-2-acetamido-5-phenyl-4-penten-3-one — were synthesized and shown to have significant anticonvulsant activity in the MES test.Key words: QSAR, anticonvulsant, benzylacetamide, functionalized amino acid, amido ketones.

The antiepileptic activity associated with ketogenic diets (KD) have been known for some time. First reports date back to the Middle Ages and even Biblical times where KD was achieved by fasting (i.e. "water diet") [see Swink, T.D., Vining, E.P.G., Freeman, J.M., 1997. The ketogenic diet: 1997. Adv. Pediatr. 44, 297-329, and references therein]. In the early 20th century, changes in the design of the KD were introduced, shifting the so-called "water diet" to a high-fat diet. Initial clinical evaluations undertaken between the 1920s and 1940s were enthusiastic, but the popularity of the KD was retrograded upon clinical introduction of phenytoin and subsequently other antiepileptic drugs. Today, despite a pharmacological arsenal targeting cerebral receptors and specific events in seizure initiation and development, about 30-40% patients are still refractory to available medications. Thus, the KD has been re-introduced in recent years as an alternative therapy, averring to be efficacious against some instances of resistant or intractable epilepsy. Despite a long historical background and enlarged clinical use, identification of the underlying anticonvulsant mechanisms associated with this nonpharmacological approach is still in stagnation. The present review is an attempt to encourage current research orientation through well-based and directed proposals for putative emerging candidates mediating KD anticonvulsant mechanisms. The reader is provided with a special emphasis on ATP-sensitive and recently cloned two-pore (or tandem) domain potassium channels, as well as several emerging conceptual views and advances such as nuclear receptors, uncoupling proteins and gap junctions that the authors speculate may contribute to understanding the basic mechanisms linked to the KD.

Various 6-substituted benzothiazolyl-2-thiosemicarbazones were synthesized and screened for anticonvulsant activity in maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. The 6-methyl benzothiazolyl-2-thiosemicarbazones showed anticonvulsant activity in both mice i.p. and rat oral MES screen. The 6-nitro benzothiazolyl thiosemicarbazone derivative 1a emerged as the most promising one with anti-MES activity in mice i.p., rat i.p. and rat p.o. evaluations. All the compounds exhibited lesser or no neurotoxicity compared to phenytoin. The isatinimino derivatives had shown better activity when compared to the benzylidene or acetophenone derivatives.

We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent.

Amino acid amides (AAA) were prepared and evaluated in seizure models. The AAA displayed moderate-to-excellent activity in the maximal electroshock seizure (MES) test and were devoid of activity in the subcutaneous Metrazol-induced (scMet) seizure test. The AAA anticonvulsant activity was neither strongly influenced by the C(2) substituent nor by the degree of terminal amine substitution. An in vitro metabolism study suggested that the structure-activity relationship pattern was due, in part, to metabolic processes that occurred at the N-terminal amine unit.

Epilepsy afflicts 1-2% of the world's population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, alpha-hydroxy-alpha-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED(50)=63 mg/kg and anti-subcutaneous Metrazol (scMet) ED(50)=74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques-including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach-in the hopes of determining the effect of caprolactam alpha-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: alpha-ethynyl-alpha-hydroxycaprolactam (10), alpha-benzyl-alpha-hydroxycaprolactam (11), and alpha-hydroxy-alpha-(phenylethynyl)caprolactam (13). Phase II results for 11 strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class.

We have reported that functionalized amino acids (FAA) are potent anticonvulsants. Replacing the N-terminal amide group in FAA with phenethyl, styryl, and phenylethynyl units provided a series of functionalized amido ketones (FAK). We show that select FAK exhibit significant anticonvulsant activities thereby providing information about the structural requirements for FAA and FAK bioactivity.

Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly −80% of the NMDA-evoked current, with EC50 of approximately 5 μM. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. CHF3381 also inhibited voltage-gated Na+ currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 μM). Consistent with the mild effects on voltage-gated Na+ channels, CHF3381 (100 μM) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anti-convulsant agent and Na+ channel blocker lamotrigine (100 μM) inhibited stimulation-evoked glutamate overflow by approximately 50%. CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation. Keywords: CHF3381, N-methyl-D-aspartate (NMDA), Na+ channel, glutamate, hippocampus, cortex Introduction Neurological disorders are very common, affecting more than 25% of all people at some time during their lives. These diseases have a large impact on individuals, families and communities. Effective treatments would certainly reduce this impact. However, many neurological disorders remain or become resistant to available drug treatments. Therefore, there is great interest in research devoted to identifying new drugs, with action mechanisms different from those currently in use. CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been recently described as a novel anticonvulsant and antiepileptic agent possessing a good therapeutic window, that is, a scant propensity to cause neurological side-effects (Villetti et al., 2001). Even more recently, it has been shown that the compound also possesses robust neuroprotective activity (Zucchini et al., 2002). Based on initial binding studies, CHF3381 has been proposed as a putative N-methyl-D-aspartate (NMDA) receptor antagonist (Gandolfi et al., 2001; Villetti et al., 2001). If this were the case, CHF3381 may demonstrate therapeutic properties not only in epilepsy, but also in hypoxic–ischemic brain injury, trauma, chronic pain and degenerative disorders like Huntington's disease, Parkinson's disease, Alzheimer's disease and AIDS dementia (Kohl & Dannhardt, 2001; Palmer, 2001; Parsons, 2001). The aim of this study was to gain more insight into the mechanism of action of CHF3381. Thus, we examined (1) its potential for interaction with voltage- and receptor-gated ion channels using whole-cell patch-clamp electrophysiology techniques with primary neuronal cell cultures, (2) its effects on electrical stimulation-evoked glutamate release from hippocampal slices, and (3) its effects on kindled seizure-induced c-fos expression using in situ hybridisation.

A series of novel 3,5-bis(phenylmethylene)-1-(N-arylmaleamoyl)-4-piperidones 3 have been synthesized which displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. In contrast, the related N-arylmaleamic acids 4 possessed little or no cytotoxicity in these four screens. Molecular modeling revealed certain interplanar and bond angles and interatomic distances which were perceived to contribute to the observed bioactivity as well as providing suggestions for future structural modifications of the piperidones 3. Evaluation of representative compounds in series 3 and 4 on the activity of human N-myristoyltransferase revealed that, at the maximum concentration utilized, namely 250 microM, only weak inhibiting properties were displayed by some of the compounds in series 4. Various members of series 3 and 4 were well tolerated in mice.

Summary: Purpose: The workshop explored the current problems, needs, and potential usefulness of existing methods of discovery of new therapies to treat epilepsy patients. Resistance to medical therapy (pharmacoresistance) and the development of epilepsy (epileptogenesis) are recognized as two of the major problems in epilepsy treatment today. At the same time, there is growing awareness that the development of new therapies has slowed, a trend that has economic and scientific roots. To move toward new and more effective therapies, novel approaches to therapy discovery are needed. Methods: A workshop was held in March 2001 with the charge to develop a plan to move the exploration and discovery process forward. Participants from academia, government, and industry reviewed the current status of epilepsy therapy and explored the identification of potential new therapies. Results: At the end of the 2-day meeting, the panel made a series of recommendations. The two major recommendations were (a) to establish a means for continuing the examination of new approaches to therapy discovery, and (b) to identify models and approaches to therapy discovery that may identify treatments that are more successful than those available. Further recommendations were made to support the development of technology (miniaturization, computerization, video monitoring, etc.) to facilitate the use of the new models and to identify the mechanisms of therapy success and failure. Conclusions: Understanding the epidemiology of therapy resistance and providing support for new approaches to therapy development were identified as key issues for introduction of new and more effective treatments.

A number of 1,3-arylidene-2-tetralones 1, 2 and 4 were synthesised and demonstrated cytotoxic activity towards murine P388 and L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes. In general, the related 1-arylidene-2-tetralones 3 possessed lower potencies in these screens than the compounds in series 1 and 4. Approximately, half of the compounds were evaluated against a panel of human tumour cell lines. In this screen, most of the enones were more cytotoxic than the established anticancer agent melphalan and some demonstrated selective toxicity towards leukemic and colon cancer cells. The modes of action of representative compounds include interfering with the biosyntheses of nucleic acids and proteins as well as altering redox potentials. The compounds were well tolerated when administered intraperiteonally to mice. Thus these novel enones are promising prototypic molecules due to their potent cytotoxic properties and lack of significant murine toxicity.

Studies have shown that functionalized amino acids (FAA) exhibit outstanding activity in the maximal electroshock-induced seizure (MES) test in rodents. Affinity labels patterned in part after the potent antiepileptic (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2) have been prepared as mechanistic probes to learn the pharmacological basis for FAA function. The chemical reactivity of the affinity labels with nucleophiles was assessed, and the labels were evaluated in in vitro radioligand assays and in the MES tests in rodents. The affinity labels did not bind to receptors known to effect seizure spread. Three affinity labels, (R,S)-N-benzyl-2-acetamido-6-isothiocyanatohexanamide ((R,S)-5), (R)-N-(4-isothiocyanatobenzyl)-2-acetamido-3-methoxypropionamide ((R)-6), and (R)-N-(3-isothiocyanatobenzyl)-2-acetamido-3-methoxypropionamide ((R)-7), possessed excellent in vivo anticonvulsant activity and exhibited maximal activity at later time periods than typically observed for FAA. The anticonvulsant activity of 6 and 7 resided primarily in the (R)-enantiomer and the activity of (R)-6 and (R)-7 in rats (po) exceeded that of phenytoin. The chemical properties, pharmacological profile, and marked stereospecificity associated with 6 and 7 anticonvulsant activity make these compounds useful pharmacological tools for the study of the mode of action of FAA.