Synthesis and Anti Convulsant Activity of "N'-{4-[2-(1h-Benzimidazol-2-Yl)-2-Oxoethyl] Phenyl}-2-Hydroxyacetohydrazide and Its Derivatives" (original) (raw)
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Anticonvulsant evaluation of some newer benzimidazole derivatives: design and synthesis
Acta poloniae pharmaceutica
A series of new 2-[(1-substituted phenylethylidine) hydrazine]-N-phenyl-1H-benzo[d]imidazole-1-carbothioamides (4a-n) were designed and synthesized to have the pharmacophoric elements essential for anticonvulsant activity. The key step in the synthesis of the title compounds involves the reaction of 2-mercaptobenzimidazole with hydrazine hydrate, substituted acetophenones and phenylisothiocyanate to get the compounds in good yields. All the newly synthesized compounds were screened by two most adopted models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Interestingly, compounds 4e, 4f, 4g, 4h and 4j exhibited potent anticonvulsant results and in the neurotoxicity screening, most of the compounds were devoid of toxicity at the dose of 60 and 100 mg/kg.
Synthesis, characterization and pharmacological screening of novel benzimidazole derivatives
In present study o-phenylenediamine and phenoxyacetic acid were used as starting material through series of steps 2-[2-(phenoxymethyl)-1H-benzimidazol-1-yl]acetohydrazide 5 was obtained. Various derivatives of 2-[2-(phenoxymethyl)-1H-benzimidazol-1-yl]-N 0-[(Z)-phenylme-thylidene]acetohydrazide and some compounds containing oxadiazole bearing benzimidazole were synthesized by using various aromatic aldehyde, cyanogens bromide and carbon disulfide/potas-sium hydroxide. These were elucidated by IR, NMR and elemental analysis and their in vivo anti-convulsant screening was performed using MES and scPTZ. Two compounds 7g and j were found to be potent in both the screens and their protective index was found to be better than standard drugs used. ª 2011 Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Medicinal Chemistry Research, 2016
A series of new benzimidazole derivatives (4ap) were synthesized and evaluated for anticonvulsant activity in albino mice against two most adopted models, i.e. maximal electroshock seizure (MES)-and subcutaneous pentylenetetrazole (scPTZ)-induced seizures. Synthesized compounds were also screened for possible neurotoxicity using rotarod test. Among the synthesized compounds, 4p showed the most promising activity in MES and scPTZ screens, which was further subjected for oral activity in rats. At a dose of 30 mg/kg, it showed tremendous activity in the scPTZ screen. The acute toxicity study (LD 50) of compounds showed that only two tested compounds 4f and 4m did not produce any mortality at any of the dose level. Molecular properties and pharmacokinetic parameters of the titled compounds were also determined using Lipinski's rule of five. The promising results encourage future investigation on the rational modification of this nucleus for development of better compounds. Keywords Anticonvulsant Á Glutamate Á Benzimidazole Á In silico Á In vivo Á Molecular docking Electronic supplementary material The online version of this article (
Journal of Medicinal Chemistry, 1981
A novel series of N-(bemylalkyl)imidazoles and N-(w-phenyl-w-hydroxyaUryl)hdazoles was synthesized and evaluated for anticonvulsant activity in mice against maximal electroshock induced seizures. Some of the compounds showed an activity comparable to or better than phenytoin and phenobarbital. The N-[fi-[4-(/3-phenylethyl)phenyl]-j3hydroxyethyllimidazole (38) was selected for further studies; preclinical toXicology and additional efficacy evaluations are in progress. Structure-activity relationships are discussed. All compounds, except 26, were prepared according t o method F.
Der Pharmacia Lettre, 2016
A new series of 5-methoxy-2-mercapto benzimidazole derivatives were synthesized by the reaction of 5-methoxy-2-mercaptobenzimidazole with chloroacetic acid and affords 2-((5-methoxy-1H-benzo[d]imidazol-2-yl)thio) acetic acid (1),which on cyclization with acetic anhydride and pyridine gives 7-methoxybenzo[4,5]imidazo[2,1-b]thiazol-3(2H)-one(2), which on condensation with different aryl aldehydes in the presence of anhydrous sodium acetate in glacial acetic acid, furnishes a arylidene thiazolidinone. The purity of the synthesized compounds was confirmed by melting point and TLC.The structures were established by different spectral analysis such as FTIR, 1 HNMR, and CHN analysis. The newly synthesized compounds (3a-d) were in vivo evaluated for their anticonvulsant activity against yohimbine hydrochloride-induced epilepsy in comparison with 2mg/kg diazepam as a reference drug. The anticonvulsant effect of the intended compounds was assessed by their ability to delay the onset of seizure attack and by a reduction in the number of attacks. All of the synthesized compounds were found to have anticonvulsant activity.
Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-ones
Journal of Medicinal Chemistry, 1989
Our previous publication (Eur. J. Pharmacol. 1995, 294, 411-422) reported preliminary chemical and biological studies of some 2,3-benzodiazepines, analogues of 1-(4-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466), which have been shown to possess significant anticonvulsant activity. This paper describes the synthesis of new 1-aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones and the evaluation of their anticonvulsant effects. The observed findings extend the structure-activity relationships previously suggested for this class of anticonvulsants. The seizures were evoked both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. 1-(4′-Aminophenyl)-(38) and 1-(3′-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (39), the most active compounds of the series, proved to be more potent than 1 in all tests employed. In particular, the ED 50 values against tonus evoked by auditory stimulation were 12.6 µmol/kg for derivative 38, 18.3 µmol/kg for 39, and 25.3 µmol/kg for 1. Higher doses were necessary to block tonic extension induced both by maximal electroshock and by pentylenetetrazole. In addition these compounds exhibited anticonvulsant properties that were longer lasting than those of compound 1 and were less toxic. The novel 2,3-benzodiazepines were also investigated for a possible correlation between their anticonvulsant activities against convulsions induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and their affinities for benzodiazepine receptors (BZR). The 2,3-benzodiazepines did not affect the binding of [ 3 H]flumazenil to BZR, and conversely, their anticonvulsant effects were not reversed by flumazenil. On the other hand the 2,3-benzodiazepines antagonized seizures induced by AMPA and aniracetam in agreement with an involvement of the AMPA receptor. In addition, both the derivative 38 and the compound 1 markedly reduced the AMPA receptor-mediated membrane currents in guinea-pig olfactory cortical neurons in vitro in a noncompetitive manner. The derivatives 25 and 38-40 failed to displace specific ligands from N-methyl-D-aspartate (NMDA), AMPA/kainate, or metabotropic glutamate receptors.
2008
The benzodiazepines (BZDs) are widely used in the treatment of central nervous system (CNS) disorders such as anxiety, insomnia and epilepsy. 1) The pharmacological effects of the BZDs result from their affinity for a specific binding domain on the gamma amino butyric acid (GABA A) receptors, known as the BZD receptor. The interaction of BZD agonists with GABA A receptor complex increases the GABA-induced chloride channel opening frequency, which results in membrane hyperpolarization, thus reducing neuronal excitability. 2,3) The BZD binding sites in the brain were identified and described by radioligand receptor binding assays and originally it was found that only 1,4-BZD derivatives bind to these receptors. It has since been shown that many groups of compounds bind to the BZD receptor with high affinity, e.g., triazolopyridazines, cyclopyrrolones, quinolines and b-carbolines. 4-7) Several pharmacophore models have been proposed for BZDs, and amongst all models suggested for binding to the BZD receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance (5 Å). Also, the presence of a second out-ofplane, aromatic ring could potentiate binding to the receptor. 8-12) On this basis, a wide variety of compounds with a chemical structure different from that of BZDs have been synthesized and tested. We recently started a wide research program aimed to design new BZD receptor ligands characterized by a higher degree of flexibility compared with classic BZD ligands. Accordingly, we reported several 1,3,4-oxadiazole derivatives which showed considerable anticonvul-sant activity. 13-15) As part of our ongoing research program to design new anticonvulsant agents, we describe herein the synthesis and biological evaluation of a novel group of 2substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles (Fig. 1) with a flexible second out-of-plane aromatic ring, benzyloxy group which has all the suggested requirements for binding to the BZD receptors. Results and Discussion Chemistry The target 1,3,4-oxadiazole derivatives were synthesized according to Chart 1. Accordingly, reaction of 2halo-2-benzyloxy benzoic acid methyl ester 1 with hydrazine hydrate in N,NЈ-dimethyleformamide (DMF) at room temperature afforded corresponding 2-halo-2-benzyloxy benzoic acid hydrazide 2 high yields (87-90%). 16) The hydrazide were converted to 2-amino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazoles 3 using cyanogen bromide in methanol (71-90%). 17) 5-(2-Halo-2-benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 4 was prepared by the reaction of hydrazide 2 with carbon disulfide under basic condition (60-70%). 18) Sonication of compound 5 in the presence of suitable alkyl halide in alkaline media afforded 2-alkylthio-5-(2-halo-2benzyloxyphenyl)-1,3,4-oxadiazole 5a-f (58-90%). 19) Treatment of hydrazide 2 with phenylisothiocyanate followed by reaction with KI/I 2 in alkaline hydro-ethanol gave 2anilino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 7 (57-80%). 20) The compounds were characterized by 1 H nuclear magnetic resonance, infrared, mass spectrometry and CHN analysis. Physicochemical data of these compounds are shown in Table 1. Conformational analysis of the synthesized compounds and estazolam were preliminarily performed by MMX force field method implemented in Hyperchem 7.0 software. The conformers were optimized further by AM1 calculation using MOPAC 6.0 program. 21) Global energy minima conformers of the designed compounds were superimposed on corresponding conformer of estazolam molecule which was considered as a reference BZD agonist. Anticonvulsant Activity The BZD activity of the synthesized compounds was determined through the evaluation of the ability of the compounds to protect mice against con