Design, synthesis and biological evaluation of novel thiosemicarbazide analogues as potent anticonvulsant agents (original) (raw)
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… System Agents in …, 2011
A series of thiosemicarbazones of halogen substituted benzaldehydes, benzophenone and acetophenone were synthesized using an appropriate synthetic route and characterized by thin layer chromatography and spectral analysis. The anticonvulsant activity of synthesized compounds was established in three seizures models which includes maximal electroshock (MES), subcutaneous pentylene tetrazole (scPTZ) induced seizures and minimal neurotoxicity test. Five compounds out of 21 exhibited protection in MES test while only one compound showed protection in scPTZ screen. Two compounds were found to be active in minimal clonic seizure (6Hz) model. Compound PS 6 i.e. 2-(3-bromobenzylidene)-N-(4-chlorophenyl) hydrazinecarbothioamide emerged as the most active compound with MES ED 50 of more than 50mg/kg and pI greater than 12, which is found to be better than the prototype drug, Phenytoin. The compound has shown neuroprotection in kainic acid model with IC 50 value of 40.97 μM. It has also shown mild activation effect on CYP2D6 and CYP 2C9 enzymes, indicating the usefulness of thiosemicarbazones as anticonvulsants.
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 (4aq) 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.
Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones
European Journal of Medicinal Chemistry, 2002
Ten 6-chlorobenzothiazolyl-2-thiosemicarbazones were synthesised and screened for anticonvulsant and neurotoxic properties. Most of the compounds showed anticonvulsant activity against both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole screens. Eight compounds have shown good protection in the rat p.o. MES test at 30 mg kg − 1 . Compound 1 [4-(6-chlorobenzothiazol-2-yl)-1-(3-isatinimino)thiosemicarbazone] emerged as the most promising one with an ED 50 of 17.86 and 6.07 mg kg − 1 in mice i.p. and rat p.o., respectively. Compound 1 showed a weak ability to block the expression of fully kindled seizures.
Synthesis of some novel N4-(naphtha[1,2-d]thiazol-2-yl)semicarbazides as potential anticonvulsants
European Journal of Medicinal Chemistry, 2009
A series of N 4 -(naphtha[1,2-d]thiazol-2-yl)semicarbazides were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure tests and minimal motor impairment was determined by rotorod test. A majority of the compounds exhibited significant anticonvulsant activity after intraperitoneal administration. Some of the selected compounds were evaluated orally in rats for activity in scPTZ test at several time points (50 mg/kg). The most active compounds carry bromo, fluoro and nitro substituents at 4-position in the phenyl ring. The biochemical estimations of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) from brain homogenate not only clearly implicated the role of free radicals in PTZ-induced convulsion but also explained the possible mechanism of protective effect of semicarbazides, through the reduced formation of MDA and increased formation of SOD and GSH-Px.
European Journal of Medicinal Chemistry
Thirty six new N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothioamides were synthesized and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity was established in three seizure models i.e. MES, scMET and 6 Hz model. The most active compound was 2-[4-(4-chlorophenoxy)benzylidene]-N-(4-fluorophenyl)hydrazinecarbothioamide PC 31 which showed 100% protection at 0.5 h in the 6 Hz test. Compound 2-[4-(4-bromophenoxy) benzylidene]-N-(4bromophenyl) hydrazinecarbothioamide PC 23 was found to be active in both the MES and 6 Hz test. A computational study was carried out from calculation of a pharmacophore pattern and the prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta and GABA (A) alpha-1 receptors, in the Lamarckian genetic algorithm based on flexible docking studies.
2015
A series of N-(1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[(1Z)-(substituted benzylidene)]thiourea 4 (4a1-a10) and N-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-2-(substitutedphenyl)-1,3-thiazolidine -3-carbothioamide 5 (5a1, a2, a4 and a10) have been synthesized. All the compounds were evaluated for their anticonvulsant activity and neurotoxicity profile in two phases. Phase I included MES, s.c. PTZ and neurotoxicity test. Phase two trial shows low toxicity with high protective index especially for MES screen. The structures of the compounds were elucidated on the basis of their spectral and elemental analysis. Keyword: Anticonvulsant; epilepsy; thiazolidinones, thiourea, neuroprotection
Journal of Enzyme Inhibition and Medicinal Chemistry, 2016
Synthesis, characterization and investigation of in vivo anticonvulsant activities of 13 novel cyclopentanecarbaldehyde-based 2,4-disubstituted 1,3-thiazoles are presented. Their structures were determined using 1 H and 13 C NMR, FAB(+)-MS, HRMS and elemental analyses. The results of anticonvulsant screening reveal that seven intraperitoneally administered compounds: 3a, 3b, 3d, 3e, 3f, 3k and 3m containing F-, Cl-, Br-, CF 3-, CH 3-and adamantyl substituents demonstrated significant anticonvulsant activity in the pentylenetetrazole model with median effective doses (ED 50) 20 mg/kg, respectively, which was approximately seven-fold lower than that reported for the reference drug, ethosuximide. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test.
Medicinal Chemistry Research, 2014
Some new substituted hydrazone derivatives were designed, synthesized, and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity was established after intrapentoneal administration in oneseizure models, which include maximal electroshock seizure (MES) model. In the MES screen, the most active compounds were PK-1 and PK-2 which showed 100 % protection. None of these compounds showed neurotoxicity. A computational study was also performed including prediction of pharmacokinetic properties, bioactivity, toxicity, and docking studies. The result reveals from the computational studies as the protein-ligand interaction energies of derivatives PK-1 and PK-2 with established epilepsy receptor namely Na/H exchanger were -8.31 and -7.30 kcal/mol, which is slightly higher than the phenytoin as -6.71 kcal/mol. The percentage of absorption (%ABS) was calculated and observed that all titled compounds exhibited a better %ABS ranging 82-90. Therefore, all pharmacological parameters are almost similar to standard drug. The above observation suggested that these compounds would serve as better lead compounds for anticonvulsant screening for future drug design perspective.
TheScientificWorldJournal, 2014
Keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity, a new series of 3-(2-(substitutedbenzylidene)hydrazinyl)-N-(substituted benzo[d]thiazol-2-yl)-propanamides were synthesized with aromatic hydrophobic aryl ring (A), NH-C=O as hydrogen bonding domain (HBD), nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). Synthesized compounds were characterized by FTIR, (1)H NMR, (13)C NMR, mass spectroscopy, and elemental analysis. Preliminary in vivo anticonvulsant screening (phase I) was performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Based on anticonvulsant screening results, two compounds, 5h and 5p, were found to be most active; they exhibited activity comparable to standard drugs phenytoin (PHY) and carbamazepine (CBZ). These active compounds were subjected to phase II and phase III screening, where they displayed much higher protecti...