Triazole incorporated thiazoles as a new class of anticonvulsants: Design, synthesis and in vivo screening (original) (raw)
Related papers
IP Innovative Publication Pvt. Ltd., 2018
Several new promising bioactive derivatives of N-(5-(Substituted)-1, 3, 4-thiadiazol-2-yl)-2-((5-(substitutes)-4H-1, 2, 4-triazol-3-yl) amino) acetamide were synthesized. The compounds were obtained in excellent yields. The synthesized compounds were confirmed on the basis of IR and NMR. Acute toxicity study was done to determine the LD50 of the newly synthesized compounds. Some of the synthesized compounds were evaluated for their anticonvulsant effect by PTZ induced convulsions method. Statistical testing was done by one way ANOVA followed by Dunnett’s test. The compounds D-III showed the highest percentage of protection as compared to PTZ, i.e. 80% at the dose of 20mg/kg among the evaluated compounds compared to control. Keywords: 1, 3, 4-thiadiazole, 1, 2, 4-triazole, Anticonvulsant.
European Journal of Medicinal Chemistry, 2014
A series of 4-alkyl-5-(3-chlorobenzyl/2,3-dichlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (1a e14a) were designed, synthesized and screened for their anticonvulsant properties. Moreover, the acute adverse-effect profile of the active compounds (1ae7a, 12a) with respect to impairment of motor performance was evaluated in the chimney test. Among 4-alkyl-5-(3-chlorobenzyl)-2,4-dihydro-3H-1,2,4triazole-3-thiones, ethyl, butyl, pentyl, hexyl, and heptyl derivatives administered intraperitoneally in a dose of 300 mg/kg protected 100% of the tested animals at four pretreatment times (i.e., 15, 30, 60, 120 min). Taking into account the median effective and toxic doses as well as the time-course profile of anticonvulsant activity, 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (4a) was proposed as the best tolerated and the most promising potential drug candidate. Finally, a radioligand binding assay was used to check whether the anticonvulsant activity of 4-alkyl-1,2,4-triazole-3-thiones was a result of their interactions (direct or allosteric) with GABA A receptor complex and/or their affinity to benzodiazepine (BDZ) binding sites.
Synthesis and Anticonvulsant Activities of Some Triazolothiadiazole Derivatives
Archiv der Pharmazie, 2012
The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n). The bioevaluation demonstrated that most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4-chlorophenyl)-[1,2,4]triazolo[3,4b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED 50 value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemicalinduced seizure tests suggested that compound 4h displayed broad-spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system.
Molecules, 2014
The anticonvulsant activity of several 1,2,4-triazole-3-thione derivatives on mouse maximal electroshock-induced seizures was tested in this study. Characteristic features of all active compounds were rapid onset of action and long lasting effect. Structure-activity observations showed that the probability of obtaining compounds exerting anticonvulsant activity was much higher when at least one of the phenyl rings attached to 1,2,4-triazole nucleus had a substituent at the para position. The obtained results, moreover, permit us to conclude that despite the structural similarity of loreclezole (second-generation anticonvulsant drug) and the titled compounds, their anticonvulsant activity is achieved via completely different molecular mechanisms.
Chemical Biology & Drug Design, 2011
A series of novel thiazole incorporated (arylalkyl)azoles were synthesized and screened for their anticonvulsant properties using maximal electroshock and pentylenetetrazole models in mice. Among target compounds, 1-[(2-(4-chlorophenyl)thiazol-4-yl)methyl]-1H-imidazole (compound 4b), 1-[(2-phenylthiazol-4-yl)methyl]-1H-1,2,4-triazole (8a), and its 4-chlorophenyl analog (compound 8b) were able to display noticeable anticonvulsant activity in both pentylenetetrazole and maximal electroshock tests with percentage protection range of 33-100%. A computational study was carried out for prediction of pharmacokinetics properties and drug-likeness. The structure-activity relationship and in silico drug relevant properties (molecular weight, topological polar surface area, clog P, hydrogen bond donors, hydrogen bond acceptors, and log BB) confirmed that the compounds were within the range set by Lipinski's ruleof-five, and possessing favorable physicochemical properties for acting as CNS-drugs, making them potentially promising agents for epilepsy therapy.
Rasayan Journal of Chemistry
A potent antiepileptic drug was developed by synthesizing a set of novel thiazoles substituted oxazole derivatives using multi-step synthesis. FT-IR, 1H-NMR, Mass spectroscopy, and elemental analyses are employed to confirm the structure of compounds. Molinspiration online tool was used to predict the molecular properties and molecular docking was employed to predict the antiepileptic potency of the title analogs. MES and scPTZ tests were employed to determine the antiepileptic potency of thirteen prepared novel thiazole substituted oxazole derivatives. In addition, the neurotoxicity of the compounds was also estimated using the rotarod test. Entire tested derivatives displayed varying degrees of antiepileptic and neurotoxicity potency. The pharmacological potency of prepared derivatives was compared with their chemical structures. Among fifteen tested title compounds the potent compound of this series was found to be 4-(4-(2-(4-chlorobenzylideneamino)thiazol-4-yl)benzylidene)-2-met...
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...
Archiv der Pharmazie, 2009
A series of novel N 1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N 4-(4-substituted benzaldehyde)semicarbazone 1-12, N 1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N 4-[1-(4-substituted phenyl)ethanone]-semicarbazone 13-16, and N 1-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N 4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazone 17-20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, 1 H-NMR, 13 C-NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8, 13, 15, and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among the synthesized compounds.
2010
A novel series of N'-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-(4-substituted benzaldehyde)-semicarbazones, N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl)ethanone]-semicarbazones and N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazones were synthesized and evaluated for their anticonvulsant potential using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPFZ) models. The minimal motor impairment (neurotoxicity) was determined by rotorod test. The results of the present study confirmed the requirements of various structural features of four binding site pharmacophore model for anticonvulsant activity.
Archiv der Pharmazie, 2015
A series of N-(substituted-2-oxo-4-phenylazetidin-1-yl)-2-((6-substitutedbenzo[d]thiazol-2-yl)amino)acetamide derivatives were synthesized using pharmacophoric features with aromatic hydrophobic aryl ring (A), NHCO as hydrogen bonding domain, the nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). The synthesized molecules were initially screened for anticonvulsant activity using the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole test in albino mice. An acute neurotoxicity study on the synthesized molecules was also carried out using the rotarod test. The results of these tests revealed that two compounds, 5b and 5q, showed promising activity with ED50 values of 15.4 and 18.6 mg/kg and protective indices of 20.7 and 34.9 in the MES test, respectively, which are found to be approximately fourfold higher than those of the standard drugs phenytoin (6.9) and carbamazepine (8.1). These molecules may act as lead of the designed schem...