Design, synthesis, pharmacological evaluation, and docking study of new acridone-based 1,2,4-oxadiazoles as potential anticonvulsant agents

Mohammadi-Khanaposhtani, Maryam; Shabani, Mohammad; Faizi, Mehrdad; Aghaei, Iraj; Jahani, Reza; Sharafi, Zeinab; Zafarghandi, Narges Shamsaei; Mahdavi, Mohammad; Akbarzadeh, Tahmineh; Emami, Saeed; Shafiee, Abbas; Foroumadi, Alireza

doi:10.1016/j.ejmech.2016.01.054

Cited by 78 publications

(32 citation statements)

References 20 publications

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“…Moreover, the hydrogen bonding between the F atom of the compound 5f and residue Glu189 may help to explain the best activity of 5f among this series of compounds. According to the reports of Richter and Mohammadi‐Khanaposhtani, Thr206, Tyr209, Phe77, His101, and Tyr159 are the critical residues in the binding mode of diazepam. Therefore, the binding mode of compound 5f in the BZD‐binding pocket of GABA A receptor resembled to that of diazepam, and the synthesized compounds may well play its anticonvulsant activity via mediating BZD receptors.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

Song

Huang

Wang

et al. 2019

Archiv der Pharmazie

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A novel series of benzoxazole derivatives containing 1,2,4‐triazolone (5a‐m) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc‐PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti‐MES activities at 100 and 300 mg/kg. Compound 5f, which showed potential anticonvulsant activity in the MES model with ED50 values of 22.0 mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3‐mercaptopropionic acid and BIC was also verified. In an enzyme‐linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ‐aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED50 value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABAA receptor confirmed possible binding of the compound 5f with BZD receptors.

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Section: Resultsmentioning

confidence: 99%

Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

Song

Huang

Wang

et al. 2019

Archiv der Pharmazie

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“…To confirm whether the anticonvulsant activity of compound 9a is mediated through BZD receptors, a docking study was performed using Discovery Studio™ Server-Client (2017). As shown in Figure 3A, α1 Thr206, α1 Tyr 209, α1 His101, α1 Tyr159, and γ2 Phe77 are the most important residues in the binding mode of diazepam [23]. As shown in Figure 3B, the oxygen atom was responsible for conventional hydrogen bond (green dotted lines) interaction with α1 Thr206 and γ2 Thr142, and the length of bond was 2.95 and 1.88 Å.…”

Section: Docking Studymentioning

confidence: 94%

“…Benzodiazepines (BZDs) are highly potent anticonvulsants that are commonly used in clinical treatment [22]. The GABA A receptor is regarded as one of the targets for development of antiepileptic drugs [23][24][25].…”

Section: Docking Studymentioning

confidence: 99%

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Synthesis and Pharmacological Evaluation of New 3,4-Dihydroisoquinolin Derivatives Containing Heterocycle as Potential Anticonvulsant Agents

et al. 2016

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Two novel series of 3,4-dihydroisoquinolin with heterocycle derivatives (4a-t and 9a-e) were synthesized and evaluated for their anticonvulsant activity using maximal electroshock (MES) test and pentylenetetrazole (PTZ)-induced seizure test. All compounds were characterized by IR, 1 H-NMR, 13 C-NMR, and mass spectral data. Among them, 9-(exyloxy)-5,6-dihydro-[1,2,4]triazolo [3,4-a] isoquinolin-3(2H)-one (9a) showed significant anticonvulsant activity in MES tests with an ED 50 value of 63.31 mg/kg and it showed wide margins of safety with protective index (PI > 7.9). It showed much higher anticonvulsant activity than that of valproate. It also demonstrated potent activity against PTZ-induced seizures. A docking study of compound 9a in the benzodiazepine (BZD)-binding site of γ-aminobutyric acid A (GABA A ) receptor confirmed possible binding of compound 9a with the BZD receptors.

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“…The structures of all the derivatives were converted into 3D before analysis. Merck Molecular Force Field (MMFF) with distance‐dependent dielectric function and energy gradient of 0.001 kcal/mol with iteration limit to 10,000 was utilized to perform energy optimization of all the molecules . On the basis of energy minimization the drug binds to effectors/receptors in the most stable form that is the minimum energy form.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

Nilkanth¹,

Ghorai²,

Sathiyanarayanan

et al. 2020

Chemistry & Biodiversity

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A variety of 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethines and 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin‐induced seizure model. The prepared 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7‐{(E)‐[(4‐nitrophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐{(E)‐[(4‐bromo‐2,6‐difluorophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one and 7‐[(E)‐{[3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.

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Design, synthesis, pharmacological evaluation, and docking study of new acridone-based 1,2,4-oxadiazoles as potential anticonvulsant agents

Cited by 78 publications

References 20 publications

Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

Synthesis and Pharmacological Evaluation of New 3,4-Dihydroisoquinolin Derivatives Containing Heterocycle as Potential Anticonvulsant Agents

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

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