5-[Aryloxypyridyl (or nitrophenyl)]-4H-1,2,4-triazoles as novel flexible benzodiazepine analogues: Synthesis, receptor binding affinity and lipophilicity-dependent anti-seizure onset of action

Navidpour, Latifeh; Shabani, Shabnam; Heidari, Alireza; Bashiri, Manouchehr; Ebrahim‐Habibi, Azadeh; Shahhosseini, Soraya; Shafaroodi, Hamed; Tabatabai, Sayyed Abbas; Toolabi, Mahsa

doi:10.1016/j.bioorg.2020.104504

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…Some studies indicated that PTZ diminishes the GABAergic function ( Macdonald and Barker, 1977 ), through competitive antagonism to the BZD receptor ( Rehavi et al, 1982 ). Correspondingly, drugs that enhance GABA A receptor neurotransmission, such as BZDs ( Shafie et al, 2020 ; Navidpour et al, 2021 ), can inhibit seizures induced by PTZ. PTZ, 3-MP, and BIC also induced seizures through GABA A receptor neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives

et al. 2022

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Epilepsy, a severe brain disease affecting a large population, is treated mainly by antiepileptic drugs (AEDs). However, toxicity, intolerance, and low efficiency of the available AEDs have prompted the continual attempts in the discovery of new AEDs. In this study, we discovered a skeleton of triazolopyrimidine for the development of new AEDs. The design, synthesis, in vivo anticonvulsant activity evaluation of triazolopyrimidines (3a–3i and 6a–6e), and pyrazolopyrimidines (4a–4i) are reported. We found that most triazolopyrimidines showed anticonvulsive activity in the maximal electroshock (MES) and pentetrazol (PTZ)-induced seizure models. On the contrary, pyrazolopyrimidines (4a–4i) showed weak or no protective effects. Among the tested derivatives, compound 6d, holding a median effective dose (ED50) of 15.8 and 14.1 mg/kg against MES and PTZ-induced seizures, respectively, was found to be the most potent one. Moreover, the protection index (PI) value of 6d was significantly higher than that of the available AEDs such as valproate, carbamazepine, and diazepam. The antiepileptic efficacy of compound 6d was also observed in the 3-mercaptopropionic acid and bicuculline-induced seizure models. Antagonistic effects of flumazenil and 3-MP for the anticonvulsive activity of 6d and also the radioligand-binding assay confirmed the involvement of GABA receptors, at least benzodiazepine (BZD) receptor, in the anticonvulsant activity of compound 6d. The docking study of compounds 4e and 6d with GABAA receptor confirmed and explained their affinity to the BZD receptors.

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Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives

et al. 2022

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“…Navidpour et al obtained novel 4 H -1,2,4-triazoles as novel benzodiazepine (BZD) analogues [ 47 ]. BZD exerts its action by binding to a specific domain of the GABA A receptor and acts as an anti-drug, a hypnotic, a muscle relaxant, and an anticonvulsant [ 48 , 49 ].…”

Section: Novel Agent With the Terminal Phenoxy Group From The Most Re...mentioning

confidence: 99%

“…Compound ( 12 ) possessed about 100-fold higher affinity for a GABA A /benzodiazepine receptor complex with an IC 50 = 0.03 nM, as compared to the reference standard—Diazepam with an IC 50 = 2.4 nM. The authors indicated that phenoxy derivatives of a benzodiazepine scaffold are a new class of non-rigid structures with potent anti-seizure activity [ 47 ].…”

Section: Novel Agent With the Terminal Phenoxy Group From The Most Re...mentioning

confidence: 99%

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

Kozyra

Pitucha

2022

IJMS

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The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013–2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure–Activity–Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety.

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“…The abundance of biological activities of 1,2,4-triazole derivatives, such as their antifungal [ 7 , 8 ], antitubercular [ 9 ], antioxidant [ 10 ], anticancer [ 11 , 12 ], anti-inflammatory [ 13 ], analgesic [ 14 ], antidiabetic [ 15 ], anticonvulsant [ 16 ], and anxiolytic activity [ 17 ], has recently piqued the interest of researchers. Triazole-based pharmacophores have supplanted the formerly common imidazole pharmacophore in systemically active azoles with regard to their antifungal activity because of lower toxicity, higher bioavailability, greater fungal cytochrome p450 selectivity, and a reduced effect on the production of human sterols [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant and antibacterial activities of 5-mercapto(substitutedthio)-4-substituted-1,2,4-triazol based on nalidixic acid: A comprehensive study on its synthesis, characterization, and In silico evaluation

Mhaidat,

Banidomi,

Wedian

et al. 2024

Heliyon

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5-[Aryloxypyridyl (or nitrophenyl)]-4H-1,2,4-triazoles as novel flexible benzodiazepine analogues: Synthesis, receptor binding affinity and lipophilicity-dependent anti-seizure onset of action

Cited by 9 publications

References 22 publications

Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives

Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

Antioxidant and antibacterial activities of 5-mercapto(substitutedthio)-4-substituted-1,2,4-triazol based on nalidixic acid: A comprehensive study on its synthesis, characterization, and In silico evaluation

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