Design, synthesis, and pharmacological evaluation of novel 1,2,4-triazol-3-amine derivatives as potential agonists of GABAA subtype receptors with anticonvulsant and hypnotic effects

Jahani, Reza; Abtahi, Seyed Reza; Nematpour, Manijeh; Dastjerdi, Hossein Fasihi; Chamanara, Mohsen; Hami, Zahra; Paknejad, Babak

doi:10.1016/j.bioorg.2020.104212

Cited by 13 publications

(4 citation statements)

References 22 publications

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“…1,2,4-Triazole motif-bearing scaffolds are known to exhibit a diverse range of biological and pharmaceutical profiles such as anticonvulsant, anti-inflammatory, antiproliferative, and antifungal activities. − In addition, 1,2,4-triazole constitutes pharmacologically active scaffolds that play an essential role as drug candidates such as anastrozole, vorozole, and letrozole and is reported to be effective aromatase inhibitors and finds application in the treatment of breast cancer . Furthermore, 1,2,4-triazole-bearing bioactive drugs were found to possess anticancer (letrozole), antibacterial (tazobactam), antifungal (isavuconazole), antidiabetic (sitagliptin), seizure disorder (rufinamide), and antiviral (ribavirin) activities − (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Vitro α-Amylase and α-Glucosidase Dual Inhibitory Activities of 1,2,4-Triazole-Bearingbis-Hydrazone Derivatives and Their Molecular Docking Study

et al. 2023

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There is an increasing prevalence of diabetes mellitus throughout the world, and new compounds are necessary to combat this. The currently available antidiabetic therapies are long-term complicated and side effect-prone, and this has led to a demand for more affordable and more effective methods of tackling diabetes. Research is focused on finding alternative medicinal remedies with significant antidiabetic efficacy as well as low adverse effects. In this research work, we have focused our efforts to synthesize a series of 1,2,4-triazole-based bis-hydrazones and evaluated their antidiabetic properties. In addition, the precise structures of the synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H-NMR, 13C-NMR, and HREI-MS. To find the antidiabetic potentials of the synthesized compounds, in vitro α-glucosidase and α-amylase inhibitory activities were characterized using acarbose as the reference standard. From structure–activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both α-amylase and α-glucosidase enzymes was due to the different substitution patterns of the substituent(s) at variable positions of both aryl rings A and B. The results of the antidiabetic assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values ranging from 0.70 ± 0.05 to 35.70 ± 0.80 μM (α-amylase) and 1.10 ± 0.05 to 30.40 ± 0.70 μM (α-glucosidase). The obtained results were compared to those of the standard acarbose drug (IC50 = 10.30 ± 0.20 μM for α-amylase and IC50 = 9.80 ± 0.20 μM for α-glucosidase). Specifically, compounds 17, 15, and 16 were found to be significantly active with IC50 values of 0.70 ± 0.05, 1.80 ± 0.10, and 2.10 ± 0.10 μM against α-amylase and 1.10 ± 0.05, 1.50 ± 0.05, and 1.70 ± 0.10 μM against α-glucosidase, respectively. These findings reveal that triazole-containing bis-hydrazones act as α-amylase and α-glucosidase inhibitors, which help develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic agents.

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Section: Introductionmentioning

confidence: 99%

Synthesis and In Vitro α-Amylase and α-Glucosidase Dual Inhibitory Activities of 1,2,4-Triazole-Bearingbis-Hydrazone Derivatives and Their Molecular Docking Study

et al. 2023

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“…Considering zolpidem as a reference structure and in continuation of previous studies, some novel derivatives of 4amino-3,5-diphenyl-1,2,4-triazole with all suggested requirements were developed. [7,[15][16][17][18][19][20][21][22] (Fig. 1) Radioligand receptor binding assay studies were done for in-vitro screening and the best compounds were evaluated in-vivo by hypnotic effect, anxiety-like behavior effects and memory impairment using pentobarbital-induced sleeping time, open eld, and passive avoidance tests respectively.…”

Section: Introductionmentioning

confidence: 99%

Novel agonists of benzodiazepine receptors: Design, synthesis, binding assay and pharmacological evaluation of diphenyl-1,2,4-triazole derivatives

Fasihi

Rezaee

Mehranfar

et al. 2023

Preprint

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Benzodiazepines (BZD) are widely used in neurological disorders. The use of classical benzodiazepines is limited due to side effects. In this study, based on the structure-activity relationship (SAR) of Benzodiazepine receptors, new derivatives of 4-amino-3,5-diphenyl-1,2,4-triazole as benzodiazepine agonists with selective effects were designed and synthesized. Docking studies showed that pharmacophore groups of the designed structures and zolpidem, a benzodiazepine receptor agonist, are properly matched and are located well in the GABA receptor. The triazole group of the compound 4j, N N-(3,5-diphenyl-4H-1,2,4-triazol-4-yl)-2-((4-fluorobenzyl)amino)acetamide, was near the nitrogen moiety of the imidazole ring of zolpidem providing the hydrogen bond acceptor in the suitable direction in the BDZ-binding site of GABAA receptor model (α1β2ϒ2). The compounds were synthesized with acceptable yield and in-vitro affinity for the BZD receptor was determined. Compound 4j had the best affinity for the BZD site of action on GABAA receptor complex (Ki = 2.56 nM and IC50 = 6.10 nM). In addition, the sedative-hypnotic effect, the locomotor activity, and evaluated memory of the novel compounds were assessed by pentobarbital-induced sleeping, open field, and passive avoidance tests respectively. Most of the novel compounds showed significant hypnotic activity with no impairment on learning and memory performance in the mouse. The pharmacological effects of the compounds were antagonized by flumazenil, a BZD antagonist, which confirms the involvement of BZD receptors in the biological effects.

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“…1,2,4‐Triazole motif bearing scaffolds are known to exhibits diverse range of biological and pharmaceuticals profile such as anticonvulsants, antiinflammatory, antiproliferative and antifungal activities [31–33]. In addition, 1,2,4‐triazole are pharmacologically active scaffolds that play an essential roles as drug candidates such as anastrozole, vorozole and letrozole and were reported to be effective aromatase inhibitors and find application in the treatment of breast cancer [34].…”

Section: Introductionmentioning

confidence: 99%

New biologically potent benzimidazole‐based‐triazole derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors along with molecular docking study

Khan

Rehman

Hussain

et al. 2022

Journal of Heterocyclic Chem

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A series of fifteen hybrid analogs (1-15) based on benzimidazole bearing triazole skeleton were synthesized and were evaluated for in vitro AChE and BuChE inhibition profile. All the newly afforded scaffolds showed moderate to good AChE and BuChE activity having IC 50 values ranging from 0.40 ± 0.05 to 19.60 ± 0.40 μM against AChE and 1.50 ± 0.10 to 23.30 ± 0.50 μM against BuChE in comparison to Donepezil (IC 50 = 0.016 ± 0.12 μM for AChE), (IC 50 = 4.5 ± 0.11 μM for BuChE) as reference drug. It was concluded from structure-activity relationship (SAR) studies that scaffolds bearing groups of strong e-withdrawing nature (-NO 2 , -F and -Cl) at different position of aryl ring were found to be potent inhibitors of both targeted AChE and BuChE enzymes. Therefore, compounds 7 (bearing para-NO 2 ), 2 (bearing para-fluoro), 6 (bearing meta-NO 2 ) and 8 (bearing meta-fluoro) were identified as the most active on screening against

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Design, synthesis, and pharmacological evaluation of novel 1,2,4-triazol-3-amine derivatives as potential agonists of GABAA subtype receptors with anticonvulsant and hypnotic effects

Cited by 13 publications

References 22 publications

Synthesis and In Vitro α-Amylase and α-Glucosidase Dual Inhibitory Activities of 1,2,4-Triazole-Bearingbis-Hydrazone Derivatives and Their Molecular Docking Study

Synthesis and In Vitro α-Amylase and α-Glucosidase Dual Inhibitory Activities of 1,2,4-Triazole-Bearingbis-Hydrazone Derivatives and Their Molecular Docking Study

Novel agonists of benzodiazepine receptors: Design, synthesis, binding assay and pharmacological evaluation of diphenyl-1,2,4-triazole derivatives

New biologically potent benzimidazole‐based‐triazole derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors along with molecular docking study

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