Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations

Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations Publisher Pubmed

Shafie A¹ ; Mohammadikhanaposhtani M² ; Asadi M³ ; Rahimi N⁴ ; Ranjbar PR¹ ; Ghasemi JB¹ ; Larijani B⁵ ; Mahdavi M⁵ ; Shafaroodi H⁶ ; Dehpour AR^{4, 7}

Show Affiliations

1. School of Chemistry, College of Science, University of Tehran, Tehran, Iran
2. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
3. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
4. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
5. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
6. Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran
7. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Source: Molecular Diversity Published:2020

Abstract

Abstract: A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a–o has been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. The synthetic approach started with diazotizing 2-aminobenzoic acids 1 to produce 2-azidobenzoic acids 2. Next, reaction of the latter compounds with propargylamine 3, benzaldehyde 4, and isocyanides 5 led to the formation of the title compounds 6a–o, in good yields. All the synthesized compounds exhibited high anticonvulsant activity in the PTZ test, comparable to or better than the standard drug diazepam. Among the tested compounds, N-(tert-butyl)-2-(9-chloro-6-oxo-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl)-2-(3-bromophenyl)acetamide 6h was the most potent compound in this assay. Moreover, compounds 6i and 6k showed excellent activity in MES test. Loss of the anticonvulsant effect of compound 6h in the presence of flumazenil in the PTZ test and appropriate interaction of this compound in the active site of benzodiazepine (BZD)-binding site of GABAA receptor confirm involvement of BZD receptors in the anticonvulsant activity of compound 6h. Graphical abstract: A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a–o have been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. All the synthesized compounds exhibited high anticonvulsant activity, comparable to or better than the standard drug diazepam in the PTZ test and compounds 6i and 6k showed excellent activity in MES test. Flumazenil test and in silico docking study confirm involvement of benzodiazepine receptors in the anticonvulsant activity of these compounds.[Figure not available: see fulltext.] © 2019, Springer Nature Switzerland AG.

2. Biological Behavior of 1, 4-Benzodiazepines and 1, 4-Benzothiazepines, Benzodiazepine-Based Drug Discovery (2022)

3. 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, Bioorganic Chemistry (2021)

4. Isatoic Anhydride: A Fascinating and Basic Molecule for the Synthesis of Substituted Quinazolinones and Benzo Di/Triazepines, Current Organic Chemistry (2019)

5. A Simple One-Pot Synthesis of 2,4-Diaryl- 9H-Pyrido[2,3-B]Indoles Under Solvent-Free Conditions, Heterocyclic Communications (2017)

6. Intramolecular Click Cycloaddition Reactions: Synthesis of 1,2,3-Triazoles, Current Organic Synthesis (2024)

7. 2-Azidobenzaldehyde: A Versatile Scaffold for the Generation of N‐Heterocyclic Compounds, Journal of Molecular Structure (2023)

8. Synthesis of Novel Fused Quinazolinone Derivatives, Molecular Diversity (2016)

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Mohammad Mahdavi (5)

Bagher Larijani (3)

Style	Citing Format
MLA	Shafie A, et al.. "Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations." Molecular Diversity, vol. 24, no. 1, 2020, pp. 179-189.
APA	Shafie A, Mohammadikhanaposhtani M, Asadi M, Rahimi N, Ranjbar PR, Ghasemi JB, Larijani B, Mahdavi M, Shafaroodi H, Dehpour AR (2020). Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations. Molecular Diversity, 24(1), 179-189.
Chicago	Shafie A, Mohammadikhanaposhtani M, Asadi M, Rahimi N, Ranjbar PR, Ghasemi JB, Larijani B, Mahdavi M, Shafaroodi H, Dehpour AR. "Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations." Molecular Diversity 24, no. 1 (2020): 179-189.
Harvard	Shafie A et al. (2020) 'Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations', Molecular Diversity, 24(1), pp. 179-189.
Vancouver	Shafie A, Mohammadikhanaposhtani M, Asadi M, Rahimi N, Ranjbar PR, Ghasemi JB, et al.. Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations. Molecular Diversity. 2020;24(1):179-189.
BibTex	@article{ author = {Shafie A and Mohammadikhanaposhtani M and Asadi M and Rahimi N and Ranjbar PR and Ghasemi JB and Larijani B and Mahdavi M and Shafaroodi H and Dehpour AR}, title = {Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations}, journal = {Molecular Diversity}, volume = {24}, number = {1}, pages = {179-189}, year = {2020} }
RIS	TY - JOUR AU - Shafie A AU - Mohammadikhanaposhtani M AU - Asadi M AU - Rahimi N AU - Ranjbar PR AU - Ghasemi JB AU - Larijani B AU - Mahdavi M AU - Shafaroodi H AU - Dehpour AR TI - Novel Fused 1,2,3-Triazolo-Benzodiazepine Derivatives As Potent Anticonvulsant Agents: Design, Synthesis, in Vivo, and in Silico Evaluations JO - Molecular Diversity VL - 24 IS - 1 SP - 179 EP - 189 PY - 2020 ER -

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