Novel spiro[indene‐1,2′‐quinazolin]‐4′(3′H)‐one derivatives as potent anticonvulsant agents: One‐pot synthesis, in vivo biological evaluation, and molecular docking studies

A new series of spiro[indene‐1,2′‐quinazolin]‐4′(3′H)‐one derivatives 4a–m were synthesized via a one‐pot method and evaluated for anticonvulsant activities using pentylenetetrazole (PTZ) and maximal electroshock (MES)‐induced seizures. Obtained results demonstrated that these compounds have not anticonvulsant activity in PTZ test while are active in the MES test. Among the synthesized compounds, the best anticonvulsant activity was obtained with compound 4h. This compound also was not neurotoxic. Given that the title new compounds have the pharmacophore requirement for benzodiazepine (BZD) receptor agonist, the most potent compound was assayed in vivo and in silico as BZD receptor agonist. After treatment with flumazenil as a standard BZD receptor antagonist, anticonvulsant activity of compound 4h decreased. Therefore, the involvement of BZD receptors in anticonvulsant activity of this compound confirmed. Furthermore, docking study of compound 4h in the BZD‐binding site of GABAA receptor confirmed that this compound interacted with the important residues.

[1]  M. Mohammadi‐Khanaposhtani,et al.  Design, synthesis, in vivo, and in silico evaluation of new coumarin-1,2,4-oxadiazole hybrids as anticonvulsant agents. , 2019, Bioorganic chemistry.

[2]  S. Emami,et al.  Design, synthesis, in vivo and in silico evaluation of phenacyl triazole hydrazones as new anticonvulsant agents. , 2018, Bioorganic chemistry.

[3]  F. Bisceglie,et al.  A mixed‐ligand quinazoline‐based Ni(II) Schiff base complex: Synthesis, characterization, crystal structure, antimicrobial investigation and catalytic activity for the synthesis of 2H–indazolo[2,1‐b]phthalazine‐triones , 2018 .

[4]  T. Mohamed,et al.  2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies. , 2017, European journal of medicinal chemistry.

[5]  A. Shafiee,et al.  Design, synthesis, pharmacological evaluation, and docking study of new acridone-based 1,2,4-oxadiazoles as potential anticonvulsant agents. , 2016, European journal of medicinal chemistry.

[6]  F. Ahmadi,et al.  Novel agonists of benzodiazepine receptors: design, synthesis, binding assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone and 3-amino-1,2,4-triazole derivatives. , 2015, Bioorganic & medicinal chemistry.

[7]  Pavan Kumar Machiraju,et al.  Design, synthesis, and biological evaluation of quinazoline derivatives as α-glucosidase inhibitors , 2015, Medicinal Chemistry Research.

[8]  S. Bari,et al.  Quinazolines: new horizons in anticonvulsant therapy. , 2014, European journal of medicinal chemistry.

[9]  G. Marzaro,et al.  Quinazoline derivatives as potential anticancer agents: a patent review (2007 – 2010) , 2012, Expert opinion on therapeutic patents.

[10]  N. Siddiqui,et al.  Synthesis of new piperidyl indanone derivatives as anticonvulsant agents , 2012, Medicinal Chemistry Research.

[11]  Wolfgang Löscher,et al.  Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs , 2011, Seizure.

[12]  K. V. Rao,et al.  Synthesis, anti-inflammatory evaluation and docking studies of some new fluorinated fused quinazolines. , 2010, European journal of medicinal chemistry.

[13]  J. Cramer,et al.  Adverse effects of antiepileptic drugs: a brief overview of important issues , 2010, Expert review of neurotherapeutics.

[14]  P. M. Reddy,et al.  6‐Substituted Indolo[1,2‐c]quinazolines as New Antimicrobial Agents , 2009, Archiv der Pharmazie.

[15]  U. Egerland,et al.  New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. , 2007, European journal of medicinal chemistry.