Synthesis and Biological Evaluation of Novel 2,3-disubstituted Benzofuran Analogues of GABA as Neurotropic Agents

Author(s): Arturo Coaviche-Yoval, Héctor Luna, Ricardo Tovar-Miranda, Marvin A. Soriano-Ursúa, José G. Trujillo-Ferrara*

Journal Name: Medicinal Chemistry

Volume 15 , Issue 1 , 2019

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Graphical Abstract:


Background: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries.

Objective: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model.

Methods: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures.

Results: The tested ligands that complied with Lipinski’s rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time.

Conclusion: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.

Keywords: 2, 3-disubstituted benzofurans (BZF), molecular docking, GABA receptor (GABA-R), seizures, pentylenetetrazol (PTZ), 4-aminopyridine (4-AP).

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Article Details

Year: 2019
Published on: 07 January, 2019
Page: [77 - 86]
Pages: 10
DOI: 10.2174/1573406414666180524091745
Price: $65

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