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