Synthesis and anticonvulsant activity of novel melatonin derivatives bearing aroylhydrazone moiety

Synthesis and anticonvulsant activity of novel melatonin derivatives bearing aroylhydrazone moiety

Poster

1-Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia
2-Department of Pharmacology and Toxicology, Medical University of Sofia
3-Department of Pharmacology, University of Sofia “St. Kliment Ohridski”
4-Institute of Biophysics and Biomedical Engineering, BAS, Sofia
5-Institute of Organic Chemistry with Centre of Phytochemistry, BAS, Sofia
6-Institute of Neurobiology, BAS, Sofia

A series of melatonin derivatives bearing aroylhydrazone moiety was synthesized and anticonvulsant activity was tested on ICR mice by measuring the time of tonic seizure after i.v. infusion of PTZ at doses of 30, 60 и 100 mg/kg, respectively. The toxicity of the active compounds was established using the minimal motor impairment-rotarod test. The most potent compounds were 4-chlorophenyl, furanyl and thienyl substituted derivatives 3с, 3е, and 3f, respectively, at a dose of 60 mg/kg, whose effects were comparable to that of melatonin and showed very low neurotoxicity. Molecular docking study was performed to find essential active site residues having a role in the activity or selectivity of the newly synthesized compounds against the epilepsy molecular target GABA A. As a result of molecular docking, melatonin derivatives bearing aroylhydrazone moiety depicted good binding properties with GABA A receptor. Based on anticonvulsant screening results these newly synthesized compounds will be explored in other seizure tests with a different mechanism of action as well as in models of epilepsy.
The project with number Н13-44 is financed by National Science Fund Bulgaria on contract 13/16 from 21.12.2017and DH 12/06from 12.12.2016.