Design, synthesis, in silico ADMET profile and GABA-A docking of novel phthalazines as potent anticonvulsants.

ABSTRACT

A new series of 2-substituted-2,3-dihydrophthalazine-1,4-diones (2- 9) were designed and synthesized to evaluate their anticonvulsant activity. The neurotoxicity was assessed using the rotarod test. Molecular docking was performed for the synthesized compounds to assess their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as a possible mechanism of their anticonvulsant action, to rationalize their anticonvulsant activity in a qualitative way. The data obtained from the molecular modeling was strongly matched with that obtained from the biological screening, which revealed that compounds 5a , 9b , and 9h showed the highest binding affinities toward the GABA-A receptor and also showed the highest anticonvulsant activities with relative potencies of 1.66, 1.63, and 1.61, respectively, compared with diazepam. The most active compounds 5a , 9b , and 9h were further tested against maximal electroshock seizures. Compounds 5a and 9b showed 100% protection at a dose level of 125 µg/kg, while compound 9h exhibited 83.33% protection at the same dose level. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and to explain the possible mechanism for their anticonvulsant action. These agents exerted low neurotoxicity and a high safety margin compared with valproate as a reference drug. Most of our designed compounds exhibited a good ADMET profile.