Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking

Molecular Diversity
Abdel-Ghany A El-HelbyHazem Elkady

Abstract

In view of the anticonvulsant activity reported for phthalazine derivatives as non-competitive AMPA receptor antagonists, a new series of phthalazine-1,4-diones (2-12) were designed and synthesized. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for the synthesized compounds to assess their binding affinities toward AMPA receptor as non-competitive antagonists. The molecular modeling data were strongly interrelated to biological screening data. Compounds 8, 7b, 7a, 10 and 3a exhibited the highest binding affinities as non-competitive AMPA receptor antagonists and also showed the highest relative potencies of 1.78, 1.66, 1.60, 1.59 and 1.29, respectively, as anticonvulsants in comparison with diazepam. The most active compounds 8, 7b, 7a, 10 and 3a were further tested against maximal electroshock seizure (MES). Compounds 8 and 7b and 3a showed 100% protection at a dose level of 125 µgm/kg, while compounds 7a and 10 exhibited 83.33% protection at the same dose level. These agents exerted low neurotoxicity and high safety margin in comparison with valproate as a reference drug. Most of our designed compounds exhibited good ADMET profile.

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Citations

Aug 12, 2019·Bioorganic & Medicinal Chemistry·Jaiprakash SangshettiDevanand B Shinde
Jun 19, 2021·Biomedit︠s︡inskai︠a︡ khimii︠a︡·E V RadchenkoV A Palyulin

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