In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

Affiliation

Abulkhair HS(1)(2), Elmeligie S(3), Ghiaty A(1), El-Morsy A(1)(4), Bayoumi AH(1), Ahmed HEA(1)(5), El-Adl K(6)(7), Zayed MF(6)(8), Hassan MH(9)(10), Akl EN(2), El-Zoghbi MS(11).
Author information:
(1)Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
(2)Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University - Egypt, New Damietta, Egypt.
(3)Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
(4)Pharmaceutical Chemistry Department, College of Pharmacy, The Islamic University, Najaf, Iraq.
(5)Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.
(6)Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
(7)Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt.
(8)Pharmaceutical Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
(9)Pharmacy Department, College of Health Sciences, Taibah University, Madinah, Saudi Arabia.
(10)Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
(11)Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shebin El-Koum, Egypt.

Abstract

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.