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

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 ED 50 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.

Discovery of dual tubulin-NEDDylation inhibitors with antiproliferative activity

“…Synthetic route of target compounds C1 – C14 in this work was demonstrated in Scheme 1 . 1-(Chloromethyl)-4-methoxybenzene and 3,4,5-trimethoxyaniline were reacted to perform the nucleophilic substitution 21 , 22 , and an acylation reaction was nextly started to obtain the amide intermediates B1 – B3 . These amide intermediates were reacted with carbon disulphide and secondary amines in the presence of potassium hydroxide to afford compounds C1 – C14 .…”

Design, Synthesis,In Vivo, andIn SilicoEvaluation of Benzothiazoles Bearing a 1,3,4-Oxadiazole Moiety as New Antiepileptic Agents

“…The control group received subcutaneous PTZ solution (in PEG-200) in the posterior midline of the mice, and the onset and severity of convulsion were noted. 42 3.2.4. Rotarod Neurotoxicity Test.…”

In vitroand computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-MProinhibitors

“…49 This molecular docking study was performed using the default protocol associated with the glide module of the Schrodinger modelling suite. [50][51][52] Results showed that compound 29 was appropriately oriented in the active site of SARS-CoV-2 M pro protein with a signicant docking score (À7.45 kcal Mol À1 ) and displayed three hydrogen binding interactions with amino acids Gly143, Cys145, and Glu166 as depicted in Fig. 5A and B.…”