Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants.

Autor: Abd-Allah WH; Pharmaceutical Chemistry Department, College of Pharmaceutical Science and Drug Manufacturing, Misr University for Science & Technology, P.O. 77, 6th of October City, Giza, Egypt. Electronic address: walaa.abdalla@must.edu.eg., Osman EEA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt., Anwar MA; Pharmaceutical Chemistry Department, College of Pharmaceutical Science and Drug Manufacturing, Misr University for Science & Technology, P.O. 77, 6th of October City, Giza, Egypt., Attia HN; Medicinal and Pharmaceutical Chemistry Department (Pharmacology Group) Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt., El Moghazy SM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 May; Vol. 98, pp. 103738. Date of Electronic Publication: 2020 Mar 10.
DOI: 10.1016/j.bioorg.2020.103738
Abstrakt: A series of coumarin derivatives 6-8, 9a-h, 11 and 13a, b -16a, b was synthesized and screened for their anticonvulsant profile. Screening of these analogues using the 'gold standard methods' revealed variable anticonvulsant potential with remarkable effects observed particularly in chemically-induced seizure test. Compounds 6, 7, 13b disclosed the highest potency among the series with 100% protection against scPTZ. Quantification study confirmed that compound 6 (ED 50 0.238 mmol/kg) was the most active congener in the scPTZ model and was approximately 1.5 folds more potent than ethosuximide as reference drug Meanwhile, in the MES test, candidate drugs exhibited mild to moderate anticonvulsant efficacy, the highest of which was compound 14a, imparting 50% protection at 2.1 mmol/kg, followed by other compounds with activity ranging from 14 to 33%, as compared to diphenylhydantoin. Additionally, all candidate compounds were screened for acute neurotoxicity using the rotarod method to identify motor impairment, where almost all compounds passed the test. Further neurochemical investigation was performed to unravel the effect of the most active compound (6) on GABA level in mouse brain, where a significant elevation was evident by 4 and 1.4 folds with respect to that of the control and reference groups at p < 0.05. Molecular modeling study using Discovery Studio program was performed, where compound 6 exhibited good binding interaction with γ-aminobutyric acid aminotransferase (GABA-AT) enzyme and this was consistent with the attained experimental results.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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