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Design and development of novel N-(pyrimidin-2-yl)-1,3,4-oxadiazole hybrids to treat cognitive dysfunctions.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2019 Apr 01; Vol. 27 (7), pp. 1327-1340. Date of Electronic Publication: 2019 Feb 16. - Publication Year :
- 2019
-
Abstract
- Novel hybrids bearing a 2-aminopyrimidine (2-AP) moiety linked to substituted 1,3,4-oxadiazoles were designed, synthesized and biologically evaluated. Among the developed compounds, 28 noncompetitively inhibited human acetylcholinesterase (hAChE; pIC <subscript>50</subscript> = 6.52; Ki = 0.17 µM) and showed potential in vitro antioxidant activity (60.0%) when evaluated using the Ellman's and DPPH assays, respectively. Compound 28 competitively displaced propidium iodide (PI) from the peripheral anionic site (PAS) of hAChE (17.6%) and showed high blood-brain barrier (BBB) permeability, as observed in the PAMPA-BBB assay. Additionally, compound 28 inhibited hAChE-induced Aβ aggregation in a concentration-dependent manner according to the thioflavin T assay and was devoid of neurotoxic liability towards SH-SY5Y cell lines, as demonstrated by the MTT assay. The behavioral studies of compound 28 in mice showed a significant reversal of scopolamine-induced amnesia, as observed in Y-maze and passive avoidance tests. Furthermore, compound 28 exhibited significant AChE inhibition in the brain in ex vivo studies. An evaluation of oxidative stress biomarkers revealed the antioxidant potential of 28. Moreover, in silico molecular docking and dynamics simulation studies were used as a computational tool to evaluate the interactions of compound 28 with the active site residues of hAChE.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetylcholinesterase metabolism
Animals
Butyrylcholinesterase metabolism
Cell Line
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors chemistry
Cognitive Dysfunction metabolism
Dose-Response Relationship, Drug
Humans
Mice
Models, Molecular
Molecular Structure
Oxadiazoles chemical synthesis
Oxadiazoles chemistry
Pyrimidines chemical synthesis
Pyrimidines chemistry
Structure-Activity Relationship
Cholinesterase Inhibitors pharmacology
Cognitive Dysfunction drug therapy
Drug Design
Oxadiazoles pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 27
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30795991
- Full Text :
- https://doi.org/10.1016/j.bmc.2019.02.031