1. Design and development of 1,3,4-oxadiazole derivatives as potential inhibitors of acetylcholinesterase to ameliorate scopolamine-induced cognitive dysfunctions.
- Author
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Mishra P, Sharma P, Tripathi PN, Gupta SK, Srivastava P, Seth A, Tripathi A, Krishnamurthy S, and Shrivastava SK
- Subjects
- Amyloid beta-Peptides antagonists & inhibitors, Amyloid beta-Peptides metabolism, Animals, Avoidance Learning drug effects, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors administration & dosage, Cholinesterase Inhibitors chemical synthesis, Cognitive Dysfunction chemically induced, Dose-Response Relationship, Drug, Electrophorus, Horses, Humans, Male, Memory drug effects, Mice, Molecular Structure, Oxadiazoles administration & dosage, Oxadiazoles chemical synthesis, Peptide Fragments antagonists & inhibitors, Peptide Fragments metabolism, Protein Aggregates drug effects, Scopolamine administration & dosage, Structure-Activity Relationship, Acetylcholinesterase metabolism, Cholinesterase Inhibitors pharmacology, Cognitive Dysfunction drug therapy, Drug Development, Oxadiazoles pharmacology
- Abstract
The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC
50 ) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2-65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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