1. Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory.
- Author
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Tripathi PN, Srivastava P, Sharma P, Tripathi MK, Seth A, Tripathi A, Rai SN, Singh SP, and Shrivastava SK
- Subjects
- Acetylcholinesterase chemistry, Acetylcholinesterase metabolism, Animals, Antioxidants chemical synthesis, Antioxidants metabolism, Antioxidants pharmacology, Biphenyl Compounds chemical synthesis, Biphenyl Compounds metabolism, Biphenyl Compounds pharmacology, Catalytic Domain, Cell Line, Tumor, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors metabolism, Drug Design, Humans, Male, Mice, Molecular Docking Simulation, Molecular Dynamics Simulation, Nootropic Agents chemical synthesis, Nootropic Agents metabolism, Piperazines chemical synthesis, Piperazines metabolism, Protein Binding, Torpedo, Triazines chemical synthesis, Triazines metabolism, Cholinesterase Inhibitors pharmacology, Learning drug effects, Memory drug effects, Nootropic Agents pharmacology, Piperazines pharmacology, Triazines pharmacology
- Abstract
A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC
50 ; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC50 : 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe (exp) , 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2019
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